Acute Mesenteric Ischemia in COVID-19 Patients

Authors: Dragos Serban 1,2,*† , Laura Carina Tribus 3,4,†, Geta Vancea 1,5,† , Anca Pantea Stoian, Ana Maria Dascalu 1,* Andra Iulia Suceveanu 6Ciprian Tanasescu 7,8, Andreea Cristina Costea 9 Mihail Silviu Tudosie 1, Corneliu Tudor 2, Gabriel Andrei Gangura 1,10, Lucian Duta 2 and Daniel Ovidiu Costea 6,11,

Abstract:

Acute mesenteric ischemia is a rare but extremely severe complication of SARS-CoV-2 infection. The present review aims to document the clinical, laboratory, and imaging findings, management, and outcomes of acute intestinal ischemia in COVID-19 patients. A comprehensive search was performed on PubMed and Web of Science with the terms “COVID-19” and “bowel ischemia” OR “intestinal ischemia” OR “mesenteric ischemia” OR “mesenteric thrombosis”. After duplication removal, a total of 36 articles were included, reporting data on a total of 89 patients, 63 being hospitalized at the moment of onset. Elevated D-dimers, leukocytosis, and C reactive protein (CRP) were present in most reported cases, and a contrast-enhanced CT exam confirms the vascular thromboembolism and offers important information about the bowel viability. There are distinct features of bowel ischemia in non-hospitalized vs. hospitalized COVID-19 patients, suggesting different pathological pathways. In ICU patients, the most frequently affected was the large bowel alone (56%) or in association with the small bowel (24%), with microvascular thrombosis. Surgery was necessary in 95.4% of cases. In the non-hospitalized group, the small bowel was involved in 80%, with splanchnic veins or arteries thromboembolism, and a favorable response to conservative anticoagulant therapy was reported in 38.4%. Mortality was 54.4% in the hospitalized group and 21.7% in the non-hospitalized group (p < 0.0001). Age over 60 years (p = 0.043) and the need for surgery (p = 0.019) were associated with the worst outcome. Understanding the mechanisms involved and risk factors may help adjust the thromboprophylaxis and fluid management in COVID-19 patients.

1. Introduction Acute mesenteric ischemia (AMI) is a major abdominal emergency, characterized by a sudden decrease in the blood flow to the small bowel, resulting in ischemic lesions of the intestinal loops, necrosis, and if left untreated, death by peritonitis and septic shock. In nonCOVID patients, the etiology may be mesenteric arterial embolism (in 50%), mesenteric arterial thrombosis (15–25%), venous thrombosis (5–15%), or less frequent, from nonocclusive causes associated with low blood flow [1]. Several systemic conditions, such as arterial hypertension, atrial fibrillation, atherosclerosis, heart failure, or valve disease are risk factors for AMI. Portal vein thrombosis and mesenteric vein thrombosis can be seen with celiac disease [2], appendicitis [3], pancreatitis [4], and, in particular, liver cirrhosis and hepatocellular cancer [5]. Acute intestinal ischemia is a rare manifestation during COVID-19 disease, but a correct estimation of its incidence is challenging due to sporadic reports, differences in patients’ selection among previously published studies, and also limitations in diagnosis related to the strict COVID-19 regulations for disease control and difficulties in performing imagistic investigations in the patients in intensive care units. COVID-19 is known to cause significant alteration of coagulation, causing thromboembolic acute events, of which the most documented were pulmonary embolism, acute myocardial infarction, and lower limb ischemia [6]. Gastrointestinal features in COVID-19 disease are relatively frequently reported, varying from less than 10% in early studies from China [7,8] to 30–60%, in other reports [9,10]. In an extensive study on 1992 hospitalized patients for COVID-19 pneumonia from 36 centers, Elmunzer et al. [7] found that the most frequent clinical signs reported were mild and self-limited in up to 74% of cases, consisting of diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). However, severe cases were also reported, requiring emergency surgery for acute bowel ischemia or perforation [5,8]. The pathophysiology of the digestive features in COVID-19 patients involves both ischemic and non-ischemic mechanisms. ACE2 receptors are present at the level of the intestinal wall, and enterocytes may be directly infected by SARS-CoV-2. The virus was evidenced in feces and enteral walls in infected subjects [4,11–13]. In a study by Xu et al., rectal swabs were positive in 8 of 10 pediatric patients, even after the nasopharyngeal swabs became negative [14]. However, the significance of fecal elimination of viral ARN is still not fully understood in the transmission chain of the SARS-CoV-2 infection. On the other hand, disturbance of lung-gut axis, prolonged hospitalization in ICU, and the pro coagulation state induced by SARS-CoV-2 endothelial damage was incriminated for bowel ischemia, resulting in intestinal necrosis and perforation [8,9,15]. Early recognition and treatment of gastrointestinal ischemia are extremely important, but it is often challenging in hospitalized COVID-19 patients with severe illness. The present review aims to document the risk factors, clinical, imagistic, and laboratory findings, management, and outcomes of acute intestinal ischemic complications in COVID-19 patients. 2. Materials and Methods A comprehensive search was performed on PubMed and Web of Science with the terms “COVID-19” AND (“bowel ischemia” OR “intestinal ischemia” OR “mesenteric ischemia” OR “mesenteric thrombosis”). All original papers and case reports, in the English language, for which full text could be obtained, published until November 2021, were included in the review. Meeting abstracts, commentaries, and book chapters were excluded. A hand search was performed in the references of the relevant reviews on the topic. 2.1. Data Extraction and Analysis The review is not registered in PROSPERO. A PRISMA flowchart was employed to screen papers for eligibility (Figure 1) and a PRISMA checklist is presented as a Supple- J. Clin. Med. 2022, 11, 200 3 of 22 mentary File S1. A data extraction sheet was independently completed by two researchers, with strict adherence to PRISMA guidelines. J. Clin. Med. 2022, 11, 200 3 2.1. Data Extraction and Analysis The review is not registered in PROSPERO. A PRISMA flowchart was employedscreen papers for eligibility (Figure 1) and a PRISMA checklist is presented as a Supmentary File S1. A data extraction sheet was independently completed by two researchwith strict adherence to PRISMA guidelines. Figure 1. PRISMA 2020 flowchart for the studies included in the review. The relevant data abstracted from these studies are presented in Tables 1–3. COV19 diagnosis was made by PCR assay in all cases. All patients reported with COVIDdisease and mesenteric ischemia were documented in terms of age, sex, comorbidittime from SARS-CoV-2 infection diagnosis, presentation, investigations, treatment, outcome. A statistical analysis of the differences between acute intestinal ischemia in pviously non-hospitalized vs. previously hospitalized patients was performed. The pottial risk factors for an adverse vital prognosis were analyzed using SciStat® softw(www.scistat.com (accessed on 25 November 2021)). Papers that did not provide sufficient data regarding evaluation at admission, domentation of SARS-CoV-2 infection, or treatment were excluded. Patients suffering frother conditions that could potentially complicate intestinal ischemia, such as liver cirrsis, hepatocellular carcinoma, intraabdominal infection (appendicitis, diverticulitis), pcreatitis, and celiac disease were excluded. Any disagreement was solved by discussioFigure 1. PRISMA 2020 flowchart for the studies included in the review. The relevant data abstracted from these studies are presented in Tables 1–3. COVID-19 diagnosis was made by PCR assay in all cases. All patients reported with COVID-19 disease and mesenteric ischemia were documented in terms of age, sex, comorbidities, time from SARS-CoV-2 infection diagnosis, presentation, investigations, treatment, and outcome. A statistical analysis of the differences between acute intestinal ischemia in previously nonhospitalized vs. previously hospitalized patients was performed. The potential risk factors for an adverse vital prognosis were analyzed using SciStat® software (www.scistat.com (accessed on 25 November 2021)). Papers that did not provide sufficient data regarding evaluation at admission, documentation of SARS-CoV-2 infection, or treatment were excluded. Patients suffering from other conditions that could potentially complicate intestinal ischemia, such as liver cirrhosis, hepatocellular carcinoma, intraabdominal infection (appendicitis, diverticulitis), pancreatitis, and celiac disease were excluded. Any disagreement was solved by discussion. J. Clin. Med. 2022, 11, 200 4 of 22 Table 1. Patients with intestinal ischemia in retrospective studies on hospitalized COVID-19 patients. Study No of Patients with Gastrointestinal Ischemia (Total No of COVID-19 Patients in ICU) Sex (M; F) Age (Mean) BMI Time from Admission to Onset (Days) Abdominal CT Signs Intraoperative/Endoscopic Findings Treatment Outcomes Kaafarani HMA [16] 5 (141); 3.8% 1;3 62.5 32.1 51.5 (18–104) days NA Cecum-1—patchy necrosis Cecum_ileon-1 Small bowel-3; yellow discoloration on the antimesenteric side of the small bowel; 1 case + liver necrosis Surgical resection NA Kraft M [17] 4 (190); 2.1% NA NA NA NA NA Bowel ischemia + perforation (2) Bowel ischemia + perforation (1) MAT+massive bowel ischemia (1) Right hemicolectomy (2) Transverse colectomy (1) Conservative, not fit for surgery Recovery (3) Death (1) Yang C [18] 20 (190 in ICU; 582 in total); 10.5% 15:5 69 31.2 26.5 (17–42) Distension Wall thickness Pneumatosis intestinalis Perforation SMA or celiac thrombosis no info Right hemicolectomy 7(35%) Sub/total colectomy12 (60%) Ileocecal resection 1(5%) Recovery (11) Death (9) Hwabejire J [19] 20 13:7 58.7 32.5 13 (1–31) Pneumatosis intestinalis 42% Portal venous gas (33%) Mesenteric vessel patency 92% large bowel ischemia (8) small bowel ischemia (4) both (8) yellow discoloration of the ischemic bowel resection of the ischemic segment abdomen left open + second look (14) Recovery (10) Death (10) O’Shea A [20] 4 (142); 2.8% NA NA NA NA bowel ischemia, portal vein gas, colic pneumatosis NA NA NA Qayed E [21] 2 (878); 0.22% NA NA NA NA NA diffuse colonic ischemia (1) Small + large bowel ischemia and pneumatosis (1) Total colectomy (1) Extensive resection (1) Recovery (1) Death (1) NA: not acknowledged; MAT: mesenteric artery thrombosis; SMA: superior mesenteric artery. J. Clin. Med. 2022, 11, 200 5 of 22 Table 2. Case reports and case series presenting gastrointestinal ischemia in hospitalized COVID-19 patients under anticoagulant medication. Article Sex Age Comorbidities Time from COVID-19 Diagnosis; Time from Admission (Days) ICU; Type of Ventilation Clinical Signs at Presentation Leukocytes (/mm3 ) CRP (mg/L) Lactat mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Azouz E [22] M 56 none 1; 2 (hospitalized for acute ischemic stroke) No info abdominal pain and vomiting No info – – – – – – Multiple arterial thromboembolic complications: AMS, right middle cerebral artery, a free-floating clot in the aortic arch Anticoagulation (no details), endovascular thrombectomy Laparotomy + resection of necrotic small bowel loops No info Al Mahruqi G [23] M 51 none 26; 24 yes, intubated Fever, metabolic acidosis, required inotropes 30,000 – 7 687 – – 2.5 Non-occlusive AMI Hypoperfused small bowel, permeable aorta, SMA, IMA + deep lower limb thrombosis enoxaparin 40 mg/day from admission; surgery refused by family death Ucpinar BA [24] F 82 Atrial fibrillation, hypertension, chronic kidney disease 3; 3 no – 14,800 196 5.1 – – – 1600 SMA thrombosis; distended small bowel, with diffuse submucosal pneumatosis portomesenteric gas fluid resuscitation; continued ceftriaxone, enoxaparin 0.4cc twice daily; not operable due to fulminant evolution Death Karna ST [25] F 61 DM, hypertension 4; 4 Yes, HFNO diffuse abdominal pain with distention 21,400 421.6 1.4 – – 464,000 No thrombosis of the distal SMA with dilated jejunoileal loops and normal enhancing bowel wall. Iv heparin 5000 ui, followed by 1000 ui, Ecospin and clopidogrel Laparotomy after 10 days with segmental enterectomy of the necrotic bowel Death by septic shock and acute renal failure Singh B [26] F 82 Hypertension, T2DM 32; 18 Yes, Ventilator support severe diffuse abdominal distension and tenderness 22,800 308 2.5 136 333 146,000 1.3 SMA—colic arteries thrombosis pneumatosis intestinalis affecting the ascending colon and cecum laparotomy, ischemic colon resection, ileostomy; heparin in therapeutic doses preand post-surgery slow recovery J. Clin. Med. 2022, 11, 200 6 of 22 Table 2. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis; Time from Admission (Days) ICU; Type of Ventilation Clinical Signs at Presentation Leukocytes (/mm3 ) CRP (mg/L) Lactat mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Nakatsutmi K [27] F 67 DM, diabetic nephropathy requiring dialysis, angina, postresection gastric cancer 16; 12 ICU, intubation hemodynamic deterioration, abdominal distension 15,100 32.14 – – – – 26.51 edematous transverse colon; abdominal vessels with sclerotic changes laparotomy, which revealed vascular micro thrombosis of transverse colon—right segment resection of the ischemic colonic segment, ABTHERA management, second look, and closure of the abdomen after 24 h death Dinoto E [28] F 84 DM, hypertension, renal failure 2; 2 no Acute abdominal pain and distension; 18,000 32.47 – – 431 – 6937 SMA origin stenosis and occlusion at 2 cm from the origin, absence of bowel enhancement Endovascular thrombectomy of SMA; surgical transfemoral thrombectomy and distal superficial femoral artery stenting Death due to respiratory failure Kiwango F [29] F 60 DM, hypertension 12; 3 no Sudden onset abdominal pain 7700 – – – – – 23.8 Not performed Not performed due to rapid oxygen desaturation Massive bowel acute ischemia death J. Clin. Med. 2022, 11, 200 7 of 22 Table 3. Case reports and case series presenting gastrointestinal ischemia in non-hospitalized COVID-19 patients. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Sevella, P [30] M 44 none 10 Acute abdominal pain constipation, vomiting 23,400 – – – 1097 360,000 1590 Viable jejunum, ischemic bowel, peritoneal thickening with fat stranding; free fluid in the peritoneal cavity LMWH 60 mg daily Piperacillin 4g/day Tazobactam 500 mg/day Extensive small bowel + right colon resection death Nasseh S [31] M 68 no info First diagnosis epigastric pain and diarrhea for 4 days 17,660 125 – – – – 6876 terminal segment of the ileocolic artery thrombosis; thickening of the right colon wall and the last 30 cm of the small bowl unfractionated heparin laparoscopy -no bowel resection needed recovery Aleman W [32] M 44 none 20 severe abdominopelvic pain 36,870 – – 456.23 – 574,000 263.87 absence of flow at SMV, splenic, portal vein; Small bowel loop dilatation and mesenteric fat edema enoxaparin and pain control medication 6 days, then switched to warfarin 6 months recovery Jeilani M [33] M 68 Alzheimer disease, COPD 9 Sharp abdominal pain +distension 12,440 307 – – – 318,000 897 a central venous filling defect within the portal vein extending to SMV; no bowel wall changes LMWH, 3 months recovery Randhawa J [34] F 62 none First diagnosis right upper quadrant pain and loss of appetite for 14 days Normal limits – – – 346 – – large thrombus involving the SMV, the main portal vein with extension into its branches Fondaparinux 2.5. mg 5 days, then warfarin 4 mg (adjusted by INR), 6 months recovery Cheung S [35] M 55 none 12 (discharged for 7 days) Nausea, vomiting and worsening generalized abdominal pain with guarding 12,446 – 0.68 – – – – low-density clot, 1.6 cm in length, causing high-grade narrowing of the proximal SMA continuous heparin infusion continued 8 h postoperative, Laparotomy with SMA thromboembolectomy and enterectomy (small bowel) recovery J. Clin. Med. 2022, 11, 200 8 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Beccara L [36] M 52 none 22 (5 days after discharge and cessation prophylactic LWMH) vomiting and abdominal pain, tenderness in epigastrium and mesogastrium 30,000 222 – – – – – arterial thrombosis of vessels efferent of the SMA with bowel distension Enterectomy (small bowel) LMWH plus aspirin 100 mg/day at discharge recovery Vulliamy P [37] M 75 none 14 abdominal pain and vomiting for 2 days 18,100 3.2 – – – 497,000 320 intraluminal thrombus was present in the descending thoracic aorta with embolic occlusion of SMA Catheter-directed thrombolysis, enterectomy (small bowel) recovery De Barry O [38] F 79 none First diagnosis Epigastric pain, diarrhea, fever for 8 days, acute dyspnea 12600 125 5.36 – – – – SMV, portal vein, SMA, and jejunal artery thrombosis Distended loops, free fluid anticoagulation Resection of affected colon+ ileum, SMA thrombolysis, thrombectomy death Romero MCV [39] M 73 smoker, DM, hypertension 14 severe abdominal pain, nausea. fecal emesis, peritoneal irritation 18,000 – – – – 120,000 >5000 RX: distention of intestinal loops, inter-loop edema, intestinal pneumatosis enoxaparin (60 mg/0.6 mL), antibiotics (no info) enterectomy, anastomotic fistula, reintervention death Posada Arango [40] M F F 62 22 65 None Appendectomy 7 days before left nephrectomy, 5 3 15 colicative abdominal pain at food intake; unsystematized gastrointestinal symptoms; abdominal pain in the upper hemiabdomen 20,100 – – – – – – – – 1536 – – 534 – – – – – – – – Case 1: thrombus in distal SMA and its branches, intestinal loops dilatation, hydroaerical levels, free fluid thrombosis of SMV Case 2: SMV thrombosis and adiacent fat edema Case 3: thrombi in the left jejunal artery branch with infarction of the corresponding jejunal loops Case 1: Laparotomy: extensive jejunum + ileum ischemia; surgery could not be performed Case 2: Anticoagulation analgesic and antibiotics Case 3: segmental enterectomy Case 1: death Case 2: recovery Case 3: recovery J. Clin. Med. 2022, 11, 200 9 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Pang JHQ [41] M 30 none First diagnosis colicky abdominal pain, vomiting – – – – – – 20 SMV thrombosis with diffuse mural thickening and fat stranding of multiple jejunal loops conservative, anticoagulation with LMWH 1mg/kc, twice daily, 3 months; readmitted and operated for congenital adherence causing small bowel obstruction recovery Lari E [42] M 38 none First diagnosis abdominal pain, nausea, intractable vomiting, and shortness of breath Mild leukocytosis – 2.2 – – – 2100 extensive thrombosis of the portal, splenic, superior, and inferior mesenteric veins + mild bowel ischemia Anticoagulation, resection of the affected bowel loop No info Carmo Filho A [43] M 33 Obesity (BMI: 33), other not reported 7 severe low back pain radiating to the hypogastric region – 58.2 – 1570 – – 879 enlarged inferior mesenteric vein not filled by contrast associated with infiltration of the adjacent adipose planes enoxaparin 5 days, followed by long term oral warfarin recovery Hanif M [44] F 20 none 8 abdominal pain and abdominal distension 15,900 62 – 1435.3 825 633,000 2340 not performed evidence of SMA thrombosis; enterectomy with exteriorization of both ends recovery Amaravathi U [45] M 45 none 5 Acute epigastric and periumbilical pain – Normal value 1.3 324.3 – – 5.3 SMA and SMV thrombus i.v. heparin; Laparotomy with SMA thrombectomy; 48 h Second look: resection of the gangrenous bowel segment No info Al Mahruqi G [23] M 51 none 4 generalized abdominal pain, nausea, vomiting 16,000 – – 619 – – 10 SMA thrombosis and non-enhancing proximal ileal loops consistent with small bowel ischemia unfractionated heparin, thrombectomy + repeated resections of the ischemic bowel at relook (jejunum+ileon+cecum) Case 2: recovery J. Clin. Med. 2022, 11, 200 10 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Goodfellow M [46] F 36 RYGB, depression, asthma 6 epigastric pain, irradiating back, nausea 9650 1.2 0.7 – – – – abrupt cut-off of the SMV in the proximal portion; diffuse infiltration of the mesentery, wall thickening of small bowel IV heparin infusion, followed by 18,000 UI delteparin after 72 h recovery Abeysekera KW [26] M 42 Hepatitis B 14 right hypochondrial pain, progressively increasing for 9 days – – – – – – – enhancement of the entire length of the portal vein and a smaller thrombus in the mid-superior mesenteric vein, mural edema of the distal duodenum, distal small bowel, and descending colon factor Xa inhibitor apixaban 5 mg ×2/day, 6 months – recovery RodriguezNakamura RM [27] M F 45 42 -vitiligo -obesity 14 severe mesogastric pain, nausea, diaphoresis 16,400 18,800 367 239 – – 970 – – – 685,000 – 1450 14,407 Case 1: SMI of thrombotic etiology with partial rechanneling through the middle colic artery, and hypoxic-ischemic changes in the distal ileum and the cecum Case 2: thrombosis of the portal and mesenteric veins and an abdominopelvic collection in the mesentery with gas Case 1: resection with entero-enteral anastomosis; rivaroxaban 10 mg/day, 6 months Case 2: Loop resection, entero-enteral manual anastomosis, partial omentectomy, and cavity wash (fecal peritonitis) Case 1: Recovery Case 2: death Plotz B [47] F 27 SLE with ITP First diagnosis acute onset nausea, vomiting, and non-bloody diarrhea – – – – – – 5446 diffuse small bowel edema enoxaparin, long term apixaban at discharge recovery J. Clin. Med. 2022, 11, 200 11 of 22 Table 3. Cont. Article Sex Age Comorbidities Time from COVID-19 Diagnosis (Days) Clinical Signs at Presentation Leukocyte Count (/mm3 ) CRP (mg/L) Lactate mmol/L Ferritin (ng/mL) LDH (U/L) Thrombocytes (/mm3 ) D-Dimers (ng/mL) Abdominal CT Signs Treatment Outcome Chiu CY [48] F 49 Hypertension, DM, chronic kidney disease 28 diffuse abdominal pain melena and hematemesis – – – – – – 12,444 distended proximal jejunum with mural thickening laparotomy, proximal jejunum resection no info Farina D [49] M 70 no info 3 abdominal pain, nausea 15,300 149 – – – – – acute small bowel hypoperfusion, SMA thromboembolism not operable due to general condition Death SMA: superior mesenteric artery; SMV: superior mesenteric vein; DM: diabetes mellitus; T2DM: type 2 diabetes mellitus; AMI: acute mesenteric ischemia; IMV: inferior mesenteric vein; RYGB: Roux-en-Y gastric bypass (bariatric surgery). J. Clin. Med. 2022, 11, 200 12 of 22 2.2. Risk of Bias The studies analyzed in the present review were comparable in terms of patient selection, methodology, therapeutic approach, and the report of final outcome. However, there were differences in the reported clinical and laboratory data. The sample size was small, most of them being case reports or case series, which may be a significant source of bias. Therefore, studies were compared only qualitatively. 3. Results After duplication removal, a total of 36 articles were included in the review, reporting data on a total of 89 patients. Among these, we identified 6 retrospective studies [16–21], documenting intestinal ischemia in 55 patients admitted to intensive care units (ICU) with COVID-19 pneumonia for whom surgical consult was necessary (Table 1). We also identified 30 case reports or case series [22–51] presenting 34 cases of acute bowel ischemia in patients positive for SARS-CoV-2 infection in different clinical settings. 8 cases were previously hospitalized for COVID-19 pneumonia and under anticoagulant medication (Table 2). In 26 cases, the acute ischemic event appeared as the first symptom of COVID-19 disease, or in mild forms treated at home, or after discharge for COVID -19 pneumonia and cessation of the anticoagulant medication (Table 3). 3.1. Risk Factors of Intestinal Ischemia in COVID-19 Patients Out of a total of 89 patients included in the review, 63 (70.7%) were hospitalized for severe forms of COVID-19 pneumonia at the moment of onset. These patients were receiving anticoagulant medication when reported, consisting of low molecular weight heparin (LMWH) at prophylactic doses. The incidence of acute intestinal ischemia in ICU patients with COVID-19 varied widely between 0.22–10.5% (Table 1). In a study by O’Shea et al. [20], 26% of hospitalized patients for COVID-19 pneumonia who underwent imagistic examination, presented results positive for coagulopathy, and in 22% of these cases, the thromboembolic events were with multiple locations. The mean age was 56.9 years. We observed a significantly lower age in non-hospitalized COVID-19 patients presenting with acute intestinal ischemia when compared to the previously hospitalized group (p < 0.0001). There is a slight male to female predominance (M:F = 1:68). Obesity might be considered a possible risk factor, with a reported mean BMI of 31.2–32.5 in hospitalized patients [16,18,19]. However, this association should be regarded with caution, since obesity is also a risk factor for severe forms of COVID-19. Prolonged stay in intensive care, intubation, and the need for vasopressor medication was associated with increased risk of acute bowel ischemia [8,18,19]. Diabetes mellitus and hypertension were the most frequent comorbidities encountered in case reports (8 in 34 patients, 23%), and 7 out of 8 patients presented both (Table 4). There was no information regarding the comorbidities in the retrospective studies included in the review. 3.2. Clinical Features in COVID-19 Patients with Acute Mesenteric Ischemia Abdominal pain, out of proportion to physical findings, is a hallmark of portomesenteric thrombosis, typically associated with fever and leukocytosis [4]. Abdominal pain was encountered in all cases, either generalized from the beginning, of high intensity, or firstly localized in the epigastrium or the mezogastric area. In cases of portal vein thrombosis, the initial location may be in the right hypochondrium, mimicking biliary colic [26,34]. Fever is less useful in COVID-19 infected patients, taking into consideration that fever is a general sign of infection, and on the other hand, these patients might be already under antipyretic medication. J. Clin. Med. 2022, 11, 200 13 of 22 Table 4. Demographic data of the patients included in the review. Nr. of Patients 89 M 48 (61.5% *) F 30 (38.5% *) NA 11 The first sign of COVID-19 6 (6.7%) Home treated 17 (19.1%) Hospitalized • ICU 63 (70.7%) 58 (92% of hospitalized patients) Discharged 3 (3.3%) Time from diagnosis of COVID-19 infection • Non-Hospitalized • Hospitalized (*when mentioned) 8.7 ± 7.4 (1–28 days) 9.6 ± 8.3 (1–26 days) Time from admission in hospitalized patients 1–104 days Age (mean) • Hospitalized • Non-hospitalized 59.3 ± 12.7 years 62 ± 9.6 years. (p < 0.0001) 52.8 ± 16.4 years. BMI 31.2–32.5 Comorbidities • Hypertension • DM • smokers • Atrial fibrillation • COPD • Cirrhosis • RYGB • Vitiligo • Recent appendicitis • Operated gastric cancer • Alzheimer disease • SLE 8 7 2 1 2 1 1 1 1 1 1 1 *: percentage calculated in known information group; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SLE: systemic lupus erythematosus. Other clinical signs reported were nausea, anorexia, vomiting, and food intolerance [23,31,38,45]. However, these gastrointestinal signs are encountered in 30–40% of patients with SARS-CoV-2 infection. In a study by Kaafarani et al., up to half of the patients with gastrointestinal features presented some degrees of intestinal hypomotility, possibly due to direct viral invasion of the enterocytes and neuro-enteral disturbances [16]. Physical exam evidenced abdominal distension, reduced bowel sounds, and tenderness at palpation. Guarding may be evocative for peritonitis due to compromised vascularization of bowel loops and bacterial translocation or franc perforation [35,39]. A challenging case was presented by Goodfellow et al. [25] in a patient with a recent history of bariatric surgery with Roux en Y gastric bypass, presenting with acute abdominal pain which imposed the differential diagnosis with an internal hernia. Upcinar et al. [24] reported a case of an 82-years female that also associated atrial fibrillation. The patient was anticoagulated with enoxaparin 0.4 cc twice daily before admission and continued the anticoagulant therapy during hospitalization for COVID-19 pneumonia. Bedside echocardiography was performed to exclude atrial thrombus. Although SMA was reported related to COVID-19 pneumonia, atrial fibrillation is a strong risk factor for SMA of non-COVID-19 etiology. J. Clin. Med. 2022, 11, 200 14 of 22 In ICU patients, acute bowel ischemia should be suspected in cases that present acute onset of digestive intolerance and stasis, abdominal distension, and require an increase of vasopressor medication [19]. 3.3. Imagistic and Lab Test Findings D-dimer is a highly sensitive investigation for the prothrombotic state caused by COVID-19 [45] and, when reported, was found to be above the normal values. Leukocytosis and acute phase biomarkers, such as fibrinogen and CRP were elevated, mirroring the intensity of inflammation and sepsis caused by the ischemic bowel. However, there was no significant statistical correlation between either the leukocyte count (p = 0.803) or D-dimers (p = 0.08) and the outcome. Leucocyte count may be within normal values in case of early presentation [34]. Thrombocytosis and thrombocytopenia have been reported in published cases with mesenteric ischemia [30,35,42,46,50]. Lactate levels were reported in 9 cases, with values higher than 2 mmol/L in 5 cases (55%). LDH was determined in 6 cases, and it was found to be elevated in all cases, with a mean value of 594+/−305 U/L. Ferritin is another biomarker of potential value in mesenteric ischemia, that increases due to ischemia-reperfusion cellular damage. In the reviewed studies, serum ferritin was raised in 7 out of 9 reported cases, with values ranging from 456 to 1570 ng/mL. However, ferritin levels were found to be correlated also with the severity of pulmonary lesions in COVID-19 patients [52]. Due to the low number of cases in which lactate, LDH, and ferritin were reported, no statistical association could be performed with the severity of lesions or with adverse outcomes. The location and extent of venous or arterial thrombosis were determined by contrastenhanced abdominal CT, which also provided important information on the viability of the intestinal segment whose vascularity was affected. Radiological findings in the early stages included dilated intestinal loops, thickening of the intestinal wall, mesenteric fat edema, and air-fluid levels. Once the viability of the affected intestinal segment is compromised, a CT exam may evidence pneumatosis as a sign of bacterial proliferation and translocation in the intestinal wall, pneumoperitoneum due to perforation, and free fluid in the abdominal cavity. In cases with an unconfirmed diagnosis of COVID-19, examination of the pulmonary basis during abdominal CT exam can add consistent findings to establish the diagnosis. Venous thrombosis affecting the superior mesenteric vein and or portal vein was encountered in 40.9% of reported cases of non-hospitalized COVID-19 patients, and in only one case in the hospitalized group (Table 5). One explanation may be the beneficial role of thrombotic prophylaxis in preventing venous thrombosis in COVID-19 patients, which is routinely administrated in hospitalized cases, but not reported in cases treated at home with COVID-19 pneumonia. In ICU patients, CT exam showed in most cases permeable mesenteric vessels and diffuse intestinal ischemia affecting the large bowel alone (56%) or in association with the small bowel (24%), suggesting pathogenic mechanisms, direct viral infection, small vessel thrombosis, or “nonocclusive mesenteric ischemia” [16]. 3.4. Management and Outcomes The management of mesenteric ischemia includes gastrointestinal decompression, fluid resuscitation, hemodynamic support, anticoagulation, and broad antibiotics. Once the thromboembolic event was diagnosed, heparin, 5000IU iv, or enoxaparin or LMWH in therapeutic doses was initiated, followed by long-term oral anticoagulation and/or anti-aggregating therapy. Favorable results were obtained in 7 out of 9 cases (77%) of splanchnic veins thrombosis and in 2 of 7 cases (28.5%) with superior mesenteric artery thrombosis. At discharge, anticoagulation therapy was continued either with LMWH, for a period up to 3 months [33,36,41], either, long term warfarin, with INR control [32,34,41] or apixaban 5 mg/day, up to 6 months [26,47]. No readmissions were reported. J. Clin. Med. 2022, 11, 200 15 of 22 Table 5. Comparative features in acute intestinal ischemia encountered in previously hospitalized and previously non-hospitalized COVID-19 patients. Parameter Hospitalized (63) NonHospitalized (26) p * Value Type of mesenteric ischemia: • Arterial • Venous • Mixt (A + V) • Diffuse microthrombosis • Multiple thromboembolic locations • NA 5 (14.7% *) 1 (2.9%) 0 30 (88.2%) 2 (5.8%) 29 10 (38.4%) 11 (42.3%) 2 (7.6%) 3 (11.5%) 1 (3.8%) 0 p < 0.0001 Management: • Anticoagulation therapy only • Endovascular thrombectomy • Laparotomy with ischemic bowel resection • None (fulminant evolution) 0 2 (1 + surgery) (3%) 60 (95.4%) 2 (3%) 10 (38.4%) 2 (+surgery) 15 (57.6%) 1 (3.8%) p < 0.0001 Location of the resected segment: • Colon • Small bowel • Colon+small bowel • NA 35 (56%) 10 (16%) 15 (24%) 6 0 12 (80%) 3 (20%) 0 p < 0.0001 Outcomes: • Recovery • Death • NA 26 (46.4%) 30 (54.4%) 7 17 (79.3%) 5 (21.7%) 3 p = 0.013 * calculated for Chi-squared test. Antibiotic classes should cover anaerobes including F. necrophorum and include a combination of beta-lactam and beta-lactamase inhibitor (e.g., piperacillin-tazobactam), metronidazole, ceftriaxone, clindamycin, and carbapenems [4]. In early diagnosis, during the first 12 h from the onset, vascular surgery may be tempted, avoiding the enteral resection [25,53]. Endovascular management is a minimally invasive approach, allowing quick restoration of blood flow in affected vessels using techniques such as aspiration, thrombectomy, thrombolysis, and angioplasty with or without stenting [40]. Laparotomy with resection of the necrotic bowel should be performed as quickly as possible to avoid perforation and septic shock. In cases in which intestinal viability cannot be established with certainty, a second look laparotomy was performed after 24–48 h [43] or the abdominal cavity was left open, using negative pressure systems such as ABTHERA [51], and successive segmentary enterectomy was performed. Several authors described in acute bowel ischemia encountered in ICU patients with COVID-19, a distinct yellowish color, rather than the typical purple or black color of ischemic bowel, predominantly located at the antimesenteric side or circumferentially with affected areas well delineated from the adjacent healthy areas [18,19]. In these cases, patency of large mesenteric vessels was confirmed, and the histopathological reports J. Clin. Med. 2022, 11, 200 16 of 22 showed endothelitis, inflammation, and microvascular thrombosis in the submucosa or transmural. Despite early surgery, the outcome is severe in these cases, with an overall mortality of 45–50% in reported studies and up to 100% in patients over 65 years of age according to Hwabejira et al. [19]. In COVID-19 patients non hospitalized at the onset of an acute ischemic event, with mild and moderate forms of the disease, the outcome was less severe, with recovery in 77% of cases. We found that age over 60 years and the necessity of surgical treatment are statistically correlated with a poor outcome in the reviewed studies (Table 6). According to the type of mesenteric ischemia, the venous thrombosis was more likely to have a favorable outcome (recovery in 80% of cases), while vascular micro thombosis lead to death in 66% of cases. Table 6. Risk factors for severe outcome. Parameters Outcome: Death p-Value Age • Age < 60 • Age > 60 27.2% 60% 0.0384 * 0.043 ** Surgery • No surgery • surgery 0% 60% 0.019 ** Type of mesenteric ischemia • Arterial • Venous • Micro thrombosis 47% 20% 66% 0.23 ** D dimers Wide variation 0.085 * 0.394 ** Leucocytes Wide variation (9650–37,000/mmc) 0.803 0.385 ** * One-way ANOVA test; ** Chi-squared test (SciStat® software, www.scistat.com (accessed on 25 November 2021)). 4. Discussions Classically, acute mesenteric ischemia is a rare surgical emergency encountered in the elderly with cardiovascular or portal-associated pathology, such as arterial hypertension, atrial fibrillation, atherosclerosis, heart failure, valve disease, and portal hypertension. However, in the current context of the COVID-19 pandemic, mesenteric ischemia should be suspected in any patient presenting in an emergency with acute abdominal pain, regardless of age and associated diseases. Several biomarkers were investigated for the potential diagnostic and prognostic value in acute mesenteric ischemia. Serum lactate is a non-specific biomarker of tissue hypoperfusion and undergoes significant elevation only after advanced mesenteric damage. Several clinical trials found a value higher than 2 mmol/L was significantly associated with increased mortality in non-COVID-patients. However, its diagnostic value is still a subject of debate. There are two detectable isomers, L-lactate, which is a nonspecific biomarker of anaerobic metabolism, and hypoxia and D-lactate, which is produced by the activity of intestinal bacteria. Higher D-lactate levels could be more specific for mesenteric ischemia due to increased bacterial proliferation at the level of the ischemic bowel, but the results obtained in different studies are mostly inconsistent [53,54]. Several clinical studies found that LDH is a useful biomarker for acute mesenteric ischemia, [55,56]. However, interpretation of the results may be difficult in COVID-19 patients, as both lactate and LDH were also found to be independent risk factors of severe forms of COVID-19 [57,58]. The diagnosis of an ischemic bowel should be one of the top differentials in critically ill patients with acute onset of abdominal pain and distension [50,59]. If diagnosed early, the J. Clin. Med. 2022, 11, 200 17 of 22 intestinal ischemia is potentially reversible and can be treated conservatively. Heparin has an anticoagulant, anti-inflammatory, endothelial protective role in COVID-19, which can improve microcirculation and decrease possible ischemic events [25]. The appropriate dose, however, is still a subject of debate with some authors recommending the prophylactic, others the intermediate or therapeutic daily amount [25,60]. We found that surgery is associated with a severe outcome in the reviewed studies. Mucosal ischemia may induce massive viremia from bowel epithelium causing vasoplegic shock after surgery [25]. Moreover, many studies reported poor outcomes in COVID-19 patients that underwent abdominal surgery [61,62]. 4.1. Pathogenic Pathways of Mesenteric Ischemia in COVID-19 Patients The intestinal manifestations encountered in SARS-CoV-2 infection are represented by inflammatory changes (gastroenteritis, colitis), occlusions, ileus, invaginations, and ischemic manifestations. Severe inflammation in the intestine can cause damage to the submucosal vessels, resulting in hypercoagulability in the intestine. Cases of acute cholecystitis, splenic infarction, or acute pancreatitis have also been reported in patients infected with SARS-CoV-2, with microvascular lesions as a pathophysiological mechanism [63]. In the study of O’Shea et al., on 146 COVID-19 hospitalized patients that underwent CT-scan, vascular thrombosis was identified in 26% of cases, the most frequent location being in lungs [20]. Gastrointestinal ischemic lesions were identified in 4 cases, in multiple locations (pulmonary, hepatic, cerebellar parenchymal infarction) in 3 patients. The authors raised awareness about the possibility of underestimation of the incidence of thrombotic events in COVID-19 patients [20]. Several pathophysiological mechanisms have been considered, and they can be grouped into occlusive and non-occlusive causes [64]. The site of the ischemic process, embolism or thrombosis, may be in the micro vascularization, veins, or mesenteric arteries. Acute arterial obstruction of the small intestinal vessels and mesenteric ischemia may appear due to hypercoagulability associated with SARS-CoV-2 infection, mucosal ischemia, viral dissemination, and endothelial cell invasion vis ACE-2 receptors [65,66]. Viral binding to ACE2Receptors leads to significant changes in fluid-coagulation balance: reduction in Ang 2 degradation leads to increased Il6 levels, and the onset of storm cytokines, such as IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, IgG -induced protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-alpha, and tumor necrosis factor α [67], but also in the expression of the tissue inhibitor of plasminogen -1, and a tissue factor, and subsequently triggering the coagulation system through binding to the clotting factor VIIa [68]. Acute embolism in small vessels may be caused by the direct viral invasion, via ACE-2 Receptors, resulting in endothelitis and inflammation, recruiting immune cells, and expressing high levels of pro-inflammatory cytokines, such as Il-6 and TNF-alfa, with consequently apoptosis of the endothelial cells [69]. Capillary viscometry showed hyperviscosity in critically ill COVID-19 patients [70,71]. Platelet activation, platelet–monocyte aggregation formation, and Neutrophil external traps (NETs) released from activated neutrophils, constitute a mixture of nucleic DNA, histones, and nucleosomes [59,72] were documented in severe COVID-19 patients by several studies [70,71,73]. Plotz et al. found a thrombotic vasculopathy with histological evidence for lectin pathway complement activation mirroring viral protein deposition in a patient with COVID19 and SLE, suggesting this might be a potential mechanism in SARS-CoV-2 associated thrombotic disorders [47]. Numerous alterations in fluid-coagulation balance have been reported in patients hospitalized for COVID-19 pneumonia. Increases in fibrinogen, D-dimers, but also coagulation factors V and VIII. The mechanisms of coagulation disorders in COVID-19 are not yet fully elucidated. In a clinical study by Stefely et al. [68] in a group of 102 patients with severe disease, an increase in factor V > 200 IU was identified in 48% of cases, the levels determined being statistically significantly higher than in non-COVID mechanically J. Clin. Med. 2022, 11, 200 18 of 22 ventilated or unventilated patients hospitalized in intensive care. This showed that the increased activity of Factor V cannot be attributed to disease severity or mechanical ventilation. Additionally, an increase in factor X activity was shown, but not correlated with an increase in factor V activity, but with an increase in acute phase reactants, suggesting distinct pathophysiological mechanisms [74]. Giuffre et al. suggest that fecal calcoprotein (FC) may be a biomarker for the severity of gastrointestinal complications, by both ischemic and inflammatory mechanisms [75]. They found particularly elevated levels of FC to be well correlated with D-dimers levels in patients with bowel perforations, and hypothesized that the mechanism may be related to a thrombosis localized to the gut and that FC increase is related to virus-related inflammation and thrombosis-induced ischemia, as shown by gross pathology [76]. Non-occlusive mesenteric ischemia in patients hospitalized in intensive care units for SARS-CoV-2 pneumonia requiring vasopressor medication may be caused vasospastic constriction [19,64,65]. Thrombosis of the mesenteric vessels could be favored by hypercoagulability, relative dehydration, and side effects of corticosteroids. 4.2. Question Still to Be Answered Current recommendations for in-hospital patients with COVID-19 requiring anticoagulation suggest LMWH as first-line treatment has advantages, with higher stability compared to heparin during cytokine storms, and a reduced risk of interaction with antiviral therapy compared to oral anticoagulant medication [77]. Choosing the adequate doses of LMWH in specific cases—prophylactic, intermediate, or therapeutic—is still in debate. Thromboprophylaxis is highly recommended in the absence of contraindications, due to the increased risk of venous thrombosis and arterial thromboembolism associated with SARS-CoV-2 infection, with dose adjustment based on weight and associated risk factors. Besides the anticoagulant role, some authors also reported an anti-inflammatory role of heparin in severe COVID-19 infection [66,78,79]. Heparin is known to decrease inflammation by inhibiting neutrophil activity, expression of inflammatory mediators, and the proliferation of vascular smooth muscle cells [78]. Thromboprophylaxis with enoxaparin could be also recommended to ambulatory patients with mild to moderate forms of COVID-19 if the results of prospective studies show statistically relevant benefits [80]. In addition to anticoagulants, other therapies, such as anti-complement and interleukin (IL)-1 receptor antagonists, need to be explored, and other new agents should be discovered as they emerge from our better understanding of the pathogenetic mechanisms [81]. Several studies showed the important role of Il-1 in endothelial dysfunction, inflammation, and thrombi formation in COVID-19 patients by stimulating the production of Thromboxane A2 (TxA2) and thromboxane B2 (TxB2). These findings may justify the recommendation for an IL-1 receptor antagonist (IL-1Ra) which can prevent hemodynamic changes, septic shock, organ inflammation, and vascular thrombosis in severe forms of COVID-19 patients [80–82]. 5. Conclusions Understanding the pathological pathways and risk factors could help adjust the thromboprophylaxis and fluid management in COVID-19 patients. The superior mesenteric vein thrombosis is the most frequent cause of acute intestinal ischemia in COVID-19 nonhospitalized patients that are not under anticoagulant medication, while non-occlusive mesenteric ischemia and microvascular thrombosis are most frequent in severe cases, hospitalized in intensive care units. COVID-19 patients should be carefully monitored for acute onset of abdominal symptoms. High-intensity pain and abdominal distension, associated with leukocytosis, raised inflammatory biomarkers and elevated D-dimers and are highly suggestive for mesenteric ischemia. The contrast-enhanced CT exam, repeated, if necessary, offers valuable information regarding the location and extent of the acute ischemic event. Early diagnosis and treatment are essential for survival.

J. Clin. Med. 2022, 11, 200 19 of 22 Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11010200/s1, File S1: The PRISMA 2020 statement. Author Contributions: Conceptualization, D.S., L.C.T. and A.M.D.; methodology, A.P.S., C.T. (Corneliu Tudor); software, G.V.; validation, A.I.S., M.S.T., D.S. and L.D.; formal analysis, A.C.C., C.T. (Ciprian Tanasescu); investigation, G.A.G.; data curation, D.O.C.; writing—original draft preparation, L.C.T., A.M.D., G.V., D.O.C., G.A.G., C.T. (Corneliu Tudor); writing—review and editing, L.D., C.T. (Ciprian Tanasescu), A.C.C., D.S., A.P.S., A.I.S., M.S.T.; visualization, G.V. and L.C.T.; supervision, D.S., A.M.D. and D.S. have conducted the screening and selection of studies included in the review All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Bala, M.; Kashuk, J.; Moore, E.E.; Kluger, Y.; Biffl, W.; Gomes, C.A.; Ben-Ishay, O.; Rubinstein, C.; Balogh, Z.J.; Civil, I.; et al. Acute mesenteric ischemia: Guidelines of the World Society of Emergency Surgery. World J. Emerg. Surg. 2017, 12, 38. [CrossRef] 2. Dumic, I.; Martin, S.; Salfiti, N.; Watson, R.; Alempijevic, T. Deep Venous Thrombosis and Bilateral Pulmonary Embolism Revealing Silent Celiac Disease: Case Report and Review of the Literature. Case Rep. Gastrointest. Med. 2017, 2017, 5236918. [CrossRef] [PubMed] 3. Akhrass, F.A.; Abdallah, L.; Berger, S.; Sartawi, R. Gastrointestinal variant of Lemierre’s syndrome complicating ruptured appendicitis. IDCases 2015, 2, 72–76. [CrossRef] 4. Radovanovic, N.; Dumic, I.; Veselinovic, M.; Burger, S.; Milovanovic, T.; Nordstrom, C.W.; Niendorf, E.; Ramanan, P. Fusobacterium necrophorum subsp. necrophorum Liver Abscess with Pylephlebitis: An Abdominal Variant of Lemierre’s Syndrome. Case Rep. Infect. Dis. 2020, 2020, 9237267. [CrossRef] 5. Sogaard, K.K.; Astrup, L.B.; Vilstrup, H.; Gronbaek, H. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol. 2007, 7, 34. [CrossRef] [PubMed] 6. Moradi, H.; Mouzannar, S.; Miratashi Yazdi, S.A. Post COVID-19 splenic infarction with limb ischemia: A case report. Ann. Med. Surg. 2021, 71, 102935. [CrossRef] [PubMed] 7. Elmunzer, B.J.; Spitzer, R.L.; Foster, L.D.; Merchant, A.A.; Howard, E.F.; Patel, V.A.; West, M.K.; Qayed, E.; Nustas, R.; Zakaria, A.; et al. North American Alliance for the Study of Digestive Manifestations of COVID-19. Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019. Clin. Gastroenterol. Hepatol. 2021, 19, 1355–1365.e4. [CrossRef] 8. Guan, W.J.; Ni, Z.Y.; Hu, Y. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [CrossRef] 9. Estevez-Cerda, S.C.; Saldaña-Rodríguez, J.A.; Alam-Gidi, A.G.; Riojas-Garza, A.; Rodarte-Shade, M.; Velazco-de la Garza, J.; Leyva-Alvizo, A.; Gonzalez-Ruvalcaba, R.; Martinez-Resendez, M.F.; Ortiz de Elguea-Lizarraga, J.I. Severe bowel complications in SARS-CoV-2 patients receiving protocolized care. Rev. Gastroenterol. Mex. Engl. Ed. 2021, 86, 378–386. [CrossRef] 10. Redd, W.D.; Zhou, J.C.; Hathorn, K.E. Prevalence and characteristics of gastrointestinal symptoms in patients with SARS-CoV-2 infection in the United States: A multicenter cohort study. Gastroenterology 2020, 159, 765–767.e2. [CrossRef] 11. Hajifathalian, K.; Krisko, T.; Mehta, A. Gastrointestinal and hepatic manifestations of 2019 novel coronavirus disease in a large cohort of infected patients from New York: Clinical implications. Gastroenterology 2020, 159, 1137–1140.e2. [CrossRef] 12. Kotfis, K.; Skonieczna-Zydecka, K. COVID-19: Gastrointestinal symptoms and potential sources of SARS-CoV-2 transmission. ˙ Anaesthesiol. Intensive Ther. 2020, 52, 171–172. [CrossRef] 13. Xiao, F.; Tang, M.; Zheng, X. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020, 158, 1831–1833. [CrossRef] [PubMed] 14. Xu, Y.; Li, X.; Zhu, B.; Liang, H.; Fang, C.; Gong, Y.; Guo, Q.; Sun, X.; Zhao, D.; Shen, J.; et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat. Med. 2020, 26, 502–505. [CrossRef] [PubMed] 15. Ludewig, S.; Jarbouh, R.; Ardelt, M.; Mothes, H.; Rauchfuß, F.; Fahrner, R.; Zanow, J.; Settmacher, U. Bowel Ischemia in ICU Patients: Diagnostic Value of I-FABP Depends on the Interval to the Triggering Event. Gastroenterol. Res. Pract. 2017, 2795176. [CrossRef] 16. Kaafarani, H.; El Moheb, M.; Hwabejire, J.O.; Naar, L.; Christensen, M.A.; Breen, K.; Gaitanidis, A.; Alser, O.; Mashbari, H.; Bankhead-Kendall, B.; et al. Gastrointestinal Complications in Critically Ill Patients With COVID-19. Ann. Surg. 2020, 272, e61–e62. [CrossRef] 17. Kraft, M.; Pellino, G.; Jofra, M.; Sorribas, M.; Solís-Peña, A.; Biondo, S.; Espín-Basany, E. Incidence, features, outcome and impact on health system of de-novo abdominal surgical diseases in patients admitted with COVID-19. Surg. J. R. Coll. Surg. Edinb. Irel. 2021, 19, e53–e58. [CrossRef] 18. Yang, C.; Hakenberg, P.; Weiß, C.; Herrle, F.; Rahbari, N.; Reißfelder, C.; Hardt, J. Colon ischemia in patients with severe COVID-19: A single-center retrospective cohort study of 20 patients. Int. J. Colorectal Dis. 2021, 36, 2769–2773. [CrossRef] J. Clin. Med. 2022, 11, 200 20 of 22 19. Hwabejire, J.O.; Kaafarani, H.M.; Mashbari, H.; Misdraji, J.; Fagenholz, P.J.; Gartland, R.M.; Abraczinskas, D.R.; Mehta, R.S.; Paranjape, C.N.; Eng, G.; et al. Bowel Ischemia in COVID-19 Infection: One-Year Surgical Experience. Am. Surg. 2021, 87, 1893–1900. [CrossRef] [PubMed] 20. O’shea, A.; Parakh, A.; Hedgire, S.; Lee, S.I. Multisystem assessment of the imaging manifestations of coagulopathy in hospitalized patients with coronavirus. Am. J. Roentgenol. 2021, 216, 1088–1098. [CrossRef] [PubMed] 21. Qayed, E.; Deshpande, A.R.; Elmunzer, B.J.; North American Alliance for the Study of Digestive Manifestations of COVID-19. Low Incidence of Severe Gastrointestinal Complications in COVID-19 Patients Admitted to the Intensive Care Unit: A Large, Multicenter Study. Gastroenterology 2021, 160, 1403–1405. [CrossRef] [PubMed] 22. Azouz, E.; Yang, S.; Monnier-Cholley, L.; Arrivé, L. Systemic arterial thrombosis and acute mesenteric ischemia in a patient with COVID-19. Intensive Care Med. 2020, 46, 1464–1465. [CrossRef] [PubMed] 23. Al Mahruqi, G.; Stephen, E.; Abdelhedy, I.; Al Wahaibi, K. Our early experience with mesenteric ischemia in COVID-19 positive patients. Ann. Vasc. Surg. 2021, 73, 129–132. [CrossRef] [PubMed] 24. Ucpinar, B.A.; Sahin, C. Superior Mesenteric Artery Thrombosis in a Patient with COVID-19: A Unique Presentation. J. Coll Physicians Surg. Pak. 2020, 30, 112–114. [CrossRef] 25. Karna, S.T.; Panda, R.; Maurya, A.P.; Kumari, S. Superior Mesenteric Artery Thrombosis in COVID-19 Pneumonia: An Underestimated Diagnosis—First Case Report in Asia. Indian J. Surg. 2020, 82, 1235–1237. [CrossRef] 26. Abeysekera, K.W.; Karteszi, H.; Clark, A.; Gordon, F.H. Spontaneous portomesenteric thrombosis in a non-cirrhotic patient with SARS-CoV-2 infection. BMJ Case Rep. 2020, 13, e238906. [CrossRef] 27. Rodriguez-Nakamura, R.M.; Gonzalez-Calatayud, M.; Martinez Martinez, A.R. Acute mesenteric thrombosis in two patients with COVID-19. Two cases report and literature review. Int. J. Surg. Case Rep. 2020, 76, 409–414. [CrossRef] 28. Dinoto, E.; Ferlito, F.; La Marca, M.A.; Mirabella, D.; Bajardi, G.; Pecoraro, F. Staged acute mesenteric and peripheral ischemia treatment in COVID-19 patient: Case report. Int. J. Surg. Case Rep. 2021, 84, 106105. [CrossRef] 29. Kiwango, F.; Mremi, A.; Masenga, A.; Akrabi, H. Intestinal ischemia in a COVID-19 patient: Case report from Northern Tanzania. J. Surg. Case Rep. 2021, 2021, rjaa537. [CrossRef] 30. Sevella, P.; Rallabhandi, S.; Jahagirdar, V.; Kankanala, S.R.; Ginnaram, A.R.; Rama, K. Acute Mesenteric Ischemia as an Early Complication of COVID-19. Cureus 2021, 13, e18082. [CrossRef] 31. Nasseh, S.; Trabelsi, M.M.; Oueslati, A.; Haloui, N.; Jerraya, H.; Nouira, R. COVID-19 and gastrointestinal symptoms: A case report of a Mesenteric Large vessel obstruction. Clin. Case Rep. 2021, 9, e04235. [CrossRef] [PubMed] 32. Alemán, W.; Cevallos, L.C. Subacute mesenteric venous thrombosis secondary to COVID-19: A late thrombotic complication in a nonsevere patient. Radiol. Case Rep. 2021, 16, 899–902. [CrossRef] [PubMed] 33. Jeilani, M.; Hill, R.; Riad, M.; Abdulaal, Y. Superior mesenteric vein and portal vein thrombosis in a patient with COVID-19: A rare case. BMJ Case Rep. 2021, 14, e244049. [CrossRef] 34. Randhawa, J.; Kaur, J.; Randhawa, H.S.; Kaur, S.; Singh, H. Thrombosis of the Portal Vein and Superior Mesenteric Vein in a Patient With Subclinical COVID-19 Infection. Cureus 2021, 13, e14366. [CrossRef] [PubMed] 35. Cheung, S.; Quiwa, J.C.; Pillai, A.; Onwu, C.; Tharayil, Z.J.; Gupta, R. Superior Mesenteric Artery Thrombosis and Acute Intestinal Ischemia as a Consequence of COVID-19 Infection. Am. J. Case Rep. 2020, 21, e925753. [CrossRef] 36. Beccara, L.A.; Pacioni, C.; Ponton, S.; Francavilla, S.; Cuzzoli, A. Arterial Mesenteric Thrombosis as a Complication of SARS-CoV-2 Infection. Eur. J. Case Rep. Intern. Med. 2020, 7, 001690. [CrossRef] [PubMed] 37. Vulliamy, P.; Jacob, S.; Davenport, R.A. Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19. Br. J. Haematol. 2020, 189, 1053–1054. [CrossRef] 38. De Barry, O.; Mekki, A.; Diffre, C.; Seror, M.; El Hajjam, M.; Carlier, R.Y. Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia. Radiol. Case Rep. 2020, 15, 1054–1057. [CrossRef] 39. Romero, M.D.C.V.; Cárdenas, A.M.; Fuentes, A.B.; Barragán, A.A.S.; Gómez, D.B.S.; Jiménez, M.T. Acute mesenteric arterial thrombosis in severe SARS-Co-2 patient: A case report and literature review. Int. J. Surg. Case Rep. 2021, 86, 106307. [CrossRef] 40. Posada-Arango, A.M.; García-Madrigal, J.; Echeverri-Isaza, S.; Alberto-Castrillón, G.; Martínez, D.; Gómez, A.C.; Pinto, J.A.; Pinillos, L. Thrombosis in abdominal vessels associated with COVID-19 Infection: A report of three cases. Radiol. Case Rep. 2021, 16, 3044–3050. [CrossRef] 41. Pang, J.H.Q.; Tang, J.H.; Eugene-Fan, B. A peculiar case of small bowel stricture in a coronavirus disease 2019 patient with congenital adhesion band and superior mesenteric vein thrombosis. Ann. Vasc. Surg. 2021, 70, 286–289. [CrossRef] 42. Lari, E.; Lari, A.; AlQinai, S. Severe ischemic complications in COVID-19-a case series. Int. J. Surg. Case Rep. 2020, 75, 131–135. [CrossRef] [PubMed] 43. Carmo Filho, A.; Cunha, B.D.S. Inferior mesenteric vein thrombosis and COVID-19. Rev. Soc. Bras. Med. Trop. 2020, 53, e20200412. [CrossRef] 44. Hanif, M.; Ahmad, Z.; Khan, A.W.; Naz, S.; Sundas, F. COVID-19-Induced Mesenteric Thrombosis. Cureus 2021, 13, e12953. [CrossRef] 45. Amaravathi, U.; Balamurugan, N.; Muthu Pillai, V.; Ayyan, S.M. Superior Mesenteric Arterial and Venous Thrombosis in COVID-19. J. Emerg. Med. 2021, 60, e103–e107. [CrossRef] [PubMed] 46. Goodfellow, M.; Courtney, M.; Upadhyay, Y.; Marsh, R.; Mahawar, K. Mesenteric Venous Thrombosis Due to Coronavirus in a Post Roux-en-Y Gastric Bypass Patient: A Case Report. Obes. Surg. 2021, 31, 2308–2310. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 200 21 of 22 47. Plotz, B.; Castillo, R.; Melamed, J.; Magro, C.; Rosenthal, P.; Belmont, H.M. Focal small bowel thrombotic microvascular injury in COVID-19 mediated by the lectin complement pathway masquerading as lupus enteritis. Rheumatology 2021, 60, e61–e63. [CrossRef] 48. Chiu, C.Y.; Sarwal, A.; Mon, A.M.; Tan, Y.E.; Shah, V. Gastrointestinal: COVID-19 related ischemic bowel disease. J. Gastroenterol. Hepatol. 2021, 36, 850. [CrossRef] [PubMed] 49. Farina, D.; Rondi, P.; Botturi, E.; Renzulli, M.; Borghesi, A.; Guelfi, D.; Ravanelli, M. Gastrointestinal: Bowel ischemia in a suspected coronavirus disease (COVID-19) patient. J. Gastroenterol. Hepatol. 2021, 36, 41. [CrossRef] 50. Singh, B.; Mechineni, A.; Kaur, P.; Ajdir, N.; Maroules, M.; Shamoon, F.; Bikkina, M. Acute Intestinal Ischemia in a Patient with COVID-19 Infection. Korean J. Gastroenterol. 2020, 76, 164–166. [CrossRef] 51. Nakatsutsumi, K.; Endo, A.; Okuzawa, H.; Onishi, I.; Koyanagi, A.; Nagaoka, E.; Morishita, K.; Aiboshi, J.; Otomo, Y. Colon perforation as a complication of COVID-19: A case report. Surg. Case Rep. 2021, 7, 175. [CrossRef] 52. Carubbi, F.; Salvati, L.; Alunno, A.; Maggi, F.; Borghi, E.; Mariani, R.; Mai, F.; Paoloni, M.; Ferri, C.; Desideri, G.; et al. Ferritin is associated with the severity of lung involvement but not with worse prognosis in patients with COVID-19: Data from two Italian COVID-19 units. Sci. Rep. 2021, 11, 4863. [CrossRef] 53. Isfordink, C.J.; Dekker, D.; Monkelbaan, J.F. Clinical value of serum lactate measurement in diagnosing acute mesenteric ischaemia. Neth. J. Med. 2018, 76, 60–64. [PubMed] 54. Montagnana, M.; Danese, E.; Lippi, G. Biochemical markers of acute intestinal ischemia: Possibilities and limitations. Ann. Transl. Med. 2018, 6, 341. [CrossRef] 55. Matsumoto, S.; Sekine, K.; Funaoka, H.; Yamazaki MShimizu, M.; Hayashida, K.; Kitano, M. Diagnostic performance of plasma biomarkers in patients with acute intestinal ischaemia. Br. J. Surg. 2014, 101, 232–238. [CrossRef] [PubMed] 56. Soni, N.; Bhutra, S.; Vidyarthi, S.H.; Sharma, V. Role of serum lactic dehydrogenase, glutamic oxaloacetic transaminase, creatine phosphokinase, alkaline phospatase, serum phosphorus in the cases of bowel Ischaemia in acute abdomen. Int. Surg. J. 2017, 4, 1997–2001. [CrossRef] 57. Han, Y.; Zhang, H.; Mu, S.; Wei, W.; Jin, C.; Tong, C.; Song, Z.; Zha, Y.; Xue, Y.; Gu, G. Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: A retrospective and observational study. Aging 2020, 12, 11245–11258. [CrossRef] 58. Carpenè, G.; Onorato, D.; Nocini, R.; Fortunato, G.; Rizk, J.G.; Henry, B.M.; Lippi, G. Blood lactate concentration in COVID-19: A systematic literature review. Clin. Chem. Lab. Med. 2021. advance online publication. [CrossRef] 59. Singh, B.; Kaur, P.; Maroules, M. Splanchnic vein thrombosis in COVID-19: A review of literature. Dig. Liver Dis. 2020, 52, 1407–1409. [CrossRef] 60. Jagielski, M.; Pi ˛atkowski, J.; Jackowski, M. Challenges encountered during the treatment of acute mesenteric ischemia. Gastroenterol. Res. Pract. 2020, 5316849. [CrossRef] [PubMed] 61. Rasslan, R.; Dos Santos, J.P.; Menegozzo, C.; Pezzano, A.; Lunardeli, H.S.; Dos Santos Miranda, J.; Utiyama, E.M.; Damous, S. Outcomes after emergency abdominal surgery in COVID-19 patients at a referral center in Brazil. Updates Surg. 2021, 73, 763–768. [CrossRef] 62. Lei, S.; Jiang, F.; Su, W.; Chen, C.; Chen, J.; Mei, W.; Zhan, L.Y.; Jia, Y.; Zhang, L.; Liu, D.; et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection. EClinicalMedicine 2020, 21, 100331. [CrossRef] 63. Serban, D.; Socea, B.; Badiu, C.D.; Tudor, C.; Balasescu, S.A.; Dumitrescu, D.; Trotea, A.M.; Spataru, R.I.; Vancea, G.; Dascalu, A.M.; et al. Acute surgical abdomen during the COVID 19 pandemic: Clinical and therapeutic challenges. Exp. Ther. Med. 2021, 21, 519. [CrossRef] [PubMed] 64. Patel, S.; Parikh, C.; Verma, D.; Sundararajan, R.; Agrawal, U.; Bheemisetty, N.; Akku, R.; Sánchez-Velazco, D.; Waleed, M.S. Bowel ischaemia in COVID-19: A systematic review. Int. J. Clin. Pract. 2021, 75, e14930. [CrossRef] [PubMed] 65. Yantiss, R.K.; Qin, L.; He, B.; Crawford, C.V.; Seshan, S.; Patel, S.; Wahid, N.; Jessurun, J. Intestinal Abnormalities in Patients With SARS-CoV-2 Infection: Histopathologic Changes Reflect Mechanisms of Disease. Am. J. Surg. Pathol. 2021, 46, 89–96. [CrossRef] [PubMed] 66. McGonagle, D.; Bridgewood, C.; Ramanan, A.V.; Meaney, J.F.M.; Watad, A. COVID-19 vasculitis and novel vasculitis mimics. Lancet Rheumatol. 2021, 3, e224–e233. [CrossRef] 67. Huang, C.; Wang, Y.; Li, X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet 2020, 395, 497–506. [CrossRef] 68. Avila, J.; Long, B.; Holladay, D.; Gottlieb, M. Thrombotic complications of COVID-19. Am. J. Emerg. Med. 2021, 39, 213–218. [CrossRef] 69. Varga, Z.; Flammer, A.J.; Steiger, P.; Haberecker, M.; Andermatt, R.; Zinkernagel, A.S.; Mehra, M.R.; Schuepbach, R.A.; Ruschitzka, F.; Moch, H. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020, 395, 1417–1418. [CrossRef] 70. Maier, C.L.; Truong, A.D.; Auld, S.C.; Polly, D.M.; Tanksley, C.L.; Duncan, A. COVID-19-associated hyperviscosity: A link between inflammation and thrombophilia? Lancet 2020, 395, 1758–1759. [CrossRef] 71. Miyara, S.J.; Becker, L.B.; Guevara, S.; Kirsch, C.; Metz, C.N.; Shoaib, M.; Grodstein, E.; Nair, V.V.; Jandovitz, N.; McCannMolmenti, A.; et al. Pneumatosis Intestinalis in the Setting of COVID-19: A Single Center Case Series From New York. Front. Med. 2021, 8, 638075. [CrossRef] [PubMed] J. Clin. Med. 2022, 11, 200 22 of 22 72. Panigada, M.; Bottino, N.; Tagliabue, P.; Grasselli, G.; Novembrino, C.; Chantarangkul, V.; Pesenti, A.; Peyvandi, F.; Tripodi, A. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J. Thromb. Haemost. 2020, 18, 1738–1742. [CrossRef] 73. Hottz, E.D.; Azevedo-Quintanilha, I.G.; Palhinha, L.; Teixeira, L.; Barreto, E.A.; Pão, C.R.; Righy, C.; Franco, S.; Souza, T.M.; Kurtz, P.; et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood J. Am. Soc. Hematol. 2020, 136, 1330–1341. [CrossRef] 74. Stefely, J.A.; Christensen, B.B.; Gogakos, T.; Cone Sullivan, J.K.; Montgomery, G.G.; Barranco, J.P.; Van Cott, E.M. Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am. J. Hematol. 2020, 95, 1522–1530. [CrossRef] 75. Giuffrè, M.; Di Bella, S.; Sambataro, G.; Zerbato, V.; Cavallaro, M.; Occhipinti, A.A.; Palermo, A.; Crescenti, A.; Monica, F.; Luzzati, R.; et al. COVID-19-Induced Thrombosis in Patients without Gastrointestinal Symptoms and Elevated Fecal Calprotectin: Hypothesis Regarding Mechanism of Intestinal Damage Associated with COVID-19. Trop. Med. Infect. Dis. 2020, 5, 147. [CrossRef] [PubMed] 76. Giuffrè, M.; Vetrugno, L.; Di Bella, S.; Moretti, R.; Berretti, D.; Crocè, L.S. Calprotectin and SARS-CoV-2: A Brief-Report of the Current Literature. Healthcare 2021, 9, 956. [CrossRef] [PubMed] 77. Buso, G.; Becchetti, C.; Berzigotti, A. Acute splanchnic vein thrombosis in patients with COVID-19: A systematic review. Dig. Liver Dis. 2021, 53, 937–949. [CrossRef] 78. Thachil, J. The versatile heparin in COVID-19. J. Thromb. Haemost. 2020, 18, 1020–1022. [CrossRef] 79. Poterucha, T.J.; Libby, P.; Goldhaber, S.Z. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb. Haemost. 2017, 117, 437–444. [CrossRef] 80. Wang, M.K.; Yue, H.Y.; Cai, J.; Zhai, Y.J.; Peng, J.H.; Hui, J.F.; Hou, D.Y.; Li, W.P.; Yang, J.S. COVID-19 and the digestive system: A comprehensive review. World J. Clin. Cases 2021, 9, 3796–3813. [CrossRef] 81. Manolis, A.S.; Manolis, T.A.; Manolis, A.A.; Papatheou, D.; Melita, H. COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management. J. Cardiovasc. Pharmacol. Ther. 2021, 26, 12–24. [CrossRef] [PubMed] 82. Conti, P.; Caraffa, A.; Gallenga, C.E.; Ross, R.; Kritas, S.K.; Frydas, I.; Younes, A.; Di Emidio, P.; Ronconi, G.; Toniato, E. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: Inhibitory effect of the IL-1 receptor antagonist (IL-1Ra). J. Biol. Regul. Homeost. Agents 2020, 34, 1623–1627. [CrossRef] [PubMed]

Review of Mesenteric Ischemia in COVID-19 Patients

Authors: Amit GuptaOshin SharmaKandhala SrikanthRahul MishraAmoli Tandon & Deepak Rajput  Indian Journal of Surgery (2022) Published: 

Abstract

The new coronavirus (COVID-19) infection, first detected in Wuhan, China in 2019 has become a pandemic that has spread to nearly every country in the world. Through October 11, 2021, more than 23 billion confirmed cases and 4.8 million fatalities were reported globally. The bulk of individuals afflicted in India during the first wave were elderly persons. The second wave, however, resulted in more severe diseases and mortality in even younger age groups due to mutations in the wild virus. Symptoms may range from being asymptomatic to fatal acute respiratory distress syndrome (ARDS). In addition to respiratory symptoms, patients may present with gastrointestinal symptoms such as stomach pain, vomiting, loose stools, or mesenteric vein thrombosis. The frequency of patients presenting with thromboembolic symptoms has recently increased. According to certain studies, the prevalence of venous thromboembolism among hospitalized patients ranges from 9 to 25%. It was also shown that the incidence is significantly greater among critically sick patients, with a prevalence of 21–31%. Although the exact origin of thromboembolism is unknown, it is considered to be produced by several altered pathways that manifest as pulmonary embolism, myocardial infarction, stroke, limb gangrene, and acute mesenteric ischemia. Acute mesenteric ischemia (AMI) is becoming an increasingly prevalent cause of acute surgical abdomen in both intensive care unit (ICU) and emergency room (ER) patients. Mesenteric ischemia should be evaluated in situations with unexplained stomach discomfort. In suspected situations, appropriate imaging techniques and early intervention, either non-surgical or surgical, are necessary to avert mortality. The purpose of this article is to look at the data on acute mesenteric ischemia in people infected with COVID-19.

Introduction

Aside from the respiratory system, the gastrointestinal system is the most common site of SARS-COV-2 infection. This might be because enterocyte and vascular endothelial membranes have large amounts of angiotensin-converting enzyme receptor 2, a membrane integral protein. As a result, the COVID virus induces direct enterocyte invasion as well as indirect endothelial injury-induced thrombosis/intestinal ischemia in the bowel [1]. ICU patients are more prone than non-ICU patients to suffer acute mesenteric ischemia. This might be because, in addition to the direct viral activity on vascular endothelium, ICU patients have extra persistent pro-inflammatory effects. Cases have been observed even among individuals who have recovered from infection [2]. A rising number of cases of acute mesenteric ischemia in COVID-19 patients have been reported in the literature since the outbreak of this pandemic (list of reported cases are summarized in the Table 1). AMI risk was shown to be increased with age, male sex, and comorbidities such as hypertension, obesity, and diabetes mellitus. Because of delayed clinical manifestation, AMI-related mortality is quite significant, with 60–80% [3].Table 1 Summary of the cases reported on mesenteric ischemia in COVID-19 patientsFull size table

Case summary

A 55 years old man with no known comorbidity presented to the emergency department of our institute with severe pain abdomen and multiple episodes of vomiting. He reported the recent recovery from the non-complicated COVID-related illness. He did not report any intake of anticoagulants. On clinical examination, abdomen was unremarkable. X-ray chest, x-ray erect abdomen, and ultrasound abdomen were unremarkable. Mesenteric ischemia was suspected and the patient was subjected to CT angiography abdomen, which revealed thrombus at the origin of the superior mesenteric artery and impending gangrene of the small bowel (Fig. 1). Emergency laparotomy was done and intraoperatively found the gangrenous bowel involving the distal jejunum and almost the entire ileum sparing the terminal ileum (Fig. 2). Resection of the gangrenous small bowel and end jejunostomy was done. Later, he was given ICU care, but unfortunately, the patient succumbed to multi-organ dysfunction syndrome.

figure 1
Fig. 1
figure 2
Fig. 2

Pathophysiology

Although the specific etiology of hypercoagulable state and subsequent mesenteric ischemia in COVID-19 patients is unknown, these thromboembolic events can be related to alterations in all three Virchow triad characteristics (vascular endothelial injury, hypercoagulability, and stasis). A variety of variables complicate the etiology of thrombus development, one of which is vascular endothelial injury. Capillary permeability, hemostasis, and fibrinolysis are all maintained by the vascular endothelium (Fig. 3). Direct invasion causes endothelial cells to be damaged and lysed, resulting in an imbalance between pro and anticoagulant states [4]. Furthermore, vascular endothelial cells displayed morphological changes such as cellular expansion, retraction, and intercellular connection breakage [5]. The elevated levels of pro-inflammatory markers, von Willebrand factor, tissue factor, fibrinogen, and circulating microvesicles in the COVID-19 patients explain their hypercoagulability [6]. Antiphospholipid antibodies are elevated in some situations [7]. Patients who are critically ill, on limited oxygen support, and mechanical breathing are less mobilized, which increases the risk of deep venous thrombosis [3].

figure 3
Fig. 3

These mesenteric vascular thromboses cause acute hypoxia in the intestinal wall, which stimulates the renin-angiotensin system, causing mesenteric vasospasm and an elevated risk of hypoxic injury. SARS-COV binds to ACE 2 receptors in intestinal cells, causing cell lysis [8]. As a result, both hypoxia and direct invasion can trigger intestinal cell death. The loss of this epithelial barrier function in the gut promotes increased contact with enteric bacteria/endotoxins and viral particle penetration into the circulation [5]. The hypoxia continues, resulting in transmural infarction, perforation, and peritonitis. In one example of mesenteric ischemia induced by invasive mucormycosis, the presence of fungal components in the mesenteric microcirculation was documented [2]. See the flow chart summarizing the pathophysiology of mesenteric ischemia in covid-19 infection.

Clinical Presentation

Patients with mesenteric ischemia may exhibit a range of symptoms, from nonspecific complaints to peritonitis-like symptoms. Most of the patients developed symptoms a few days after being discharged successfully with proper symptomatic inpatient care. Although the respiratory symptoms predominate mesenteric ischemia presents with nonspecific abdominal symptoms such as loose stools, abdominal pain, nausea, vomiting, abdominal distension, and bleeding per rectum may occur in addition to the usual clinical presentation with respiratory features [6]. When opposed to arterial thrombosis, venous thrombosis has a delayed onset of symptoms. At first, sudden onset pain in the abdomen may be the sole symptom, and it may develop after 5–14 days. Abdominal clinical examination is nonyielding in the majority of cases. Abdominal signs would not develop unless the bowel gangrene or bowel perforation with peritonitis occurs [9].

Investigations

Blood investigations

Despite extensive study on the subject of acute mesenteric ischemia, the associated biomarkers were shown to be neither sensitive nor selective [10]. Elevated lactic acid levels and fibrin degradation products like D-dimer have low specificity and remain elevated in severe COVID-19 without AMI. However, biomarkers associated with hypercoagulable conditions aid in the initiation of preventive treatment and, to a lesser extent, in the management of COVID-related thrombotic events. Increased biomarkers of inflammation and infection include leukopenia (due to corticosteroid usage) and other signs such as C-reactive protein, procalcitonin, and IL-6. D-dimer, ferritin, prothrombin time, and lactate dehydrogenase are additional significant markers. The severity of increased lactate dehydrogenase and ferritin levels is associated with high mortality[8].

Radiological imaging

In the emergency room, an X-ray of the abdomen and an ultrasound are helpful for early examinations. X-ray of the erect abdomen helps in initial assessment in cases presented with features of obstruction or perforation. Ultrasound in the early phase may show SMA occlusion and bowel spasm or ultrasound findings in the early stages of acute mesenteric ischemia may appear normal [11]. In the intermediate phase, USG is not useful because of the presence of a large amount of gas-filled intestinal loops. In the late phase, USG may reveal fluid-filled lumen, bowel wall thinning, evidence of extra-luminal fluid, decreased or absent peristalsis. Therefore, USG may be helpful in the diagnosis of advanced bowel obstruction, gangrene, and perforation with peritoneal collection [12]. Ultrasonography revealed some other important features with distended and sludge-filled gall bladder with bile stasis. Portal venous gas also can be detected on ultrasonography which can be better characterized with the help of computed tomography [13].

Computed tomography

The gold standard investigation is CT angiography. CT observations commonly encountered in acute mesenteric ischemia secondary to COVID-19 includes thrombus in the aorta/SMA/portal circulation, augmentation of the bowel wall, thickness of the bowel wall with distention(> 3 cm), edema, and stranding of the mesentery, pneumatosis intestinalis or portal venous gas suggesting bowel wall ischemia, and non-enhancing thick bowel wall seen in bowel infarction, bowel perforation secondary to bowel infarction may present discontinuity of bowel wall with localized air collection. One should remember that pneumatosis intestinalis may also occur due to mechanical ventilation. Pneumoperitoneum occurs when there is severe intestinal necrosis and perforation. There were additional reports of nonspecific features such as a dilated gut with a fluid-filled lumen, distended gallbladder with bile stasis, features of solid organ ischemia, and pancreatitis [14]. MRI, despite its accessibility, has drawbacks such as a longer acquisition time and lower resolution than CT angiography [12].

Management

A summary of cases of acute mesenteric ischemia has been tabulated (Table 1). Management of acute mesenteric ischemia in COVID-19 includes the following:

  • Supportive measures: Crystalloid rehydration and empirical antibacterial treatment should begin before angiography or any surgical resection. Comorbidity management, hemodynamic support in unstable patients, and electrolyte balance correction are all critical components of patient care [10].
  • Anticoagulation: There is insufficient data in 19 patients to warrant thromboprophylaxis. According to the Tang et al. study, low-dose heparin prophylaxis decreased thrombotic events and mortality in those with D-dimer levels over 3 mg/ml. Despite the increased risk of bleeding, mesenteric ischemia should be treated with intraoperative and postoperative anticoagulation [15].
  • Revascularisation: Revascularization with catheter-directed thrombolysis and thrombectomy by percutaneous/surgical intervention can be explored in instances where there is no indication of significant intestinal ischemia. Catheter-directed thrombolysis with unfractionated heparin and recombinant tissue plasminogen activators can accomplish this. Because of the increased risk of re-thrombosis, vascular clearance is not indicated in instances of superior mesenteric vein thrombus [15].
  • Resection of the gangrenous bowel: Depending on clinical suspicion, a CT angiography examination of mesenteric vasculature and bowel health can be performed, and an emergency exploration call should be placed. Intraoperatively, if the patient is normotensive, has no sepsis or peritonitis, and the remaining bowel viability is unquestionable, the gangrenous bowel is to be removed, and the remaining bowel can be considered for re-anastomosis. In unfavorable circumstances, a stoma should be created following gangrenous bowel resection [11]. The margin dissection in venous thrombosis should be broader than in arterial thrombosis. To assure the bowel’s survivability, abdominal closure should be temporary, and a relook laparotomy should be done 48 h later. Histopathological examination of the resected intestine may indicate patchy or widespread necrotic changes from mucosa to transmural thickness. In the submucosal vasculature, fibrin-containing microthrombi with perivascular neutrophilic infiltration is observed.
  • Management of short bowel syndrome: The therapy varies depending on the length of colon left after excision of infarcted bowel caused by mesenteric ischemia.
  • Medical- In severe diarrhea, fluid and electrolyte loss must be replaced. TPN for feeding and histamine-2 receptor antagonists or PPIs for stomach acid secretion reduction. Loperamide and diphenoxylate are anti-motility medicines that delay small intestine transit whereas Octreotide reduces the volume of gastrointestinal secretions.
  • Non-transplant surgical therapy- Done to improve the absorption capacity of the remaining intestine by restoring intestinal continuity. Increased nutrient and fluid absorption is the goal. Segmental reversal of the small bowel, fabrication of small intestinal valves, and electrical pacing of the small bowel are all procedures used to delay intestinal transit. Longitudinal intestinal lengthening and tailoring technique (LILT) and serial transverse arthroplasty process are two intestinal lengthening procedures (STEP).
  • Intestinal transplantation- Life-threatening problems such as liver failure, thrombosis of major central veins, frequent episodes of severe dehydration, and catheter-related sepsis are reasons for intestinal transplantation [16].

Prognosis

Acute mesenteric ischemia has a poor prognosis, and life is reliant on prompt diagnosis and treatment. If detected within 24 h, the likelihood of survival is 50%, but it declines to 30% beyond that [17].In operated cases, COVID infection acts as an independent risk factor and is responsible for higher mortality [18].

Conclusion

SARS-COV-2 infection even though initially thought to be respiratory infection; later cases detected presenting with multisystem involvement. The presentation may vary from asymptomatic or mildly symptomatic to severe respiratory distress syndrome or thromboembolic phenomenon requiring ICU care. The exact mechanism of thromboembolism is not established. However, the increasing number of acute mesenteric ischemia is quite alarming. The treating physician should be overcautious in patients presenting with abdominal symptoms either currently affected or recovered from COVID-related illness. In high-risk patients, early start of prophylactic anticoagulation may be beneficial. Earlier intervention is known acute mesenteric ischemia cases with operative or minimally invasive procedures may give higher survival benefits. It mandates more research to determine the causes of thromboembolism, as well as preventive and therapeutic anticoagulation in these individuals.

References

  1. Jin B, Singh R, Ha SE, Zogg H, Park PJ, Ro S (2021) Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19. World J Gastroenterol. Baishideng Publishing Group Co 27:2341–52CAS Article Google Scholar 
  2. Jain M, Tyagi R, Tyagi R, Jain G (2021) Post-COVID-19 gastrointestinal invasive mucormycosis. Indian J Surg 22:1–3
  3. Kerawala AA, Das B, Solangi A (2021) Mesenteric ischemia in COVID-19 patients: a review of current literature. World J Clin Cases 9(18):4700–4708Article Google Scholar 
  4. Kichloo A, Dettloff K, Aljadah M, Albosta M, Jamal S, Singh J et al (2020) COVID-19 and hypercoagulability: a review. Clin Appl Thromb 26
  5. Parry AH, Wani AH, Yaseen M (2020) Acute mesenteric ischemia in severe Coronavirus-19 (COVID-19): possible mechanisms and diagnostic pathway. Acad Radiol 27(8):1190Article Google Scholar 
  6. Cheung S, Quiwa JC, Pillai A, Onwu C, Tharayil ZJ, Gupta R (2020) Superior mesenteric artery thrombosis and acute intestinal ischemia as a consequence of COVID-19 infection. Am J Case Rep 21:1–3Google Scholar 
  7. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W et al (2020) Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 382(17):e38Article Google Scholar 
  8. Al Mahruqi G, Stephen E, Abdelhedy I, Al WK (2021) Our early experience with mesenteric ischemia in COVID-19 positive patients. Ann Vasc Surg 73:129–132Article Google Scholar 
  9. Karna ST, Panda R, Maurya AP, Kumari S (2020) Superior mesenteric artery thrombosis in COVID-19 Pneumonia: an underestimated diagnosis—first case report in Asia. Indian J Surg 82(6):1235–1237Article Google Scholar 
  10. Singh B, Kaur P (2021) COVID-19 and acute mesenteric ischemia: a review of literature. Hematol Transfus Cell Ther 43(1):112–116Article Google Scholar 
  11. Janež J, Klen J (2021) Multidisciplinary diagnostic and therapeutic approach to acute mesenteric ischaemia: a case report with literature review. SAGE Open Med Case Rep 9:2050313X2110048Article Google Scholar 
  12. Mc W (2010) Acute mesenteric ischemia: diagnostic approach and surgical treatment. Semin Vasc Surg 23(1):9–20Article Google Scholar 
  13. Bhayana R, Som A, Li MD, Carey DE, Anderson MA, Blake MA et al (2020) Abdominal imaging findings in COVID-19: Preliminary observations. Radiology 297(1):E207–E215
  14. Keshavarz P, Rafiee F, Kavandi H, Goudarzi S, Heidari F, Gholamrezanezhad A (2021) Ischemic gastrointestinal complications of COVID-19: a systematic review on imaging presentation. Clin Imaging 73:86–95Article Google Scholar 
  15. Bergqvist D, Svensson PJ (2010) Treatment of mesenteric vein thrombosis. Semin Vasc Surg 23(1):65–68Article Google Scholar 
  16. Seetharam P, Rodrigues G (2011) Short bowel syndrome: a review of management options. Saudi J Gastroenterol 17(4):229–235Article Google Scholar 
  17. Krothapalli N, Jacob J (2021) A rare case of acute mesenteric ischemia in the setting of COVID-19 infection. Cureus 13(3):0–4Google Scholar 
  18. Haffner MR, Le HV, Saiz AM, Han G, Fine J, Wolinsky P et al (2021) Postoperative In-hospital morbidity and mortality of patients with COVID-19 infection compared with patients without COVID-19 infection. JAMA Netw Open 4(4):10–13Article Google Scholar 
  19. Ucpinar BA, Sahin C (2020) Superior mesenteric artery thrombosis in a patient with COVID-19: a unique presentation. J Coll Physicians Surg Pak 30(10):S112–S114Google Scholar 
  20. Khesrani LS, Chana k, Sadar FZ, Dahdouh A, Ladjadj Y, Bouguermouh D (2020) Intestinal ischemia secondary to Covid-19. J Pediatr Surg Case Rep 61:101604Article Google Scholar 
  21. Norsa L, Valle C, Morotti D, Bonaffini PA, Indriolo A, Sonzogni A (2020) Intestinal ischemia in the COVID-19 era. Dig Liver Dis 52(10):1090–1091CAS Article Google Scholar 
  22. Rodriguez-Nakamura RM, Gonzalez-Calatayud M, Martinez Martinez AR (2020) Acute mesenteric thrombosis in two patients with COVID-19. Two cases report and literature review. Int J Surg Case Rep 76:409–14Article Google Scholar 
  23. VartanogluAktokmakyan T, Tokocin M, Meric S, Celebi F (2021) Is mesenteric ischemia in COVID-19 patients a surprise? Surg Innov 28(2):236–238Article Google Scholar 
  24. Levolger S, Bokkers RPH, Wille J, Kropman RHJ, de Vries JPPM (2020) Arterial thrombotic complications in COVID-19 patients. J Vasc Surg Cases Innov Tech 6(3):454–459Article Google Scholar 
  25. Thuluva SK, Zhu H, Tan MML, Gupta S, Yeong KY, Wah STC et al (2020) A 29-year-old male construction worker from india who presented with left-sided abdominal pain due to isolated superior mesenteric vein thrombosis associated with SARS-CoV-2 infection. Am J Case Rep 21:1–5Article Google Scholar 
  26. Lari E, Lari A, AlQinai S, Abdulrasoul M, AlSafran S, Ameer A et al (2020) Severe ischemic complications in Covid-19—a case series. Int J Surg Case Rep 75(June):131–135Article Google Scholar 
  27. Singh B, Mechineni A, Kaur P, Ajdir N, Maroules M, Shamoon F et al (2020) Acute intestinal ischemia in a patient with COVID-19 infection. Korean J Gastroenterol 76(3):164–166Article Google Scholar 
  28. De Roquetaillade C, Chousterman BG, Tomasoni D, Zeitouni M, Houdart E (2020) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19. The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. (January)
  29. Sehhat S, Talebzadeh H, Hakamifard A, Melali H, Shabib S, Rahmati A et al (2020) Acute mesenteric ischemia in a patient with COVID-19: a case report. Arch Iran Med 23(9):639–643Article Google Scholar 
  30. Beccara LA, Pacioni C, Ponton S, Francavilla S, Cuzzoli A (2020) Arterial mesenteric thrombosis as a complication of SARS-CoV-2 infection. Eur J Case Rep Intern Med 7(5).
  31. Ignat M, Philouze G, Aussenac-belle L (2020) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. (Jan)
  32. Farina D, Rondi P, Botturi E, Renzulli M, Borghesi A, Guelfi D et al (2021) Gastrointestinal: bowel ischemia in a suspected coronavirus disease (COVID-19) patient. J Gastroenterol Hepatol 36(1):41CAS Article Google Scholar 
  33. Azouz E, Yang S, Monnier-Cholley L, Arrivé L (2020) Systemic arterial thrombosis and acute mesenteric ischemia in a patient with COVID-19. Intensive Care Med 46(7):1464–1465CAS Article Google Scholar 
  34. Vulliamy P, Jacob S, Davenport RA (2020) Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19. Br J Haematol 189(6):1053–1054CAS Article Google Scholar 
  35. Bianco F, Ranieri AJ, Paterniti G, Pata F, Gallo G (2020) Acute intestinal ischemia in a patient with COVID-19. Tech Coloproctol 24(11):1217–1218CAS Article Google Scholar 
  36. Filho A do C, Cunha B da S (2020) Case report – inferior mesenteric vein thrombosis and COVID-19. 2020060282
  37. Mitchell JM, Rakheja D, Gopal P (2021) SARS-CoV-2-related hypercoagulable state leading to ischemic enteritis secondary to superior mesenteric artery thrombosis. Clin Gastroenterol Hepatol 19(11):e111CAS Article Google Scholar 
  38. English W, Banerjee S (2020) Coagulopathy and mesenteric ischaemia in severe SARS-CoV-2 infection. ANZ J Surg 90(9):1826Article Google Scholar 
  39. de Barry O, Mekki A, Diffre C, Seror M, El Hajjam M, Carlier RY (2020) Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia. Radiol Case Rep 15(7):1054–1057Article Google Scholar 
  40. Kraft M, Pellino G, Jofra M, Sorribas M, Solís-Peña A, Biondo S, Espín-Basany E (2021) Incidence, features, outcome and impact on health system of de-novo abdominal surgical diseases in patients admitted with COVID-19. Surg J R Coll Surg Edinb Irel 19:e53–e58Google Scholar 
  41. Besutti G, Bonacini R, Iotti V, Marini G, Riva N, Dolci G et al (2020) Abdominal visceral infarction in 3 patients with COVID-19. Emerg Infect Dis 26(8):1926–1928CAS Article Google Scholar 
  42. Kielty J, Duggan WP, O’Dwyer M (2020) Extensive pneumatosis intestinalis and portal venous gas mimicking mesenteric ischaemia in a patient with SARS-CoV-2. Ann R Coll Surg Engl 102(6):E145–E147CAS Article Google Scholar 
  43. Pang JHQ, Tang JH, Eugene-Fan B (2021) A peculiar case of small bowel stricture in a coronavirus disease 2019 patient with congenital adhesion band and superior mesenteric vein thrombosis. Ann Vasc Surg 70:286–289Article Google Scholar 
  44. Osilli D, Pavlovica J, Mane R, Ibrahim M, Bouhelal A, Jacob S (2020) Case reports: mild COVID-19 infection and acute arterial thrombosis. J Surg Case Rep (9):1–3

Elevated clotting factor V levels linked to worse outcomes in severe COVID-19 infections

Authors: Jonathan A. Stefely,Bianca B. Christensen,Tasos Gogakos,Jensyn K. Cone Sullivan … See all authors First published: 24 August 2020 https://doi.org/10.1002/ajh.25979

Abstract

Coagulopathy causes morbidity and mortality in patients with coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Yet, the mechanisms are unclear and biomarkers are limited. Early in the pandemic, we observed markedly elevated factor V activity in a patient with COVID-19, which led us to measure factor V, VIII, and X activity in a cohort of 102 consecutive inpatients with COVID-19. Contemporaneous SARS-CoV-2-negative controls (n = 17) and historical pre-pandemic controls (n = 260-478) were also analyzed. This cohort represents severe COVID-19 with high rates of ventilator use (92%), line clots (47%), deep vein thrombosis or pulmonary embolism (DVT/PE) (23%), and mortality (22%). Factor V activity was significantly elevated in COVID-19 (median 150 IU/dL, range 34-248 IU/dL) compared to contemporaneous controls (median 105 IU/dL, range 22-161 IU/dL) (P < .001)—the strongest association with COVID-19 of any parameter studied, including factor VIII, fibrinogen, and D-dimer. Patients with COVID-19 and factor V activity >150 IU/dL exhibited significantly higher rates of DVT/PE (16/49, 33%) compared to those with factor V activity ≤150 IU/dL (7/53, 13%) (P = .03). Within this severe COVID-19 cohort, factor V activity associated with SARS-CoV-2 load in a sex-dependent manner. Subsequent decreases in factor V were linked to progression toward DIC and mortality. Together, these data reveal marked perturbations of factor V activity in severe COVID-19, provide links to SARS-CoV-2 disease biology and clinical outcomes, and nominate a candidate biomarker to investigate for guiding anticoagulation therapy in COVID-19.

1 INTRODUCTION

Typically, COVID-19, caused by SARS-CoV-2, presents as a respiratory illness, but coagulopathy can cause morbidity and mortality.17 Line clots, arterial clots, pulmonary thrombosis with microangiopathy, pedal acro-ischemia (“COVID-toes”), bleeding, and venous thromboembolism (VTE)—including deep venous thrombosis (DVT) and pulmonary embolism (PE)—have been associated with COVID-19, especially in severe cases.813 However, the underlying mechanisms remain unclear. Hypothesized mechanisms for thrombosis invoke inflammation, endothelial dysregulation, patient immobilization, antiphospholipid antibodies, and coagulation factor VIII dysregulation.1420 However, direct links between the SARS-CoV-2 virus and coagulopathy remain unmapped. Common laboratory findings include elevations of D-dimer and the acute phase reactants fibrinogen and factor VIII,2128 but additional and more specific biomarkers for guiding prognosis and anticoagulation therapy would be valuable.

Near the beginning of the COVID-19 pandemic in Massachusetts, USA in March of 2020, we obtained an early specimen from a patient with severe COVID-19 on a ventilator. Coagulation laboratory testing revealed an unexpected and unusual elevation of factor V activity at 248 IU/dL (reference range 60-150 IU/dL), and 4 days later this patient developed a saddle PE. This was the highest factor V activity level ever observed in our high-volume coagulation laboratory. Since initiating daily interpretation for every patient tested by our high-volume coagulation laboratory starting in 1994, we had never seen factor V activity >200 IU/dL before, and factor V elevations above 150 IU/dL (above the reference range) were uncommon prior to the pandemic. In the coagulation cascade, activated factor V interacts with activated factor X to form the prothrombinase complex, which catalyzes formation of thrombin and leads to fibrin clot formation. Dysregulation of factor V due to factor V Leiden is a well-known cause of a prothrombotic state.29 Concurrent elevations of factor V activity and factor VIII activity have also been linked to increased VTE risk in one study.30 Thus, we hypothesized that venous thromboembolism and possibly other complications of severe COVID-19 are associated with perturbations of factor V activity.

2 METHODS

2.1 Study population and design

2.1.1 COVID-19 cases

The primary patient specimens in this prospective cohort study were collected over approximately 1 month at the beginning of the COVID-19 pandemic in Massachusetts, USA (March 23, 2020 to April 27, 2020) under an institutional review board-approved study protocol. All authors had access to and analyzed the primary data set, which is also included here as a resource (Table S1). The study site was the Massachusetts General Hospital (MGH), an approximately 1000-bed academic medical center and one of the primary regional referral centers for patients with severe COVID-19. Both SARS-CoV-2 polymerase chain reaction (PCR) positive (“COVID-19”) cases and SARS-CoV-2 PCR negative (“contemporaneous control”) cases were collected from the population of patients with specimens submitted to the MGH Special Coagulation Laboratory. During most of the study period, the inpatient hematology team sent special coagulation testing specimens to our laboratory from all patients in the intensive care units with COVID-19 because of reports of coagulopathy associated with COVID-19. The resultant cohort of 102 inpatients with COVID-19 is comprised of all 102 SARS-CoV-2 positive patient specimens submitted to our coagulation laboratory during the study period without any exclusion criteria. We did not specify additional inclusion criteria other than a positive SARS-CoV-2 test. We measured a panel of coagulation parameters in the earliest available specimen from each of these 102 inpatients with COVID-19.

2.1.2 Contemporaneous control cases

Our study period during the initial peak of the COVID-19 pandemic limited access to contemporaneous specimens from confirmed SARS-CoV-2 negative (“contemporaneous control”) patients submitted to our coagulation laboratory because hospital policies temporarily discontinued elective procedures and outpatient visits for patients without COVID-19. Nevertheless, we were able to obtain a group of specimens from SARS-CoV-2 negative controls (n = 17). We included all submitted specimens from SARS-CoV-2 negative patients on ventilators during the study period (n = 7), which was done by design to include patients with similar illness severity compared to our COVID-19 patients.

2.1.3 Historical control cases

For factors V, X, and VIII, D-dimer, and fibrinogen we also retrospectively obtained historical values from patients with specimens submitted to our laboratory prior to the COVID-19 pandemic. Factor V activity values were obtained from all patient specimens during the 4 years prior to the COVID-19 pandemic (April 2016 – February 2020) (n = 446), as well as all factor VIII activities from March 2019 – February 2020 (n = 478), all factor X activities from May 2016 – February 2020 (n = 346), and all fibrinogen (n = 260) and D-dimer (n = 373) measurements from days 1-14 of January 2020.

2.2 Determination of clinical variables

Patients with COVID-19 and contemporaneous controls were followed forward from the time of their first coagulation laboratory specimen to a median of 78 days (range 64-99 days) to determine clinical outcomes such as the development of DVT/PE. Clinical variables were determined by review of electronic medical records and reviewers were blinded to the results of the research coagulation factor assays. For COVID-19 cases, the date of symptom onset was determined by manual chart review, as documented in the admission note or the first note of the infectious disease consult. When discrepant dates were reported, the date reported in the note closest to admission was chosen. Ventilator use, extracorporeal membrane oxygenation (ECMO) use, and anticoagulation use at the time of the coagulation specimen collection were recorded. Line clots any time during the admission were recorded. DVT/PE and arterial clots were recorded if they occurred any time during the admission or if they were part of the reason for admission (the latter only occurred in SARS-CoV-2 negative patients, some of which were admitted for DVT/PE or stroke). Death was recorded. Discharge was noted if the patient was discharged to home or to a rehabilitation facility.

2.3 Determination of laboratory variables

Factor V, VIII, and X activities and activated partial thromboplastin time (aPTT) waveforms were measured in the same leftover clinical specimens using validated clinical laboratory assays (details below). The remaining parameters in the study were determined by review of existing clinical data. Note, SARS-CoV-2 real-time PCR (RT-PCR) cycle threshold (Ct) values for the diagnostic specimen were obtained from the instrument runs on either a Roche Cobas 6800 or a Cepheid GeneXpert Infinity System. If the Ct values for the diagnostic specimen were not available, the Ct values for the specimen closest to onset of symptoms were recorded. Prothrombin time (PT), aPTT, heparinase aPTT (all by Stago, Asnieres, France), and the activities of factors II, VII, IX, XI, and XII were recorded only if determined on a specimen collected within 6 hours of the study specimen. Both D-dimer (bioMerieux, Marcy-l’Étoile France) and fibrinogen (Stago) values were recorded at the closest time point to the study specimen and were only included if they were measured within 2 days of the study specimen. The following results were recorded at the closest time to the study specimen during the admission: PTT-LA, STACLOT-LA, protein S and antithrombin activity (all by Stago), platelet count, anticardiolipin and beta-2 glycoprotein I (INOVA, San Diego CA), chromogenic protein C activity and activated protein C resistance/factor V Leiden (APC V, Chromogenix, West Chester, OH). The International Society on Thrombosis and Haemostasis (ISTH) DIC scores were determined according to published guidelines.31

2.4 Coagulation factor assay methods

Factor assays were one-stage, PT-based for factors II, V, VII and X, and aPTT-based for factors VIII, IX, XI, and XII, using an ACL TOP 750 analyzer, Hemosil calibrator, Synthasil or Recombiplastin, all from Instrumentation Laboratory (Bedford MA, USA), and factor-deficient plasma from Precision Biologic (Dartmouth, NS, Canada). Three dilutions (1:10, 1:20, and 1:40) were automatically performed for each factor assay.

2.5 APTT waveform analyses

The ACL TOP analyzer automatically generates an aPTT waveform every time an aPTT is performed. Since the ACL TOP does not provide a quantitative measurement of the initial slope, waveforms were manually reviewed to determine if the initial slope was flat (normal) or sloped (abnormal and suggestive of DIC).3233 These determinations were made while blinded to all aspects of the study. The ACL TOP also provides a quantitative measurement of the aPTT waveform’s first derivative peak and second derivative peak and trough.3435

2.6 Statistical methods

For quantitative variables, P values were determined with a two-sided, heteroscedastic Student t test for normally-distributed data, and Mann-Whitney U-test for non-parametric data. Fisher’s exact test was used for categorical variables.

3 RESULTS

3.1 A cohort of patients with severe COVID-19

To begin testing the hypothesis that factor V activity elevation is associated with COVID-19, we measured a panel of coagulation parameters in the earliest available specimen from the first 102 SARS-CoV-2 positive patient specimens submitted to our coagulation laboratory without any exclusion criteria, 17 contemporaneous controls, and 260 to 478 historical controls per test prior to the COVID-19 pandemic.

This cohort of patients with COVID-19 was almost entirely comprised of severe cases based on the observed rate of ventilator use (92%) and ECMO use (7%) at the time of the analyzed coagulation specimen (Table 1). Our prospective follow-up revealed development of line clots (arterial or venous) in 47% (48/102) of the COVID-19 cases, suggesting widespread coagulopathy (Table 2). Furthermore, DVT and/or PE occurred in a striking 23/102 (23%) of these patients with COVID-19. Additionally, 22/102 (22%) of these patients with COVID-19 died before the end of the study period. The primary data set for this cohort, including clinical features and laboratory data, are provided as a resource (Table S1).TABLE 1. COVID-19 cohort characteristics

Patients with COVID-19 (n = 102)Contemporaneous controls (n = 17)
Age (years) median (range)61 (27-87)57 (15-85)P > .05
Male sex − no. (%)68 (67)9 (53)P > .05
Ventilator use − no. (%)94 (92)7 (41)P < .001
ECMO use − no. (%)7 (7)4 (24)P > .05
Anticoagulation at the time of the coagulation lab specimen
Prophylactic SQ heparin or enoxaparin − no. (%)59 (58)2 (12)P > .05
Therapeutic heparin or enoxaparin − no. (%)26 (25)4 (24)P > .05
Other dose of heparin or enoxaparin − no. (%)6 (6)0 (0)P < .001

TABLE 2. Clinical outcomes and features

Patients with COVID-19 (n = 102)Contemporaneous controls (n = 17)
Line clot − no. (%)48 (47)3 (18)P < .05
VTE (DVT or PE) − no. (%)23 (23)7 (41)P > .05
Arterial clot − no. (%)9 (9)3 (18)P > .05
Discharge − no. (%)75 (74)12 (71)P > .05
Death − no. (%)22 (22)5 (29)P > .05
  • a Arterial clots included ischemic strokes and mesenteric ischemia.

3.2 Factor V is elevated in patients with severe COVID-19

Using a validated clinical laboratory assay, we found factor V activity to be markedly elevated in many patients in this severe COVID-19 cohort (median 150 IU/dL, n = 102) compared to the expected reference median value of 100 IU/dL activity (Figures 1A,B). Forty-nine of these cases (48%) fell above the reference range of 60-150 IU/dL. The degree of factor V elevation seen in these COVID-19 cases was notably higher than those seen previously at our hospital before COVID-19 (Figure 1A). Compared to all patient specimens tested in our laboratory during the 4 years prior to the COVID-19 pandemic (April 2016 – February 2020) (n = 446), factor V activity was significantly higher in our cohort of patients with severe COVID-19 (COVID-19 median 150 IU/dL, historical control median 81 IU/dL, P < .001) (Figure 1A). Among COVID-19 patients, 16/102 (16%) had factor V > 200 IU/dL, which was not seen in any of the contemporaneous or historical controls, and which has never been observed at MGH before (extending back to 1994 when daily review of all coagulation results began).

Details are in the caption following the image
FIGURE 1Open in figure viewerPowerPointFactor V activity is markedly elevated in patients with severe COVID-19. A, Box plot indicating factor V activity in a cohort of severe COVID-19 cases compared to contemporaneous SARS-CoV-2 negative controls and historical controls prior to the COVID-19 pandemic. Center lines show the medians; box limits indicate the 25th and 75th percentiles as determined by R software; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles; notches represent the 95% confidence interval for each median; data points are plotted as open circles. n = 446, 102, 17 sample points (left to right in figure). P values, two-sided, heteroscedastic Student t test. B, Histogram of factor V activity values in the COVID-19 cohort (n = 102), contemporaneous controls (n = 17), and historical controls (n = 446). C, Scatter plot of the activities of factor V and factor VIII in a cohort of patients with severe COVID-19. The reference ranges are indicated by gray-blue (lower limit) and red (upper limit) lines. D, Table of cases with elevations of factor V or factor VIII activity and the rate of DVT/PE in these groups. E, Matrix of correlations (Spearman’s rho) for the indicated coagulation parameters. Asterisks indicate significant correlations with a Bonferroni-corrected P value < .05. F, Example of a normal aPTT waveform and the first and second derivatives of this waveform. The solid black line tracks light absorbance over time during the aPTT. Initially, the line is flat. The abrupt rise in the black line is when clot formation occurs, and the time at which it occurs is the aPTT result in seconds. When the clot occurs, the sample changes from a liquid (plasma) to a solid (clot), which absorbs more light. After clot formation, the sample undergoes no further changes, therefore the light absorbance remains unchanged and the line is flat again. The waveform and its first and second derivatives are automatically calculated by the analyzer. G, Comparison of a normal aPTT waveform and an abnormal aPTT waveform in COVID-19 patients from the current study. The portion within the rectangle is expanded in panel H. H, Expanded view of the initial portion of the aPTT waveforms in panel G, showing the abnormal slope. When the initial slope of the line rises upward instead of remaining flat before clot formation, this indicates an abnormal waveform that is suggestive of DIC [Color figure can be viewed at wileyonlinelibrary.com]

Our factor V assay is regularly validated for consistency across time. However, to alleviate concerns for a temporal drift in assay performance, we also measured factor V activity in contemporaneous SARS-CoV-2 negative control cases (median 105 IU/dL, n = 17), which were found to be overall similar to the historical controls (P > .1). Furthermore, factor V activity was significantly elevated in our cohort of patients with severe COVID-19 (median 150 IU/dL) compared to these contemporaneous controls (P <,001) (Figure 1A).

A sub-group analysis also demonstrated that factor V was significantly elevated in the COVID-19 cases (median 150 IU/dL) compared to both the contemporaneous control cases on ventilators (n = 7, median 54 IU/dL, P < .05) and the non-ventilated contemporaneous control cases (n = 10, median 107 IU/dL, P < .001). These findings suggest that the elevation of factor V in severe COVID-19 cannot be simply explained by a general state of severe illness or by ventilator use. Together with the rarity of factor V elevations before the COVID-19 pandemic, these findings suggest a more specific relationship between COVID-19 and factor V elevation.

3.3 Factor V elevation in severe COVID-19 is associated with DVT/PE

We examined DVT/PE events in this cohort to begin testing the hypothesis that elevated factor V activity is a risk factor for DVT/PE in severe COVID-19. Patients with COVID-19 and factor V activity above the upper limit of the reference range (>150 IU/dL) exhibited significantly higher rates of DVT/PE (16/49, 33%) compared to those with factor V activity less than or equal to 150 IU/dL (7/53, 13%) (P = .03). Moreover, among patients with COVID-19, factor V trends toward higher activities in patients who went on to develop DVT/PE (median 165 IU/dL, n = 23) compared to those that did not develop DVT/PE (median 145 IU/dL, n = 79) (P = .05). Together, these findings nominate factor V as a candidate biomarker for future clinical trials investigating VTE and anticoagulation therapies in patients with COVID-19.

The VTE rates were lower in patients with COVID-19 treated with anticoagulation (19/91, 21%) compared to those not treated with anticoagulation (4/11, 36%) at the time of the factor V activity specimen, but this difference was not statistically significant in this cohort (P = .3). Similarly, when restricting the analysis to COVID-19 cases with elevated factor V activity (>150 IU/dL), VTE rates were lower in patients treated with anticoagulation (13/44, 30%) compared to those not treated with anticoagulation (3/5, 60%), but this difference was not significant in this cohort (P = .3). Nonetheless, these findings provide a foundation for larger prospective studies of anticoagulation in cases of COVID-19, especially in cases with elevated factor V activity.

3.4 Factor V activity relationships in COVID-19

A study prior to the COVID-19 pandemic suggested that concurrent elevations of both factor V and its homolog factor VIII can increase risk for VTE in general,30 and factor VIII has been shown to be elevated in COVID-19. Thus, we also measured factor VIII activity in our cohort of patients with COVID-19 and the contemporaneous controls. Factor VIII activity was elevated in the COVID-19 cases (median 298 IU/dL, n = 100) compared to the reference range (50-200 IU/dL), the contemporaneous controls (median 222 IU/dL, n = 17, P < .01), and the historical controls (median 125 IU/dL, n = 478, P < .001) (Figure S1). The activities of factors V and VIII were not significantly correlated in our cohort (Spearman’s rho = 0.16; P > .05), suggesting distinct regulation (Figure 1C). Yet, 43/100 (43%) of the COVID-19 cases showed elevations of both factor V (>150 IU/dL) and factor VIII (>200 IU/dL) above their reference ranges. Thus, some patients with severe COVID-19 could be at risk for DVT/PE because of elevations of both factor V and factor VIII. In this cohort of COVID-19 cases, DVT/PE occurred in 13/43 (30%) of cases with elevations of both factor V and factor VIII but did not occur in the 11 cases with factor V < 150 IU/dL and factor VIII <200 IU/dL (P = .048) (Figure 1D).

We also measured the activity of factor X because its active form physically interacts with activated factor V and we questioned whether all coagulation factors were elevated. However, factor X activity was not altered in COVID-19 cases (median 106 IU/dL) compared to the reference range (60-150 IU/dL).

Additional coagulation parameters were extracted from existing clinical laboratory data (Table 3). Elevations of fibrinogen and D-dimer have been a point of emphasis in studies of COVID-19 coagulopathy. We also observed an elevation of D-dimer in COVID-19 cases (median 2849 ng/mL, n = 101) compared to the reference range (< 500 ng/mL) and historical controls (median 546, n = 373, P < .001). Likewise, we observed an elevation of fibrinogen in COVID-19 cases (median 763 mg/dL, n = 91) compared to the reference range (150-400 mg/dL), historical controls (median 349, n = 260, P < .001), and contemporaneous controls (median 212 mg/dL, n = 9, P < .001). In patients with COVID-19, we observed a correlation between the acute phase reactants fibrinogen and factor VIII (Figure 1E). Factor V showed a moderate correlation with its functional partner factor X, but factor V was not significantly correlated with the acute phase reactants fibrinogen and factor VIII (P > .05) (Figure 1E). Notably, among the coagulation parameters analyzed (Table 3, Figures 1 and S1), the elevation of factor V in these COVID-19 cases was the most significant difference compared to the contemporaneous controls and distinguished itself as the most striking difference compared to our laboratory’s historical results prior to the COVID-19 pandemic.TABLE 3. Coagulation parameters

Reference rangePatients with COVID-19(n)Contemporaneous controls(n)P value
Primary prospective study test results
Factor V activity (IU/dL) median60–15015010210517P < .001
Factor VIII activity (IU/dL) median50-20029810022217P < .01
Factor X activity (IU/dL) median60–1501061027817P < .01
Secondary retrospective study test results (obtained from existing clinical data when available)
D-dimer (ng/mL) median< 5002849101242010P > .05
Fibrinogen (mg/dL) median150–400763912129P < .001
PT (seconds) median11.5-14.515.19714.117P > .05
aPTT (seconds) median22-3638.110131.917P > .05
Abnormal aPTT waveform slope − no. (%)Normal14 (15)945 (33)15P > .05
aPTT waveform first derivative (TU/sec) median150-2914619425715P < .001
aPTT waveform second derivative peak (TU/seĉ2) median488-102614859499315P < .001
aPTT waveform second derivative trough medianNA5859443015P < .05
Platelet count (K/μL) median150–40027510116916P < .01
ISTH DIC score median< 528646P < .05
Antithrombin activity (IU/dL) median80-13079797810P > .05
Protein S activity (IU/dL) median70-15050.51891.56P < .05
Protein C activity (IU/dL) median70–1508019118.56P > .05
Lupus anticoagulant − no. (%)Negative25 (57)442 (15)13P < .05
Anticardiolipin antibody − no. (%)Negative21 (54)391 (9)11P < .05
Beta-2-glycoprotein antibody − no. (%)Negative3 (10)290 (0)5P > .05
Activated protein C resistance (factor V Leiden screen) − no. (%)Negative0 (0)90 (0)6NA
Factor II activity (IU/dL) median60–150955NA0NA
Factor VII activity (IU/dL) median60-150525NA0NA
Factor IX activity (IU/dL) median60-160135161261NA
Factor XI activity (IU/dL) median60–1609816571NA
Factor XII activity (IU/dL) median60–160518NA0NA

Nine COVID-19 patients were tested for activated protein C resistance (factor V Leiden), and all were normal (Table 3). As some of these patients had factor V activity above 200 IU/dL, it appears that factor V Leiden is not involved in the unusual factor V elevation.

3.5 COVID-19 progression toward DIC and death is associated with lower FV

Two patients with severe COVID-19 in our cohort had a second factor V activity measured later during their hospital course, in each case after worsening of clinical status as measured by increased ventilation requirements or increased vasopressor requirements. In one case, the initial factor V activity was 248 IU/dL, and 5 days later after severe clinical decompensation it dropped to 28 IU/dL. In a second case, the initial factor V activity was 206 IU/dL and after slight clinical worsening it decreased to 171 IU/dL. Based on these cases, we hypothesized that while patients with severe COVID-19 might initially present with markedly elevated factor V activity, a subsequent decline in factor V activity could be associated with clinical decompensation.

In our severe COVID-19 cohort, cases with factor V activity ≤150 IU/dL had a higher mortality (16/53, 30%) than those with factor V activity >150 IU/dL (6/49, 12%, P < .05). To investigate if this relationship with mortality could be due to consumption of factor V at the beginning stages of DIC, the aPTT waveform slope was assessed, which if abnormal, is associated with DIC or the prediction of DIC.3233 We examined the aPTT waveform shape and the peaks of the first and second derivatives of the aPTT waveform (Figure 1F). A sub-set of patients with severe COVID-19 showed an abnormal slope at the beginning of the aPTT waveform (Figures 1G,H), suggesting progression toward DIC. Factor V was lower in COVID-19 patients with an abnormal waveform slope, compared to COVID-19 patients with a normal slope (median 116 IU/dL vs 158 IU/dL, P = .005). Since these tests were performed on the earliest available specimen, ISTH DIC scores were calculated for all COVID-19 patients and contemporaneous controls, and none of them had scores indicating acute overt DIC at the time that the earliest specimen was collected. Thus, an abnormal slope in the aPTT waveform and/or factor V below 150 IU/dL may be early markers of a DIC-like process that appear before routine laboratory tests can diagnose DIC (D-dimer, fibrinogen, platelet count, and PT).

3.6 Factor V levels in severe COVID-19 are linked to SARS-CoV-2 load in a sex-dependent manner

Note, SARS-CoV-2 differentially affects patients based on their sex, with men often presenting with more severe COVID-19.636 Coagulation parameters also vary based on sex.37 A review of our historical cases prior to the COVID-19 pandemic showed a small, but significant, difference in factor V activity in males compared to females (median 78 IU/dL and 84 IU/dL, respectively; P < .05). (Figure S2A). Thus, we investigated the possibility of a sex-dependent interaction between SARS-CoV-2 and factor V activity. Interestingly, males show a weak anticorrelation (Spearman’s R ~ −0.3) between SARS-CoV-2 RT-PCR Ct values and factor V activity (Figures S2B,C), suggesting that male COVID-19 patients with higher viral loads (lower Ct values) have higher factor V activity. The opposite trend is seen in women, where there is a weak correlation (Spearman’s R ~ 0.4) between Ct values and factor V activity (Figures S2D,E). These findings suggest a complex sex-dependent biological interaction between SARS-CoV-2 and the coagulation system of the infected patient. While many questions about possible biological mechanisms remain to be answered, these findings, together with the unique nature of the marked factor V activity elevations in severe COVID-19, raise the possibility of a specific link between SARS-CoV-2 disease biology and dysregulation of human coagulation.

4 DISCUSSION

In this COVID-19 cohort, representing severe cases with a high rate of line clots, VTE, and mortality, we observed marked elevation of factor V activity. To our knowledge, this is a novel characteristic of COVID-19. Previous studies linked elevations of D-dimer and the acute phase reactants fibrinogen and factor VIII to severe COVID-19,2124 but these are non-specific findings that appear in many disease states and thus might not on their own explain the coagulopathy of COVID-19.26810 In contrast, since initiating daily interpretation for every patient tested by our high-volume coagulation laboratory starting in 1994, we had not seen factor V activity >200 IU/dL prior to the COVID-19 pandemic, suggesting that factor V elevation could be a relatively specific finding in severe COVID-19. The observed relationships between factor V activity and SARS-CoV-2 viral load also raises the possibility of a specific relationship between factor V and COVID-19.

Recently it was discovered that megakaryocytes are abundant in the lungs, heart, and other organs of patients with COVID-19.38 Since megakaryocytes produce platelets, which normally contain about 20%-25% of the factor V in blood, this might be related to the mechanism for the high factor V in our COVID-19 cohort. Normally, factor V in blood is produced by the liver and then some of the factor V is endocytosed by megakaryocytes.

Dysregulation of factor V due to factor V Leiden is a well-known cause of a prothrombotic state.29 Concurrent elevations of factor V and factor VIII activity have also been linked to increased VTE risk in general in a pre-COVID-19 cohort.30 In the present cohort of severe COVID-19 cases, we observed a statistically significant association between DVT/PE event rates and factor V activity elevations above the reference range. Moreover, we observed a trend toward higher factor V activities in COVID-19 cases complicated by DVT/PE. These findings nominate factor V as a candidate for mechanistic studies of COVID-19 coagulopathy and as a candidate biomarker for VTE risk in COVID-19. Further study is needed to determine if factor V activity can help guide initiation and dosing of anticoagulants in COVID-19.223940 For example, in light of the findings presented here, one could hypothesize that patients with severe COVID-19 who have elevated factor V activity (>150 IU/dL) would benefit more from anticoagulation, such as low-molecular weight heparin doses above typical prophylactic doses, yet this hypothesis remains to be tested and must be balanced with the risk of bleeding in such cases.

In our severe COVID-19 cases, further progression toward a DIC-like state as assessed by aPTT waveform analysis was associated with a decrease in factor V activity, and relatively lower factor V activity was also associated with death. An abnormally sloped waveform is an early predictor of DIC.3233 In patients with COVID-19 and contemporaneous controls, first derivative peak, second derivative peak, and second derivative trough values for each aPTT waveform were also lower in patients with an abnormally sloped waveform (predicting DIC) compared to those with a normal waveform (data not shown). This is consistent with a prior report before the pandemic (not in COVID-19 patients) showing that the first and second derivative peaks are decreased in infectious DIC, but higher in patients with infections without DIC.34 Taken together, the results support that the abnormal slope identified in our study predicts DIC, which consequently may explain the significantly lower factor V and higher mortality seen in our patients with an abnormal waveform slope. These findings suggest that in severe COVID-19 cases, while elevations in factor V are common and are associated with hypercoagulability, normal or low factor V activity may be associated with progression toward DIC and risk of death. As such, measuring factor V activity could potentially be useful in two ways: first for identifying COVID-19 coagulopathy and the risk for DVT/PE, and second, for monitoring progression toward DIC in the most severe cases. Thus, factor V activity assays could have diagnostic and prognostic potential in COVID-19.

We re-measured DIC scores on the day of death for the 22 patients with COVID-19 who died, and their DIC scores had increased on average by one point and all had positive D-dimers, but the scores remained below the ISTH cut-off for acute DIC (data not shown). This could be because fibrinogen and factor V are higher with COVID-19 than with other patients at risk for DIC, therefore making it more difficult for two of the four DIC score components to cross the DIC cut-off (fibrinogen and PT, since the PT is shortened by higher fibrinogen and factor V levels). However, platelet counts also did not reach the DIC cut-off in most cases. As noted, the DIC scores could suggest that the aPTT waveform is detecting a DIC-like state that routine laboratory tests do not detect as easily.

Another reason that it is important for hematologists to know that factor V can be elevated with COVID-19 is that it can cause misdiagnosis when interpreting coagulation factor panels. In our experience, factor V elevation in COVID-19 can cause an erroneous diagnosis of vitamin K deficiency in patients with liver dysfunction or DIC (factors II, VII, and X low with normal or elevated factor V). Usually factor V would be low in liver dysfunction or DIC, and the fact that it is normal or elevated gives the false appearance of a deficiency of only the vitamin K dependent PT factors. Thus our findings are important for clinical interpretation of coagulation panels for patients with COVID-19, and could alter management decisions for some patients with suspected liver dysfunction, DIC, or vitamin K deficiency.

Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and beta-2 glycoprotein I antibodies) were detected in a high percentage of COVID-19 patients (Table 3). Repeat testing after 12 weeks would be needed to determine if these are transient due to infection or if they persist and could increase the risk for thrombosis.

A limitation of this study is the lack of mildly symptomatic or asymptomatic COVID-19 cases in our cohort, and the relatively small number of contemporaneous controls. Our ability to collect an equivalent contemporaneous control census was limited due to a markedly decreased non-COVID-19 inpatient census at the height of the pandemic at our hospital. Nevertheless, our contemporaneous control group was as severely ill as the COVID-19 group, as indicated by the similar rates of death, discharge, venous or arterial thrombosis, ECMO, and similar ages and sex ratio. The rate of line clots with COVID-19 was markedly high, and significantly higher than in the contemporaneous controls, which might help answer the question as to whether the risk for thrombosis is higher in COVID-19 than in other similarly ill ICU patients without COVID-19. Strengths of this study include the number of severe COVID-19 cases in our cohort, the depth of our coagulation testing for this cohort, and the large number of historical controls, which provide a comprehensive view of pre-COVID-19 pandemic factor V activities and other coagulation parameters. Our de-identified primary data set is included here as a resource (Table S1).

In summary, factor V activity was significantly higher in severe COVID-19 patients than in contemporaneous controls as well as historical controls, and high factor V activity was associated with thromboembolic complications of COVID-19. In contrast, patients with COVID-19 and a relatively lower factor V activity had a higher mortality and a higher incidence of an abnormally sloped waveform, which is an early predictor of DIC. Thus, our study reveals factor V perturbations as a previously unrecognized feature of severe COVID-19, adds a mechanistic candidate to ongoing investigations of COVID-19 coagulopathy with potential links to SARS-CoV-2 disease biology, and provides a foundation for future studies of COVID-19 coagulopathy diagnosis and biomarkers for guiding anticoagulation therapy in severe COVID-19.

ACKNOWLEDGEMENTS

We thank all members of the MGH Special Coagulation Laboratory for their selfless dedication to patient care during the COVID-19 pandemic and for their support of this research study, in particular: Briana Malley, Barbara Pereira, Stoja Islamovic, Ryan Mize, and Fils-Amie Lucien. We thank Sarah E. Turbett and Melis N. Anahtar for help with viral load data collection and input in analysis of the viral load data.

Nuts and bolts of COVID-19 associated coagulopathy: the essentials for management and treatment

Authors: Patrick J Lindsay, a Rachel Rosovsky, b Edward A Bittner, c and Marvin G. Chang c

ABSTRACT

Introduction

COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. Major societal guidelines that have published on the management of CAC are based on consensus of expert opinion, with the current evidence available. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management.

Methods

In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. We have also provided three clinical scenarios that implement important principles of anticoagulation in patients with COVID-19.

Conclusion

Overall, decisions should be made on a case by cases basis and based on the providers understanding of each patient’s medical history, clinical course and perceived risk.

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 in Wuhan, China. The disease was initially identified as a cluster of pneumonia cases; however, the disease dispersed rapidly and was formally declared a pandemic by the World Health Organization (WHO) in March 2020. As of June 2021, there have been greater than 172 million cases reported worldwide, including more than 3.7 million deaths [1]. The initial manifestations of SARS-CoV-2 vary, and usually occur between one and 14 days from exposure to the virus. Risk factors identified for COVID-19 include male gender, obesity, cardiovascular disease, diabetes mellitus, and older age [2–5]. The most common initial symptoms include fever, cough, fatigue, and loss of smell or taste [6]. During this period, the virus infects the epithelial cells through the angiotensin-converting enzyme 2 receptors and may eventually present as a viral pneumonia.

Although the disease primarily affects the respiratory system, multi-system organ involvement can occur with increasing severity of disease [6–8]. COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure [7,9]. This identification has led to significant clinical questions regarding the optimal prevention and management of CAC, which in turn, has led to many ongoing clinical trials. To help guide the management of these patients in the interim, numerous major societies have put forth recommendations regarding diagnosis, monitoring, and treatment of CAC. In this report, we discuss the pathogenesis, prevalence, diagnosis, and treatment of CAC to help providers understand this complicated condition and to apply best practices to the care of their patients.

From a practical perspective, societal guidelines are based on consensus of expert opinion, with the current evidence available. Major societal guidelines that have published on the management of CAC include but are not limited to Centers for Disease Control and Prevention (CDC), International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG), American Society of Hematology (ASH), American College of Chest Physicians (ACCP), Scientific and Standardization Committee of ISTH (SCC-ISTH), Anticoagulation Forum (ACF), and American College of Cardiology (ACC) [9–13]. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management. In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. To supplement the manuscript, we have provided three clinical scenarios (supplemental material) which implement important principles of anticoagulation in patients with COVID-19. Overall, decisions should be made on a case by cases basis and based on the providers understanding of each patient’s medical history, clinical course and perceived risk.

Prevalence

There is an increasing body of evidence suggesting patients with COVID-19 demonstrate a higher incidence of thromboembolic disease compared to historical data [14,15], with patients admitted to the ICU being at highest risk [16,17]. The true incidence of thromboembolism in patients admitted to hospital remains controversial with rates as low as 1% in those admitted to the medical ward and up to 69% of patients in the ICU [5,18]. In one study of 107 ICU patients, 91% of whom received VTE prophylaxis and 9% who received therapeutic anticoagulation, the prevalence of PE was 20.4%. In comparison to patients admitted to ICU for other reasons, patients with COVID-19 were 3–4 fold more likely to develop a pulmonary embolism (PE) [19]. However, there is also data to suggest that the prevalence of VTE is similar to that of patients admitted to hospital with similar non COVID illnesses, of similar severity [20,21]. The reported increase in prevalence of VTE remains despite thromboprophylaxis in some studies and not in others [15,22]. In addition to macro-vascular thrombosis, autopsy studies have demonstrated significant microvascular thrombosis in the lungs of patients who have died from COVID-19’s [7,23]. It is hypothesized that these microvascular thrombi cause end organ dysfunction such as renal failure [7,23,24]. Although the prevalence of microvascular thrombosis is yet to be determined, it may be greater than in patients with non COVID respiratory viral illnesses [24].

The majority of data on the prevalence of thromboembolic disease in patients with COVID-19 have been observational studies of VTE. However, there is emerging evidence suggesting an increase in arterial thromboses in COVID-19 patients as well. One study identified five cases of acute ischemic stroke in a two-week period in COVID-19 patients under the age of 50, in comparison to 0.7 large vessel strokes per two-weeks prior to the pandemic [25]. There are also studies reporting an increase in the prevalence of acute limb ischemia in patients hospitalized with COVID-19 compared to the general population [26,27].

The micro- and macro-thrombosis associated with CAC often leads to multisystem complications resulting in increased morbidity and mortality [8]. Despite many policies aimed at curbing viral spread, many countries/regions still see their weekly ICU admissions related to COVID-19 increasing [1]. With the introduction of vaccinations and targeted novel treatments for COVID-19, the prevalence and incidence of CAC and its related complications will hopefully decrease.

Pathogenesis

Although the pathogenesis of CAC has not been fully elucidated, there are multiple contributing factors that include hypercoagulability, endothelial dysfunction and abnormal blood flow (especially in the pulmonary vasculature) [28]. In severe COVID-19 disease, excess proinflammatory cytokines trigger the coagulation system resulting in a hypercoagulable state [29]. In addition to direct damage by viral invasion, this cytokine storm also results in endothelial injury and dysfunction, leading to endothelial cell activation [30]. The dysfunctional endothelial cells produce excess thrombin as well as shutdown fibrinolysis, leading to a prothrombotic state [31]. Furthermore, infection induced inflammatory changes in endothelial cells have been shown to increase coagulation biomarkers, including factor VIII, von Willebrand Factor (vWF), fibrinogen and P-selectin [24,32]. All of these mechanisms create an imbalance in the normal hemostatic system, with a resulting prothrombotic state, manifesting as both macro and micro-vascular thrombosis [30].

In patients with CAC, biomarkers supporting the hypercoagulability pathogenesis have been demonstrated to be elevated in vivo. Specifically, the procoagulant markers Factor VIII, Von Willebrand antigen and Von Willebrand activity have been found to be markedly elevated in patients with COVID-19 who develop thromboembolism [33]. Biochemically, this hypercoagulable state appears to be most significant in those patients with the most severe form of the disease. One study demonstrated that many prothrombotic markers are increased above their upper limit of normal in patients with COVID-19, with the greatest increase in patients admitted to the intensive care unit (ICU) as compared to non-ICU patients [34]. In support of this recognition, descriptive studies using viscoelastic hemostasis assays including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) in patients with COVID-19 are more consistent with a hypercoagulable state rather than acute disseminated intravascular coagulation (DIC). For example, in a study of 24 ICU patients with COVID-19, TEG parameters demonstrated a hypercoagulable state with decreased K (kinetic) time (increased fibrinogen activity), increased alpha angle (increased fibrinogen activity), increased maximum amplitude (Ma) (increased platelet activity), and decreased LY30 (decreased fibrinolysis) [33]. These findings suggest decreased time to clot accumulation, increased strength and stability of the clot, and decreased breakdown of the clot. This study also found that fibrinogen, D-dimer, C-reactive protein, Factor VIII, vWF and protein C were all increased, while platelet count was normal or increased, prothrombin time (PT) and partial thromboplastin time (PTT) were near normal and antithrombin (AT) was marginally decreased. These discoveries are all consistent with a hypercoagulable state rather than DIC where one would expect decreased platelet count and increased PT and PTT. In another study of 21 ICU patients with COVID-19, the TEG MA was significantly higher in those with high thrombotic events (≥2 thrombotic events, defined as an arterial, central venous, or dialysis catheter or filter thromboses) compared to those with low thrombotic events (0–1 thrombotic events) [35]. Moreover, the mean fibrinogen and D-dimer levels were elevated in those with high thrombotic events although there was no significant differences in PT, international normalized ratio (INR), PTT or platelets between the two groups.

D-dimer elevation has also been associated with severity of COVID-19 and may be useful as a prognostic marker [36]. D-dimers are fibrin degradation product which can be measured in the blood after a clot is broken down through fibrinolysis [37]. As a result, elevated D-dimer levels are suggestive of venous thromboembolism (VTE), pulmonary embolism (PE) or DIC; however, it is also elevated in the context of systemic inflammation, which has been demonstrated in numerous clinical settings [20,38]. With COVID-19 stimulating a systemic inflammatory response, it is likely that D-dimers are elevated whether thromboembolic disease is present or not.

Despite the increased inflammatory response associated with COVID-19, patients are less likely to develop a reactive thrombocytosis and often have a mild thrombocytopenia [39]. Platelets in patients with COVID-19 have been found to have increased activity compared to healthy patients, with increased aggregation, thromboxane generation and platelet activation [40]. It is unclear whether these changes in platelet function are associated with an increased risk of thrombosis [39,41]. One study in hospitalized patients with COVID-19 found that a platelet count >450 × 109/L on admission was associated with an increased risk of VTE (adjusted OR of 3.56 [95% CI, 1.27–9.97]) [20]. However, another study of 1476 patients hospitalized with COVID-19 found that the platelet count was inversely associated with risk of in-hospital mortality, although, it is unclear if this increased risk in mortality was a result of consumption in the context of DIC [42]. The appropriate workup of a decreasing platelet count and thrombocytopenia should be pursued in the COVID-19 patient as it would be for non-COVID patients. Given that the majority of patients with COVID-19 receive some form of heparin, a diagnosis of heparin-induced thrombocytopenia (HIT) may be considered, and the subsequent use of Platelet Factor 4 (PF4) and platelet serotonin release assay (SRA) can be used to diagnose this potentially life-threatening condition.

Upon initial screening, many patients with COVID-19 have an elevated PTT in the context of minimal clinical bleeding. This finding raises the question of whether the thrombotic related biomarker, lupus anticoagulant is affected by COVID-19 disease [43,44]. The lupus anticoagulant is an immunoglobulin which binds to phospholipids and proteins associated with the cell membrane. When evaluated in vitro, these immunoglobulins interfere with the phospholipids which induce coagulation, leading to a prolonged PTT. In vivo, however, these antibodies are often prothrombotic [45]. Two studies of patients with COVID-19 and prolonged PTT on initial presentation have demonstrated high rates of lupus anticoagulant positivity [15,43]. However, it has been noted that upon repeat testing, many patients become negative, suggesting that the lupus anticoagulant positivity may be transient and associated with severe viral illness [46]. Overall, more studies are needed to determine if lupus anticoagulant is truly associated with COVID-19 and related to an increase in VTE, and if so, whether the use of anticoagulation should be changed based on the presence of this abnormality [47].

Antithrombin deficiency, a marker of thrombophilia, can be acquired or inherited and may place patients at increased risk of thrombosis. Antithrombin is a natural anticoagulant that inhibits thrombin and factor Xa, thereby helping to prevent thrombosis. There have been case reports of AT deficiency in COVID-19 patients which may place such patients are at higher risk of thrombosis [48]. However, as with the other biochemical testing, more studies are needed to determine if this knowledge is related to adverse outcomes such as thrombosis and if these results should be used to help guide anticoagulation practices.

Manifestations

Since the emergence of COVID-19, the associated increased risk of thrombotic complications such as deep vein thrombosis (DVT), pulmonary embolism (PE) and microvascular thrombosis have been well described [17]. The spectrum of CAC is broad and may present with either or both arterial and venous thromboembolic disease [22]. In general, the majority of the thrombotic events when present are DVT or PE, however catheter associated thrombosis, other venous thrombosis and arterial events, including stroke, acute limb ischemia, bowel ischemia and myocardial infarction, have been reported [14]. Patients also appear to be at risk for microvascular thrombosis. Multiple autopsy studies have demonstrated microvascular thrombosis in the lungs of patients who have died from COVID-19’s, suggesting the multisystem organ failure often seen in COVID-19 may be a result of microvascular thrombosis [23,49].

Bleeding was initially believed to be much less common than thrombosis in patients with COVID-19, however, further data has emerged suggesting the rates of bleeding may be similar to the rates of thrombosis [20]. One autopsy study involving 82 patients found that, 6% died from hemorrhage and that over 80% of patients had some kind of hemorrhagic complication [50]. Another study of 400 hospitalized COVID-19 patients found a radiographically confirmed VTE rate of 4.8% (95% confidence interval [CI], 2.9–7.3), which was identical to the overall bleeding rate of 4.8% (95% CI, 2.9–7.3) [20].

Although clinically significant DIC is uncommon in COVID-19 patients, and if suspected, it is important to identify and aggressively treat the underlying etiology, including any superimposed bacterial infections in addition to managing the coagulopathy [51].

Diagnosis

Currently, there are no diagnostic criteria for CAC. At present, there is no evidence or guideline to support routine screening for VTE, PE or other thrombotic complications in patients with COVID-19. However, the threshold to investigate for DVT or PE should be low given the frequency with which these complications may occur in patients with COVID-19. If thromboembolic disease is suspected, appropriate investigations should depend on the clinical context, acuity of disease and resources available. A position paper from the National Pulmonary Embolism Response Team (PERT) Consortium provides a step wise approach to a suspected PE, which includes ordering a computed tomography pulmonary angiogram (CTPA) if available [52]. If the computed tomography (CT) is not available or the patient is too unstable, a lower limb ultrasound to assess for a proximal DVT, or an echocardiography to assess right heart strain may be pursued. However, it should be noted that neither of these investigations are sensitive. If none of those modalities are available, nor do they rule in a PE/DVT, and there is a high clinical suspicion for a PE, therapeutic anticoagulation should be considered pending no absolute contraindications [52].

In patients with COVID-19, many routine biomarkers of the coagulation cascade have been found to fall outside the normal range, including PTT/PT, platelet count, and fibrinogen [53]. Derangement of these tests may suggest increased disease severity. A D-dimer elevated by three- to fourfold, a prolonged prothrombin time and a platelet count <100 × 109 are all predictors of a poorer prognosis [13,54]. Despite this evidence, most of the major societal guidelines (ACF, ACCP, SCC-ISTH, CDC) have either not recommended nor commented on the routine monitoring of laboratory values to guide management, risk stratification, or triage of patients with COVID-19. For instance, the SCC-ISTH guidelines state that further study is required before using laboratory testing for risk stratification and triage of CAC. The CDC guidelines state that there is a lack of prospective data demonstrating laboratory testing as a way to risk stratify patients, and that there are insufficient data to recommend for or against using laboratory values to guide management. If a patient is bleeding or has a confirmed, or is highly suspected of having a VTE; then, the patient should be treated based on clinical context. Repeat testing of CBC, coagulation studies, fibrinogen, and d-dimer should also be performed based on the clinical setting.

When considering the use of D-dimer assays, a negative D-dimer can be useful in excluding a VTE in patients with COVID-19. However, a positive D-dimer does not necessarily equate to a diagnosis of VTE as this test is not specific and can be elevated in many other pathological and non-pathological processes [55]. Moreover, studies have demonstrated that D-dimer levels tend to be higher in severe COVID-19 cases and may be used as a potential prognostic marker [56]. Despite this connection, none of the major societal guidelines recommend routine monitoring of D-dimer nor using it to guide anticoagulation practices.

Treatment

At least seven major societal guidelines have been published to address prevention and treatment of CAC in the critical care settings, with all authors of these guidelines having prior expertise in the management of VTE [57]. Some of the societies with published guidelines include Centers for Disease Control and Prevention (CDC), International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG), American Society of Hematology (ASH), American College of Chest Physicians (ACCP), Scientific and Standardization Committee of ISTH (SCC-ISTH), Anticoagulation Forum (ACF), and American College of Cardiology (ACC) [9–13]. Currently, there are no separate recommendations for prevention or management of arterial thrombosis in CAC; therefore, this patient population should follow the recommendations of the clinical syndrome in question (e.g., acute myocardial infarction requires dual antiplatelets).

Here, we review the recommendations for prevention, treatment, and monitoring of anticoagulation for CAC in the critical care setting by reviewing the common questions. A summary of the recommendations can be seen in Table 1Table 2 and Table 3:

  1. How should biomarkers be used to guide management?
  2. What are the preferred prophylactic anticoagulation regimens?
  3. When should the intensity of anticoagulation be increased?
  4. What are the preferred therapeutic anticoagulation regimens?
  5. When are thrombolytics recommended?
  6. When should anticoagulation be held?
  7. What is the utility of mechanical thromboprophylaxis?
  8. What is the appropriate method of monitoring anticoagulation?
  9. What is the recommended approach for correction of active bleeding?
  10. Should patients receive post-discharge prophylactic anticoagulation and if so, what regimens are recommended?

Table 1.

Major societal recommendations regarding using biomarkers to guide anticoagulation, choice of prophylactic anticoagulation and when to consider increasing intensity of anticoagulation

 How should biomarkers be used to guide management?What are the preferred prophylactic anticoagulation regimens?When should the intensity of anticoagulation be increased?
CDCInsufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions.LMWH or UFH (standard dosing). Insufficient data to recommend for or against the increase of anticoagulation intensity outside of a
clinical trial.
Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation. Insufficient data to recommend for or against the increase of anticoagulation intensity outside the context of a clinical trial. Mentions patients who have thrombosis of catheters or extracorporeal filters should be treated accordingly to standard institutional protocols for patients without COVID-19.
ISTH-IGNot mentionedLMWH (standard dosing)No specific recommendations
ACFBiomarker thresholds such as D-dimer for guiding anticoagulation management should not be done outside the setting of a clinical trial.Suggests an increased intensity of venous thromboprophylaxis be considered for critically ill patients# (i.e. LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion) that they state is based largely on expert opinion.Consider when a clinically suspected thromboembolic event is present or highly suspected despite imaging confirmation.
ASHNo particular change to regimen recommended for patients with lupus like inhibitors. TEG and ROTEM should not be used routinely to guide management.LMWH over UFH (standard dosing) to reduce exposure unless risk of bleeding outweighs risk of thrombosis.Consider increasing the intensity of anticoagulation regimen (i.e. from standard to intermediate intensity, from intermediate to therapeutic intensity) or change anticoagulants in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e. ECMO, CRRT) on prophylactic anticoagulation regimens.
ACCPNot mentionedLMWH (standard dosing)Patients with PE or proximal DVT.
SCC-ISTHD-dimer levels should not be used solely to guide anticoagulation regimens.LMWH or UFH. Intermediate intensity LMWH can be considered in high risk critically ill patients (50% of responders) and may be considered in non-critically ill hospitalized patients (30% of respondents). Mentions that there are several advantages of LMWH over UFH including once vs twice or more injections and less heparin-induced thrombocytopenia. Regimens may be modified based on extremes of body weight (50% increase in dose if obese), severe thrombocytopenia*, or worsening renal function.Therapeutic anticoagulation should not be considered for
primary prevention until randomized controlled trials are available. Increased intensity of anticoagulation regimen (i.e. from standard or intermediate intensity to therapeutic intensity) can be considered in patients without confirmed VTE or PE but have deteriorating pulmonary status or ARDS.
ACCFurther investigation is required to determine the role of antiphospholipid antibodies in pathophysiology of COVID-19- associated thrombosis. D-dimer > 2 times the upper limit may suggest that patient is at high risk for VTE and consideration of extended prophylaxis (up to 45 days) in patients at low risk of bleeding. Mentions that therapeutic anticoagulation is the key to VTE treatment. Does not make distinction between confirmed or suspected VTE. Hemodynamically stable patients with submassive PE should receive anticoagulation rather than thrombolytics

Open in a separate window

Table 2.

Major societal recommendations regarding therapeutic anticoagulation regimens, when thrombolytics should be used and when anticoagulation should be held

 What are the preferred therapeutic anticoagulation regimens?When should anticoagulation be held?When are thrombolytics recommended?
CDCStandard regimens for non-COVID-19 patients.Active hemorrhage or severe thrombocytopenia (Platelet count not defined)Insufficient data to recommend for or against thrombolytic therapy outside the context of a clinical trial. In pregnant patients, thrombolytic therapy should only be used for acute PE with life-threatening hemodynamic instability due to risk for maternal hemorrhage.
ISTH-IGNot mentionedHold when signs of active bleeding or platelet count < 25 x 109/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis.Not mentioned
ACFLMWH over UFH whenever possible to avoid additional laboratory monitoring, exposure, and personal protective equipment. In patients with AKI or creatinine clearance < 15–30 mL/min, UFH is recommended over LMWH.Active bleeding or profound thrombocytopenia (Platelet count not defined)Consider if clinical indication such as STEMI, acute ischemic stroke, or high-risk massive PE with hemodynamic instability. Otherwise, it is not recommended outside context of a clinical trial.
ASHLMWH or UFH over direct oral anticoagulants due to reduced drug-drug interactions and shorter half-life.Thromboprophylaxis is recommended even with abnormal coagulation tests in the absence of active bleeding and held only if platelet count < 25 x 109/L or fibrinogen < 0.5 g/L. Abnormal PT or PTT is not a contraindication to thromboprophylaxis. Therapeutic anticoagulation may need to be held if platelet count < 30–50 x 109/L or fibrinogen < 1.0 g/L.Not mentioned
ACCPLMWH or fondaparinux over UFH. UFH preferred in patients at high bleeding risk and in renal failure or needing imminent procedures. Recommend increasing dose of LMWH by 25–30% in patients with recurrent VTE despite therapeutic LMWH anticoagulation.Not mentionedThrombolytics over no such therapy in patients with objectively confirmed PE with hemodynamic instability or signs of obstructive shock who are not at high risk of bleeding. Peripheral thrombolysis recommended over catheter-directed thrombolysis
SCC-ISTHNot mentionedNo specific recommendations. Reports that 50% of respondents report holding if platelet count < 25 x 109/L.Not mentioned
ACCMedication regimen likely to change depending on comorbidities (i.e. renal or hepatic dysfunction, gastrointestinal function, thrombocytopenia). Parenteral anticoagulation (i.e. UFH) may be preferred in many ill patients given it may be withheld temporarily and has no known drug-drug interactions with COVID-19 therapies. LMWH may be preferred in patients who are unlikely to need procedures as there are concerns with UFH regarding the time to achieve therapeutic PTT and increased exposure to healthcare workers. DOACs have advantages including lack of monitoring that is ideal for outpatient management but may have risks in settings of organ dysfunction related to clinical deterioration and lack of timely reversal at some centers.In patients with moderate or severe COVID-19 on chronic therapeutic anticoagulation who develop suspected or confirmed DIC without overt bleeding,
it is reasonable to consider the indication of anticoagulation and risk of bleeding for adjusting dose or discontinuation of anticoagulation. The majority of authors recommended reducing the intensity of anticoagulation unless there was an exceedingly high risk of thrombosis.
A multidisciplinary PERT may be helpful for intermediate and high-risk patient with VTE. For hemodynamically high-risk PE, systemic fibrinolysis is indicated with catheter-based therapies reserved for situations that are not amenable to systemic fibrinolysis. Patients with hemodynamically stable intermediate-low or intermediate-high risk PE should receive anticoagulation and rescue systemic fibrinolysis should be considered in cases of further deterioration with catheter-directed therapies as an alternative. Catheter directed therapies should be limited to most critical situations given minimal data showing mortality benefit. When considering fibrinolysis vs percutaneous coronary intervention for STEMI, clinicians should weigh risks and severity of STEMI presentation, severity of COVID-19 in patient, risk of COVID-19 to individual clinicians and healthcare system.

Open in a separate window

Table 3.

Major societal recommendations regarding monitoring of anticoagulation, correction of active bleeding and prophylactic anticoagulation post-discharge

 What is the appropriate method of monitoring anticoagulation?What is the recommended approach for correction of active bleeding?Should patients receive post-discharge prophylactic anticoagulation
CDCPer standard of care for patients without COVID-19Not mentionedRoutine venous thromboprophylaxis post-discharge is not recommended. FDA-approved prophylactic anticoagulation regimen (rivaroxaban and betrixaban) can be considered if high risk for VTE and low risk for bleeding using criteria from clinical trials.
ISTH-IGNot mentionedTransfuse to keep platelet count > 50 x 109/L, fibrinogen > 1.5 g/L, PT ratio < 1.5No specific recommendations
ACFRecommend monitoring anti-Xa levels to monitor UFH due to potential baseline PTT abnormalities. Reasonable to monitor anti-Xa or PTT in patients with normal baseline PTT levels and do not exhibit heparin resistance (> 35,000 u heparin over 24 h).Not mentionedNo evidence for anticoagulation beyond hospitalization, but reasonable to consider if low risk for bleeding and high risk for VTE including intubated, sedated, and paralyzed for multiple days.
ASHMay necessitate anti-Xa monitoring of UFH given artefactual increases in PTT.Transfuse one adult unit of platelets if platelets < 50 x 109/L, give 4 units of plasma if INR > 1.8, and fibrinogen concentrate (4 g) or cryoprecipitate (10 u) if fibrinogen < 1.5 g/L. In patients with severe coagulopathy and bleeding can consider 4 F-PCC (25 u/kg) instead of plasma.Reasonable to consider FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) or aspirin if criteria from trials for post-discharge thromboprophylaxis are met.
ACCPMonitor anti-Xa levels in all patients receiving UFH given potential of heparin resistance.Not mentionedCan be considered in patients who are at low risk of bleeding if emerging data suggests a clinical benefit.
SCC-ISTHNo specific recommendations. Mentions that expert clinical guidance statements and clinical pathways from large academic healthcare systems target an anti-factor Xa level of 0.3–0.7 IU/mL for UFH.Not mentionedEither LMWH or FDA-approved post-discharge prophylactic anticoagulation regimen (rivaroxaban and betrixaban) should be considered in patients with high VTE risk criteria. Duration is 14 days at least and up to 30 days. Of note, they report that none of the respondents recommended aspirin for post-discharge thromboprophylaxis.
ACCNot mentionedTransfuse platelets to maintain platelets > 50 x 109/L in DIC and active bleeding or if platelets < 20 x 109/L in patients at high risk of bleeding or requiring invasive procedures. FFP (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or PTT ratios (> 1.5 times normal) or decreased fibrinogen (< 1.5 g/L). Fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (< 1.5 g/L). Prothrombin complex concentrate if FFP is not possible. Tranexamic acid should not be used routinely in patients with COVID-19-associated DIC given the existing data.Reasonable to consider extended prophylaxis with LMWH or DOACs for up to 45 days in patients at high risk for VTE (i.e. D-dimer > 2 times the upper limit, reduced mobility, active cancer) and low risk of bleeding.

Open in a separate window

How should biomarkers be used to guide management?

Despite CAC being associated with biomarker abnormalities, none of the major societies to date recommend the use of biomarkers to help guide inpatient anticoagulation decisions. Most notably, D-dimer elevation has been associated with severity of COVID-19, and may be useful as a prognostic marker [36]. With COVID-19 triggering a systemic inflammatory response, it is likely D-dimers will be elevated whether thromboembolic disease is present or not. Therefore, none of the major societies recommend any role for routine monitoring of D-dimer, with its use limited to risk stratification as per ISTH-IG and ASH. Furthermore, the CDC guidelines specifically state that there is insufficient data to recommend for or against using hematologic and coagulation parameters to guide management decisions in CAC. The ACF guidelines also states that using biomarkers such as D-dimer for guiding anticoagulation management should only be done in the setting of a clinical trial. One society’s guidelines, the ACC, mentions a potential role for the use of biomarkers in decision-making: in patients with a D-dimer >2 times the upper limit may be considered for extended prophylaxis (up to 45 days) if patients are at low risk of bleeding. Currently, a multicenter randomized controlled trial is underway to evaluate the efficacy and safety of antithrombotic strategies in COVID-19 adults not requiring hospitalization at time of diagnosis. The trial is designed to compare aspirin, low dose and regular dose apixaban prophylaxis and placebo, with the results of VTE compared across increasing D-dimer levels [58]. This study will help ascertain the value of baseline D-dimer levels in this population. Another clinical trial, ATTACC, was performed to determine whether therapeutic anticoagulation improved organ support-free days [59]. This study also assessed the efficacy of therapeutic anticoagulation across subgroups based on initial D-dimer level. The D-dimer level did not appear to be useful in risk stratification.

When considering other biomarkers, none of the major societal guidelines recommend a change to the anticoagulation regimen in patients with COVID19 who have positive antiphospholipid antibodies or any other biomarker abnormality. Finally, although viscoelastic hemostasis assays such as TEG and ROTEM may suggest hypercoagulability, the ASH guidelines specifically recommend against the routine use of these tests to guide management.

What are the preferred prophylactic anticoagulation regimens?

VTE prophylaxis should be provided to all hospitalized patients with COVID-19 unless contraindicated. The majority of societal guidelines have recommended once daily administration using low molecular weight heparin (LMWH) to reduce healthcare worker exposure given the lower frequency of administration compared to unfractionated heparin (UFH), to conserve personal protective equipment and because it has a lower risk for heparin-induced thrombocytopenia. LMWH may not be preferred over UFH when the risk of bleeding outweighs the risk of thrombosis and in patients with renal dysfunction (i.e. creatinine clearance <30 mL/min). An additional benefit of heparin is its possible anti-inflammatory effects in both the vasculature and the airway [59]. With COVID-19 stimulating a proinflammatory state in both the airways and vasculature, heparin not only provides value as an anticoagulant but also may exert benefit as an anti-inflammatory agent [60]. The efficacy of heparin as an anti-inflammatory agent in patients with COVID-19 warrants further investigation.

The dosing of prophylactic anticoagulation remains controversial given that some studies have demonstrated that up to one quarter of patients with COVID in the ICU develop VTE despite thromboprophylaxis [17,22,61]. As a result, it has been suggested that intermediate or therapeutic doses of LMWH could be considered [10,12,62,63]. There is emerging evidence that initiation of therapeutically dosed anticoagulation in place of prophylactically dosed anticoagulation may decrease the need for mechanical ventilation and other life supporting interventions in non-critically ill hospitalized population but this has not been published in a peer review journal [59]. With thrombosis being a prominent feature of COVID-19, three clinical trials conducted a multiplatform clinical trial (ATTACC) to determine whether therapeutic anticoagulation improved organ support-free days (ICU level care and receipt of mechanical ventilation, vasopressors, extracorporeal membrane oxygenation (ECMO) or high-flow nasal oxygen). Although full results have not been published, the pre-publication, non-peer-reviewed, interim results show that patients who are moderately ill (hospitalized but not on ICU organ-support) had improved organ support-free days with therapeutically dosed anticoagulation in comparison to standard of care [64]. However, full-dose anticoagulation when started in critically ill patients with COVID19 was not found to be beneficial and may be harmful. Current societal guidelines which do not account for these interim findings do not recommend the use of therapeutically dosed anticoagulation as a replacement for prophylactically dosed anticoagulation. Until the results of these studies are published and validated, following current guidelines seems reasonable. Of note, ASH published new guidelines in March 2021 which continue to recommend prophylactically dosed anticoagulation in the context of hospitalized patients diagnosed with COVID-19 [65].

A retrospective analysis of 4389 COVID-19 patients found that compared with no anticoagulation, therapeutic and prophylactic anticoagulation were associated with a lower in-hospital mortality and intubation. Furthermore, when anticoagulation was initiated ≤48 h from admission, there was no statistically significant difference in outcomes between the patients that received therapeutic vs. prophylactic doses [66].

Finally, aspirin has been a proposed treatment for CAC given its anti-inflammatory and anti-thrombotic effects [67–70]. A recent meta-analysis demonstrated no association between the use of aspirin and mortality in COVID-19 [71]. The RECOVERY trial conducted a multicentre randomized control trial (RCT) testing aspirin against usual care [72]. The results of this trial released in preprint showed that aspirin was not associated with a reduction in 28-day mortality or in risk of progressing to invasive mechanical ventilation or death.

When to increase intensity of anticoagulation

At this stage, there is no consensus as to when to increase the intensity of anticoagulation with the exception of documented thromboembolism. The ACF states that increased intensity of anticoagulation regimen (i.e., from standard or intermediate intensity to therapeutic intensity) can be considered in patients, without confirmed VTE or PE, who have deteriorating pulmonary function or ARDS without clear underlying cause. They also suggest an increased intensity of venous thromboprophylaxis could be considered for critically ill patients (i.e. LMWH 40 mg SC twice daily, LMWH 0.5 mg/kg subcutaneous twice daily, heparin 7500 SC three times daily, or low-intensity heparin infusion). The SCC-ISTH guidelines state that intermediate intensity LMWH may be considered in high risk critically ill patients. They also suggest anticoagulation prophylaxis regimens may be modified based on extremes of body weight. If the patient is obese (BMI >30 kg/m2), an increase of 50% in dose has been deemed reasonable.

ASH guidelines state that in patients who have recurrent thrombosis of catheters and extracorporeal circuits (i.e., ECMO, continuous renal replacement therapy (CRRT)) on prophylactic anticoagulation regimens, may have the intensity of anticoagulation increased (i.e. from standard to intermediate intensity, from intermediate to therapeutic intensity) or change the anticoagulant regimen. The CDC guidelines state that patients who have thrombosis of catheters or extracorporeal filters should be treated according to standard institutional protocols (which may include increasing anticoagulation intensity) for patients without COVID-19. Our institution, the Massachusetts General Hospital found that a low dose heparinized saline protocol is associated with improved duration of arterial line patency in critically ill COVID-19 patients [73]. Additionally, we also found that a protocol where systemic unfractionated heparin is dosed by anti-factor Xa levels lead to lower rates of CRRT filter clotting and loss [74].

What is the preferred therapeutic anticoagulation regimens?

Several of societal guidelines (ACF, ACCP, and ACC) recommend LMWH over UFH to avoid additional laboratory monitoring, minimize healthcare worker exposure, preserve personal protective equipment (PPE) utilization, benefit from the greater anti-inflammatory effects, and decrease time to achieve therapeutic anticoagulation levels. LMWH is preferred over UFH when no imminent procedures are planned, the risk of thrombosis is greater than the risk of bleeding, and patients do not have significant renal failure. In addition to LMWH, the ACCP guidelines also recommend fondaparinux over UFH with a similar rationale, and fondaparinux may be used in patients with suspected or confirmed HIT. UFH may be preferred in patients who need imminent procedures, are at high risk of bleeding or have significant renal failure. In patients with recurrent VTE despite therapeutic LMWH anticoagulation, the ACCP guidelines recommends increasing the dose of LMWH by 25–30%. While direct oral anticoagulants (DOACs) have advantages including no need for monitoring, none of the major societal guidelines recommend their use in this critical care setting given their lack of timely reversal at some hospitals. Parenteral anticoagulants also have no known drug–drug interactions with COVID-19 therapies, and this may not be true with DOACs.

When are thrombolytics recommended?

Given autopsy findings of patients with COVID-19 revealing significant pulmonary micro- and macro-thrombosis, the question has been raised as to whether there is a role for thrombolytic therapy. There are a number of case series that suggest the use of thrombolytics in patients with severe ARDS and COVID-19 may lead clinical improvement [75,76]. Given this potential benefit, there are a number of ongoing clinical trials investigating the use of parenteral and nebulized thrombolytic therapy for patients with severe COVID-19 ARDS. If a PE is suspected, consultation with a pulmonary embolism response team (PERT) is advised if available. These teams can provide expert advice regarding issues related to diagnosis and management of a PE in patients with COVID-19. If PERT consultation is unavailable, the National PERT Consortium paper has provided an algorithm to assist in decision-making for patients with a suspected PE [52]. Our institution, the Massachusetts General Hospital, has a PERT team which is a multidisciplinary team composed of experts from cardiology, cardiac surgery, emergency medicine, hematology, pulmonary and critical care, radiology, and vascular medicine and delivers immediate and evidence-based care to patients with suspected or confirmed high risk PE [77]. When major societal guidelines do recommend thrombolytic therapy, it is in the clinical context where their use would otherwise be clinically indicated such as STEMI, acute ischemic stroke, or high-risk massive PE with hemodynamic instability and when the benefits outweigh the risks of administration. In general, thrombolytic therapy is not recommended in patients who have a PE and are hemodynamically stable [57].

When to hold anticoagulation?

Most major society’s guidelines (CDC, ISTH-IG, ACF, ASH, SCC-ISTH) advise holding therapeutic and prophylactic anticoagulation in patients who have significant active bleeding and/or severe thrombocytopenia. Both the ACF and SCC-ISTH guidelines suggest holding anticoagulation if platelet count <25 x 10^9/L. ASH recommends holding prophylactic anticoagulation if platelet count is <25 x 10^9/L or fibrinogen <0.5 g/L, and holding therapeutic anticoagulation may necessary if platelet count is <30–50 x 10^9/L or fibrinogen <1.0 g/L. Of note, many patients with COVID-19 may have abnormal baseline PT or PTT, which is not a contraindication to thromboprophylaxis according to the ISTH-IG and ASH guidelines. Therefore, PT and PTT should not be used as a guide to hold prophylactic or therapeutic anticoagulation.

What is the utility of mechanical thromboprophylaxis?

Most of the major society’s guidelines (ACF, ASH, ACCP, SCC-ISTCH, and ACC) recommend or suggest mechanical thromboprophylaxis when pharmacological thromboprophylaxis is contraindicated. Intermittent pneumatic compression devices are the preferred type of mechanical thromboprophylaxis. ACCP suggests against the additional use of mechanical thromboprophylaxis in critically ill patients receiving pharmacological prophylaxis but mentions that its addition is unlikely to cause harm.

What is the appropriate method of monitoring anticoagulation?

Monitoring of patients receiving therapeutic anticoagulation with LMWH

Currently, none of the major society guidelines recommend the routine monitoring of anti-Xa levels of patients receiving LMWH. LMWH is generally preferred if there are no contraindications given the added benefit of not needing routine monitoring. However, the ISTH-IG guidelines state that monitoring of LMWH is advised in patients with severe renal impairment, a patient population generally for which LMWH is not routinely recommended. However, the ACCP guidelines state that body weight adjusted doses for LMWH do not require laboratory monitoring in majority of patients, and the ACF guidelines state that anti-Xa level monitoring is not recommended in patients with elevated PTT levels given the lack of evidence on outcomes for thrombosis or bleeding.

Monitoring of patients receiving therapeutic anticoagulation with UFH

The PTT measures the intrinsic coagulation pathway and is the most commonly used test to monitor UFH [78]. It is not uncommon for patients with COVID-19 to have baseline coagulation abnormalities of PT and PTT. Although these abnormalities are not contraindications to anticoagulation, it may lead to difficulties measuring heparin effectiveness. When in doubt, the majority of society guidelines (ACF, ASH, ACF and ACCP) advise that therapeutic anticoagulation should be monitored with an anti-Xa level rather than PTT. The SCC-ISTH guideline does not make any particular recommendations but does mention that expert clinical guidance statements and clinical pathways from large academic healthcare systems target for therapeutic anticoagulation, an anti-factor Xa level of 0.3–0.7 IU/mL for UFH. While the ACF guideline recommends monitoring of anti-Xa levels to monitor UFH due to potential baseline PTT abnormalities and heparin resistance (>35,000 U heparin over 24 hours), they also mention that it is reasonable to monitor anti-Xa or PTT in patients with normal baseline PTT levels and in those unlikely to have heparin resistance. There is evidence in the value of implementing an anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels. At our institution, The Massachusetts General Hospital, we found that patients with COVID-19 infection on CRRT had lower rates of CRRT filter clotting and loss when using this protocol where systemic unfractionated heparin was dosed by anti-factor Xa levels [74]. However, this needs to be studied further in clinical trials.

Heparin resistance

An important consideration when making decisions about DVT prophylaxis and monitoring of anticoagulation in COVID-19 patients is the concern for heparin resistance, which has been well documented [79]. Heparin resistance should be suspected when disproportionately large doses of heparin are required to achieve therapeutic anticoagulation. This problem is usually due to low heparin concentrations, which results from binding of heparin to acute phase proteins in the context of systemic inflammation. There is also some evidence of AT deficiency in COVID-19 patients which may contribute to suspected heparin resistance [48]. Heparin functions as an anticoagulant by binding to AT, activating it, and then inhibiting clotting factors, most notably factor Xa [80]. A way to measure the capacity of the heparin-AT complex is with anti-Xa levels. It has been well documented that patients with COVID-19 may have artefactual increases in PTT, and therefore measuring anti-Xa levels may be a more accurate way to assess the level of anticoagulation in these situations. Additionally, LMWH can’t be measured with PTT, and as a result, anti-Xa levels may be used to ensure appropriate anticoagulation levels have been achieved if necessary. Unfortunately, not all centers have the capacity to monitor anti-Xa levels.

What is the recommended approach to control active bleeding?

When addressing active bleeding, the major society guidelines recommend holding both prophylactic and therapeutic anticoagulation. However, only the ISTH-IG, ASH and ACC guidelines provide specific recommendations for blood product replacement. The ISTH-IG guidelines recommend transfusing to keep platelet count >50 x 10^9/L, fibrinogen concentrate to target fibrinogen >1.5 g/L, and FFP to target PT ratio <1.5. ASH guidelines recommend transfusing one adult unit of platelets if platelet count <50 x 10^9/L, 4 units of plasma if INR > 1.8 and fibrinogen concentrate (4 g) or cryoprecipitate (10 units) if fibrinogen <1.5 g/L. The ACC guidelines recommend transfusing platelets in patients with active bleeding or requiring invasive procedures if platelet count <20 x 10^9/L, and providing FFP (15 to 25 mL/kg) in patients with active bleeding with either prolonged PT or PTT ratios (>1.5 times normal) as well as transfusing fibrinogen concentrate or cryoprecipitate in patients with persisting severe hypofibrinogenemia (<1.5 g/L).

If volume overload is a concern in patients with active bleeding and severe COVID-19, ASH and ACC guidelines recommend the use of 4 F-PCC (25 u/kg) instead of FFP. The ACC guidelines also state that tranexamic acid should not be routinely used in patients with COVID-19 associated DIC given the lack of existing data. None of the major societies mention the use of TEG to monitor coagulopathy in patients who are actively bleeding.

DIC is an uncommon but serious complication in patients with COVID-19 [81]. It’s important to note that DIC is a clinical diagnosis with exclusion of alternate explanations for coagulation dysfunction. In patients with COVID-19, a superimposed bacterial infection is the most likely precipitant, however other causes such as HIT, drug-induced DIC and malignancy may also be contributing. Treating the underlying cause is the most important component of treating DIC, with transfusion targets the same as for active bleeding. If there is no active bleeding, replacement of fibrinogen and coagulation factors remain controversial. However, if platelet count is <10 x 10^9/L, platelets should be transfused.

Should patients receive post-discharge prophylactic anticoagulation and what regimens are available?

There is no evidence to support post-discharge DVT prophylaxis in patients who were hospitalized with COVID-19 infection. A number of studies have identified very low rates of post-discharge VTE; therefore, there is no universal recommendation for VTE prophylaxis for all patients post-discharge [82–84]. However, in high-risk patients and those who are at low risk of bleeding, the majority of major societal guidelines (CDC, ACF, ASH, ACCP, SCC-ISTH and ACC) state that it is reasonable to consider post-discharge prophylactic anticoagulation. Currently, there is an ongoing randomized trial evaluating the effectiveness and safety of low-dose apixaban in reducing thrombosis in patients who have been discharged from the hospital [85].

At the point of discharge, if a patient is deemed high risk (i.e., D-dimer >2 times the upper limit, reduced mobility, active cancer) of thrombosis and low risk of bleeding, it is reasonable to use criteria from clinical trials involving FDA-approved prophylactic anticoagulation regimens such as LMWH, rivaroxaban and betrixaban for thromboprophylaxis [57]. In terms of how long to provide thromboprophylaxis once discharged, the SCC guidelines recommend following post-discharge prophylactic anticoagulation regimen for 14–30 days. The ACC guideline states that it is reasonable to consider extended prophylaxis with LMWH or DOACs for up to 45 days in patients with high risk for VTE. For those diagnosed with COVID-19, and not admitted to hospital, there is no recommendation for DVT prophylaxis as an outpatient. However, a multicenter randomized controlled trial is underway to evaluate the efficacy and safety of antithrombotic strategies (aspirin compared with low dose and regular dose apixaban, and with placebo) in adults with COVID-19 not requiring hospitalization at time of diagnosis [58]. However, this trial is evaluating outpatients, not patients admitted post-discharge.

Conclusion

CAC is associated with macro- and micro-thrombosis, which can lead to a myriad of different presentations, and may result in multiorgan injury and ultimately death. As a result, important clinical questions regarding the optimal prevention and management of thrombosis has led to many ongoing clinical trials. Whilst data continues to be collected, major hematological societies have put forth recommendations regarding diagnosis, monitoring, and treatment of CAC. Overall, decisions should be made based on the providers understanding of a patient’s medical history, clinical course and perceived risk, in conjunction with the major societal guidelines and results from emerging clinical trial results.

Acknowledgments

We thank the educational division of Roche for allowing us to incorporate this manuscript into their CoagYOUlation platform (http://www.coagYOUlation.com). This manuscript incorporates literature and guidelines available at the time of submission. It is anticipated that the guidelines and practice management provided on the platform will be updated as additional literature becomes available.

Declaration of funding

We would also like to thank Roche for providing support for the article processing fees required in publishing this article and for initial compensation related to the creation of educational content provided in this article.Go to:

Declaration of financial/other relationships

No potential conflict of interest was reported by the author.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors contributions

PJL, RPR, EAB, MGC wrote and reviewed the manuscript.

Take home message

COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC.

COVID-19: Coronavirus disease 2019

WHO: World Health Organization

CAC: COVID-19 associated coagulopathy

CDC: Centers for Disease Control and Prevention (CDC),

ISTH-IG: International Society on Thrombosis and Hemostasis interim guidance (ISTH-IG)

ASH: American Society of Hematology (ASH)

ACCP: American College of Chest Physicians

SCC-ISTH: Scientific and Standardization Committee of ISTH

ACF: Anticoagulation Forum

ACC: American College of Cardiology

vWF: von Willebrand Factor

ICU: Intensive Care Unit

TEG: Thromboelastography

ROTEM: Rotational thromboelastometry

DIC: Disseminated intravascular coagulation

PT: Prothrombin time

PTT: Partial thromboplastin time

AT: Antithrombin

MA: Maximum amplitude

INR: International normalized ratio

VTE: Venous thromboembolism

HIT: Heparin-induced thrombocytopenia

SRA: Serotonin release assay

PE: Pulmonary embolism

CTPA: Computed tomography pulmonary angiogram (CTPA)

LMWH: Low molecular weight heparin

UFH: Unfractionated heparin

RCT: Randomized control trial

DOAC: Direct oral anticoagulants

PPE: Personal protective equipment

CRRT: Continuous renal replacement therapyGo to:

Declaration of interest

No potential conflict of interest was reported by the author(s).Go to:

References

1. Organisation WH . WHO coronavirus disease (COVID-19) dashboard. 2021. [Google Scholar]

2. Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421–1424. [PMC free article] [PubMed] [Google Scholar]

3. Klok FA, Kruip M, NJM VDM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020;191:148–150. [PMC free article] [PubMed] [Google Scholar]

4. Lax SF, Skok K, Zechner P, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med. 2020;173(5):350–361. [PMC free article] [PubMed] [Google Scholar]

5. Nopp S, Moik F, Jilma B, et al. Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Res Pract Thromb Haemost. 2020;4(7):1178–1191. [PMC free article] [PubMed] [Google Scholar]

6. Siddiqi HK, Mehra MRCOVID-19. illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–407. [PMC free article] [PubMed] [Google Scholar]

7. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–128. [PMC free article] [PubMed] [Google Scholar]

8. White-Dzuro G, Gibson LE, Zazzeron L, et al. Multisystem effects of COVID-19: a concise review for practitioners. Postgrad Med. 2021;133(1):20–27. [PMC free article] [PubMed] [Google Scholar]

9. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019 CHEST guideline and expert panel report. Chest. 2020;158(3):1143–1163. [PMC free article] [PubMed] [Google Scholar]

10. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72–81. [PMC free article] [PubMed] [Google Scholar]

11. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-Art review. J Am Coll Cardiol. 2020;75(23):2950–2973. [PMC free article] [PubMed] [Google Scholar]

12. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859–1865. [PMC free article] [PubMed] [Google Scholar]

13. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023–1026. [PubMed] [Google Scholar]

14. Bilaloglu S, Aphinyanaphongs Y, Jones S, et al. Thrombosis in hospitalized patients with COVID-19 in a New York city health system. JAMA. 2020;324(8):799–801. [PMC free article] [PubMed] [Google Scholar]

15. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089–1098. [PMC free article] [PubMed] [Google Scholar]

16. Giustozzi M, Vedovati MC, Agnelli G.. Venous thromboembolism and COVID-19: mind the gap between clinical epidemiology and patient management. Eur J Intern Med. 2020;82:18–20. [PMC free article] [PubMed] [Google Scholar]

17. Moll M, Zon RL, Sylvester KW, et al. VTE in ICU patients with COVID-19. Chest. 2020;158(5):2130–2135. [PMC free article] [PubMed] [Google Scholar]

18. Jimenez D, Garcia-Sanchez A, Rali P, et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Chest. 2020. [PMC free article] [PubMed] [Google Scholar]

19. Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation. 2020;142(2):184–186. [PubMed] [Google Scholar]

20. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489–500. [PMC free article] [PubMed] [Google Scholar]

21. Boyd S, Martin-Loeches I. The incidence of venous thromboembolism in critically ill patients with COVID-19 compared with critically ill non-COVID patients. Ir J Med Sci. 2021. DOI:10.1007/s11845-020-02503-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

22. Klok FA, Kruip M, NJM VDM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–147. [PMC free article] [PubMed] [Google Scholar]

23. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020;77(2):198–209. [PMC free article] [PubMed] [Google Scholar]

24. Lowenstein CJ, Solomon SD, Severe COVID-19. Is a microvascular disease. Circulation. 2020;142(17):1609–1611. [PMC free article] [PubMed] [Google Scholar]

25. Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;382(20):e60. [PMC free article] [PubMed] [Google Scholar]

26. Etkin Y, Conway AM, Silpe J, et al. Acute arterial thromboembolism in patients with COVID-19 in the New York city area. Ann Vasc Surg. 2021;70:290–294. [PMC free article] [PubMed] [Google Scholar]

27. Bellosta R, Luzzani L, Natalini G, et al. Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc Surg. 2020;72(6):1864–1872. [PMC free article] [PubMed] [Google Scholar]

28. Lillicrap D. Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia. J Thromb Haemost. 2020;18(4):786–787. [PMC free article] [PubMed] [Google Scholar]

29. Iba T, Levy JH, Levi M, et al. Coagulopathy in COVID-19. J Thromb Haemost. 2020;18(9):2103–2109. [PMC free article] [PubMed] [Google Scholar]

30. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–1418. [PMC free article] [PubMed] [Google Scholar]

31. Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost. 2018;16(2):231–241. [PubMed] [Google Scholar]

32. Grobler C, Maphumulo SC, Grobbelaar LM, et al. Covid-19: the rollercoaster of fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and their interactions with endothelial cells, platelets and erythrocytes. Int J Mol Sci. 2020;21(14):5168. [PMC free article] [PubMed] [Google Scholar]

33. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18(7):1738–1742. [PubMed] [Google Scholar]

34. Goshua G, Pine AB, Meizlish ML, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575–e82. [PMC free article] [PubMed] [Google Scholar]

35. Mortus JR, Manek SE, Brubaker LS, et al. Thromboelastographic results and hypercoagulability syndrome in patients with coronavirus disease 2019 who are critically Ill. JAMA Network Open. 2020;3(6):e2011192. [PMC free article] [PubMed] [Google Scholar]

36. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol. 2020;75(18):2352–2371. [PMC free article] [PubMed] [Google Scholar]

37. Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113(13):2878–2887. [PubMed] [Google Scholar]

38. Li J, Liu Z, Wu G, et al. d-dimer as a prognostic indicator in critically Ill patients hospitalized with COVID-19 in Leishenshan hospital, Wuhan, China. Front Pharmacol. 2020;11:600592. [PMC free article] [PubMed] [Google Scholar]

39. Battinelli EMCOVID-19. concerns aggregate around platelets. Blood. 2020;136(11):1221–1223. [PMC free article] [PubMed] [Google Scholar]

40. Rampotas A, Pavord S. Platelet aggregates, a marker of severe COVID-19 disease. J Clin Pathol. 2020. DOI:10.1136/jclinpath-2020-206933 [PubMed] [CrossRef] [Google Scholar]

41. Manne BK, Denorme F, Middleton EA, et al. Platelet gene expression and function in patients with COVID-19. Blood. 2020;136(11):1317–1329. [PMC free article] [PubMed] [Google Scholar]

42. Yang X, Yang Q, Wang Y, et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost. 2020;18(6):1469–1472. [PubMed] [Google Scholar]

43. Bowles L, Platton S, Yartey N, et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med. 2020;383(3):288–290. [PMC free article] [PubMed] [Google Scholar]

44. Harzallah I, Debliquis A, Drenou B. Lupus anticoagulant is frequent in patients with Covid-19. J Thromb Haemost. 2020;18(8):2064–2065. [PMC free article] [PubMed] [Google Scholar]

45. Giannakopoulos B, Passam F, Ioannou Y, et al. How we diagnose the antiphospholipid syndrome. Blood. 2009;113(5):985–994. [PubMed] [Google Scholar]

46. Devreese KMJ, Linskens EA, Benoit D, et al. Antiphospholipid antibodies in patients with COVID-19: a relevant observation? J Thromb Haemost. 2020;18(9):2191–2201. [PMC free article] [PubMed] [Google Scholar]

47. Reyes Gil M, Barouqa M, Szymanski J, et al. Assessment of Lupus anticoagulant positivity in patients with coronavirus disease 2019 (COVID-19). JAMA Network Open. 2020;3(8):e2017539. [PubMed] [Google Scholar]

48. Mills K, Sobukonla T, Lee M, et al. DECODING COVID-19: a NOVEL ROLE OF ANTITHROMBIN DEFICIENCY IN THE NOVEL CORONAVIRUS. Chest. 2020;158(4):4. [Google Scholar]

49. Connors JM, Levy JH. Thrombo inflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020;18(7):1559–1561. [PubMed] [Google Scholar]

50. Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 cases of death from COVID-19. PLoS One. 2020;15(7):e0235458. [PMC free article] [PubMed] [Google Scholar]

51. Asakura H, Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol. 2021;113(1):45–57. [PMC free article] [PubMed] [Google Scholar]

52. Rosovsky RP, Grodzin C, Channick R, et al. Diagnosis and treatment of pulmonary embolism during the coronavirus disease 2019 pandemic: a position paper from the national PERT consortium. Chest. 2020;158(6):2590–2601. [PMC free article] [PubMed] [Google Scholar]

53. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844–847. [PMC free article] [PubMed] [Google Scholar]

54. Zhang L, Yan X, Fan Q, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020;18(6):1324–1329. [PMC free article] [PubMed] [Google Scholar]

55. Linkins LA, Takach Lapner S. Review of D-dimer testing: good, bad, and ugly. Int J Lab Hematol. 2017;39(Suppl 1):98–103. [PubMed] [Google Scholar]

56. Yao Y, Cao J, Wang Q, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care. 2020;8(1):49. [PMC free article] [PubMed] [Google Scholar]

57. Flaczyk A, Rosovsky RP, Reed CT, et al. Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations. Crit Care. 2020;24(1):559. [PMC free article] [PubMed] [Google Scholar]

58. Connors JM. 2021. ACTIV-IV COVID-19 outpatient thrombosis prevention trial.

59. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743–752. [PubMed] [Google Scholar]

60. Hippensteel JA, LaRiviere WB, Colbert JF, et al. Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol. 2020;319(2):L211–L7. [PMC free article] [PubMed] [Google Scholar]

61. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 2020;120(6):998–1000. [PMC free article] [PubMed] [Google Scholar]

62. Lin L, Lu L, Cao W, et al. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727–732. [PMC free article] [PubMed] [Google Scholar]

63. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094–1099. [PubMed] [Google Scholar]

64. Health NIo . Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. 2021. [Google Scholar]

65. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872–888. [PMC free article] [PubMed] [Google Scholar]

66. Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with coVID-19. J Am Coll Cardiol. 2020;76(16):1815–1826. [PMC free article] [PubMed] [Google Scholar]

67. Wang L, Li H, Gu X, et al. Effect of Antiplatelet therapy on acute respiratory distress syndrome and mortality in critically Ill patients: a meta-Analysis. PLoS One. 2016;11(5):e0154754. [PMC free article] [PubMed] [Google Scholar]

68. D’Souza R, Malhame I, Teshler L, et al. A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID-19. Acta Obstet Gynecol Scand. 2020;99(9):1110–1120. [PMC free article] [PubMed] [Google Scholar]

69. DiNicolantonio JJ, Barroso-Aranda J. Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: potential of pentoxifylline and dipyridamole. Med Hypotheses. 2020;143:110051. [PMC free article] [PubMed] [Google Scholar]

70. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin use is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized patients with COVID-19. Anesth Analg. 2020. [PubMed] [Google Scholar]

71. Salah HM, Mehta JL. Meta-Analysis of the effect of aspirin on mortality in COVID-19. Am J Cardiol. 2021. [PMC free article] [PubMed] [Google Scholar]

72. Trial R. Aspirin to be investigated as a possible treatment for COVID-19 in the RECOVERY trial.

73. Maurer LR, Luckhurst CM, Hamidi A, et al. A low dose heparinized saline protocol is associated with improved duration of arterial line patency in critically ill COVID-19 patients. J Crit Care. 2020;60:253–259. [PMC free article] [PubMed] [Google Scholar]

74. Endres P, Rosovsky R, Zhao S, et al. Filter clotting with continuous renal replacement therapy in COVID-19. J Thromb Thrombolysis. 2020. [PMC free article] [PubMed] [Google Scholar]

75. Barrett CD, Oren-Grinberg A, Chao E, et al. Rescue therapy for severe COVID-19-associated acute respiratory distress syndrome with tissue plasminogen activator: a case series. J Trauma Acute Care Surg. 2020;89(3):453–457. [PMC free article] [PubMed] [Google Scholar]

76. Wang J, Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series. J Thromb Haemost. 2020;18(7):1752–1755. [PMC free article] [PubMed] [Google Scholar]

77. Kabrhel C, Rosovsky R, Channick R, et al. A multidisciplinary pulmonary embolism response team: initial 30-Month experience with a novel approach to delivery of care to patients with submassive and massive pulmonary embolism. Chest. 2016;150(2):384–393. [PubMed] [Google Scholar]

78. Streng AS, Delnoij TSR, Mulder MMG, et al. Monitoring of unfractionated Heparin in severe COVID-19: an observational study of patients on CRRT and ECMO. TH Open. 2020;4(4):e365–e75. [PMC free article] [PubMed] [Google Scholar]

79. White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;50(2):287–291. [PMC free article] [PubMed] [Google Scholar]

80. Trunfio M, Salvador E, Cabodi D, et al. Anti-Xa monitoring improves low-molecular-weight heparin effectiveness in patients with SARS-CoV-2 infection. Thromb Res. 2020;196:432–434. [PMC free article] [PubMed] [Google Scholar]

81. Zhou X, Cheng Z, Luo L, et al. Incidence and impact of disseminated intravascular coagulation in COVID-19 a systematic review and meta-analysis. Thromb Res. 2021;201:23–29. [PMC free article] [PubMed] [Google Scholar]

82. Patell R, Bogue T, Koshy A, et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood. 2020;136(11):1342–1346. [PMC free article] [PubMed] [Google Scholar]

83. Roberts LN, Whyte MB, Georgiou L, et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood. 2020;136(11):1347–1350. [PMC free article] [PubMed] [Google Scholar]

84. Hill JB, Garcia D, Crowther M, et al. Frequency of venous thromboembolism in 6513 patients with COVID-19: a retrospective study. Blood Adv. 2020;4(21):5373–5377. [PMC free article] [PubMed] [Google Scholar]

85. Ortel T. 2021. COVID-19 thrombosis prevention trials: post-hospital thromboprophylaxis.

Formats:

Share

Similar articles in PubMed

Links

Compound

PubMed

Recent Activity

See more…

See more …

Support CenterSupport Center

Whole genome sequencing reveals host factors underlying critical Covid-19

Authors: Athanasios KousathanasErola Pairo-CastineiraJ. Kenneth BaillieArticle

Published:  nature  articles  article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. We identify 16 new independent associations, including variants within genes involved in interferon signalling (IL10RBPLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELEICAM5CD209) and coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

Author information

Author notes

  1. These authors contributed equally: Athanasios Kousathanas, Erola Pairo-Castineira
  2. These authors jointly supervised this work: Sara Clohisey Hendry, Loukas Moutsianas, Andy Law, Mark J Caulfield, J. Kenneth Baillie
  3. A list of authors and their affiliations appears in the Supplementary Information

Affiliations

  1. Genomics England, London, UKAthanasios Kousathanas, Alex Stuckey, Christopher A. Odhams, Susan Walker, Daniel Rhodes, Afshan Siddiq, Peter Goddard, Sally Donovan, Tala Zainy, Fiona Maleady-Crowe, Linda Todd, Shahla Salehi, Greg Elgar, Georgia Chan, Prabhu Arumugam, Christine Patch, Augusto Rendon, Tom A. Fowler, Richard H. Scott, Loukas Moutsianas & Mark J. Caulfield
  2. Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UKErola Pairo-Castineira, Konrad Rawlik, Clark D. Russell, Jonathan Millar, Fiona Griffiths, Wilna Oosthuyzen, Bo Wang, Marie Zechner, Nick Parkinson, Albert Tenesa, Sara Clohisey Hendry, Andy Law & J. Kenneth Baillie
  3. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UKErola Pairo-Castineira, Lucija Klaric, Albert Tenesa, Chris P. Ponting, Veronique Vitart, James F. Wilson, Andrew D. Bretherick & J. Kenneth Baillie
  4. Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UKClark D. Russell & J. Kenneth Baillie
  5. Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UKTomas Malinauskas, Katherine S. Elliott & Julian Knight
  6. Institute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaYang Wu
  7. Biostatistics Group, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, ChinaXia Shen
  8. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh, UKXia Shen, Albert Tenesa & James F. Wilson
  9. Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UKKirstie Morrice, Angie Fawkes & Lee Murphy
  10. Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, UKSean Keating, Timothy Walsh & J. Kenneth Baillie
  11. Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, Kingston, ON, CanadaDavid Maslove
  12. Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, IrelandAlistair Nichol
  13. NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of Liverpool, Liverpool, UKMalcolm G. Semple
  14. Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UKMalcolm G. Semple
  15. Illumina Cambridge, 19 Granta Park, Great Abington, Cambridge, UKDavid Bentley & Clare Kingsley
  16. Regeneron Genetics Center, 777 Old Saw Mill River Rd., Tarrytown, USAJack A. Kosmicki, Julie E. Horowitz, Aris Baras, Goncalo R. Abecasis & Manuel A. R. Ferreira
  17. Geisinger, Danville, PA, USAAnne Justice, Tooraj Mirshahi & Matthew Oetjens
  18. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADaniel J. Rader, Marylyn D. Ritchie & Anurag Verma
  19. Test and Trace, the Health Security Agency, Department of Health and Social Care, Victoria St, London, UKTom A. Fowler
  20. Department of Intensive Care Medicine, Guy’s and St. Thomas NHS Foundation Trust, London, UKManu Shankar-Hari
  21. Department of Medicine, University of Cambridge, Cambridge, UKCharlotte Summers
  22. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKCharles Hinds
  23. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UKPeter Horby
  24. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, ChinaLowell Ling
  25. Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UKDanny McAuley
  26. Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, Northern Ireland, UKDanny McAuley
  27. UCL Centre for Human Health and Performance, London, UKHugh Montgomery
  28. National Heart and Lung Institute, Imperial College London, London, UKPeter J. M. Openshaw
  29. Imperial College Healthcare NHS Trust: London, London, UKPeter J. M. Openshaw
  30. Imperial College, London, UKPaul Elliott
  31. Intensive Care National Audit & Research Centre, London, UKKathy Rowan
  32. School of Life Sciences, Westlake University, Hangzhou, Zhejiang, ChinaJian Yang
  33. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, ChinaJian Yang
  34. Great Ormond Street Hospital, London, UKRichard H. Scott
  35. William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UKMark J. Caulfield

Consortia

GenOMICC Investigators

23andMe

Covid-19 Human Genetics Initiative

Corresponding authors

Correspondence to Mark J. Caulfield or J. Kenneth Baillie.

Supplementary information

Supplementary Information

This file contains Supplementary Figures; Supplementary Tables and Supplementary References

The coagulopathy, endotheliopathy, and vasculitis of COVID-19

Authors: Toshiaki Iba 1Jean Marie Connors 2Jerrold H Levy 3

Abstract

Background

COVID-19-associated coagulopathy (CAC) characterized by the elevated D-dimer without remarkable changes of other global coagulation markers is associated with various thrombotic complications and disease severity. The purpose of this review is to elucidate the pathophysiology of this unique coagulopathy.

Methods

The authors performed online search of published medical literature through PubMed using the MeSH (Medical Subject Headings) term “COVID-19,” “SARS-CoV-2,” “coronavirus,” “coagulopathy,” and “thrombus.” Then, selected 51 articles that closely relevant to coagulopathy in COVID-19.

Results

The primary targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the pneumocytes, immune cells, and vascular endothelial cells. The alveolar damage and the pulmonary microvascular thrombosis are the major causes of acute lung injury in COVID-19. The endotheliopathy that occurs is due to direct SARS-CoV-2 infection and activation of other pathways that include the immune system and thromboinflammatory responses leading to what is termed CAC. As a result, both microvascular and macrovascular thrombotic events occur in arterial, capillary, venule, and large vein vascular beds to produce multiorgan dysfunction and thrombotic complications. In addition to the endothelial damage, SARS-CoV-2 also can cause vasculitis and presents as a systemic inflammatory vascular disease. Clinical management of COVID-19 includes anticoagulation but novel therapies for endotheliopathy, hypercoagulability, and vasculitis are needed.

Conclusion

The endotheliopathy due to direct endothelial infection with SARS-COV-2 and the indirect damage caused by inflammation play the predominant role in the development of CAC. The intensive control of thromboinflammation is necessary to improve the outcome of this highly detrimental contagious disease.

Introduction

Ongoing reports have described the hypercoagulability and thrombotic tendency in COVID-19 [1]. The high incidence of deep vein thrombosis and pulmonary embolism has focused on the critical role of routine antithrombotic prophylaxis for COVID-19 management, especially in critically ill patients and/or elevated D-dimer levels [2,3,4]. Current reports of venous and arterial thrombotic events in the patients treated in ICU is up to 30% even with pharmacological thromboprophylaxis, and thrombotic events are associated with 5.4 times higher risk of mortality [5]. Recent postmortem evaluation of COVID-19 patients has demonstrated severe endothelial injury with cellular death/apoptosis, and the presence of intracellular virus in the autopsy lung with thrombosis and small to middle-size pulmonary vessels. The clotting and vascular damage were also confirmed in the alveolar capillary and these changes are more remarkable in COVID-19 compared to influenza induced lung injury [6]. In this summary, we will review the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced endotheliopathy, COVID-19-associated coagulopathy (CAC), and vasculitis.

Coagulopathy in COVID-19

The mechanism of coagulopathy in COVID-19

Thromboembolic complications are the hallmark of COVID-19 that can cause death even in asymptomatic COVID-19 [7]. The new coronavirus SARS-CoV-2 elicits an acute inflammatory effect with hypercoagulability, platelet activation, and endothelial dysfunction [8]. Although, this presentation has similarities with sepsis-induced coagulopathy (SIC) due to bacterial infections and disseminated intravascular coagulation (DIC), there are several important differences [8]. In CAC, patients often initially present with increased fibrinogen levels, increased D-dimers, but minor changes in prothrombin time and platelet count compared to acute bacterial sepsis that can produce thrombocytopenia, prolonged prothrombin times, and decreased antithrombin levels [49]. It is also known that inflammatory cytokine levels are elevated in COVID-19 and excess production of inflammatory cytokines can induce hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) that can result in a thrombotic coagulation disorder [10]. Although the pathophysiology of HLH/MAS seems similar to COVID-19, the reported cytokine level is much lower in COVID-19 [11]. Conversely, the endothelial derangement, detailed in the next section, is predominant in COVID-19. Other than HLH/MAS, various thrombotic diseases such as thrombotic microangiopathy, and antiphospholipid syndrome can occur, and the characteristics of these diseases look similar to CAC [12]. Even though the pathogeneses of these thrombotic diseases partially overlap with CAC, it is important to delineate the unique statue of CAC to plan a therapeutic strategy.

The evaluation of COVID-19-associated coagulopathy

D-Dimer monitoring is important in COVID-19 coagulopathy. Although D-dimer is initially elevated, other conventional coagulation laboratory tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count are often normal, and are not useful indicators of the thrombotic risk. The increase of factor VIII and von Willebrand factor (VWF) [13], potentially the presence of antiphospholipid antibodies [14], and increased activity of complement system are also reported, however, monitoring these biomarkers is not practical. The pathogenesis of coagulopathy in COVID-19 is complex but the typical CAC can be diagnosed by increased D-dimer, elevated fibrinogen and VWF levels, but relatively normal PT, aPTT, and platelet count. A pathway for diagnosing CAC versus other coagulopathies is illustrated in Fig. 1.

figure 1
Fig. 1

Thrombin generation testing (TGT) measures ex vivo thrombin formation in plasma upon activation with tissue factor. TGT allows calculation of peak and total thrombin generation, as well as time to initial and peak thrombin generation. This assay can identify both reduced and increased thrombin generation. Nougier et al. [15] revealed increased thrombin generation in COVID-19 patients despite undergone anticoagulation. The major drawbacks of TGT are the lack of standardization and the requirement of technical training.

Other potential assays to assess global coagulation status include viscoelastic testing, especially in ICU patients, as a point of care test. An increasing number of studies report hypercoagulability as indicated by decreased R or clot times, and increased maximal amplitude/maximal clot firmness by viscoelastic monitoring [16,17,18]. However, these changes are consistent with high fibrinogen levels that affect both maximal amplitude on thromboelastography (TEG), and maximum clot firmness on rotational thromboelastometry (ROTEM). Ranucci et al. [17] reported the median fibrinogen level was nearly 800 mg/dL in the COVID-19 patients treated in ICU, and such a high fibrinogen level affects TEG and ROTEM parameters considerably by itself [19].

Endotheliopathy in COVID-19

The endothelial damage and thrombosis

An important feature of CAC is the microcirculatory endothelial damage in pulmonary circulation and other vascular beds. Since SARS-CoV-2 directly infects the vascular endothelial cell causing cellular damage and apoptosis, the antithrombotic activity of the luminal surface is remarkably decreased [20]. In COVID-19, both alveolar damage and microcirculatory disturbance associated with thrombus formation contribute to respiratory dysfunction. At autopsy, findings reported include clot formation in pulmonary arterioles with diffuse alveolar damage and hyaline membranes [21]. Normal endothelial function refers to the ability of regulating vascular tonus, permeability, cell adhesion, and anticoagulation. Healthy endothelial cells synthesize nitric oxide (NO) by conversion of L-arginine to L-citrulline by nitric oxide synthase. NO released by endothelium prevents leukocyte and platelet adhesion, inflammatory cell migration into the vessel wall, smooth muscle cell proliferation, and suppresses apoptosis and inflammation. SARS-Cov-2 enters endothelial cells through endocytosis and is mediated by an interplay of Angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS-2) which sheds a part of spike protein and helps SARS-Cov-2 to enter into endothelial cell. The infected endothelial cells lose their ability to maintain aforementioned physiological functions. Subsequently, the damage of the endothelium leads to the procoagulant change of the vascular lumen, formation of immunothrombosis, and organ malcirculation.

Both systemic pulmonary microthrombosis and thromboembolism are commonly seen in COVID-19. This typical figure is thought to be the result of hypercoagulability due to the dysregulated endothelial function of the pulmonary vessels and systemic inflammation. In addition to the deep vein thrombus that results in an embolic event, in situ formation in the pulmonary arteries can be the main reason of pulmonary dysfunction. Lax et al. [22] performed autopsies in 11 patients and reported that despite the absence of clinical presentations of thromboembolism, thrombus formation in small and mid-sized pulmonary arteries was found in all of the examined cases. In these cases, thrombus is suspected to form at the peripheral arteriole and elongate proximally. According to another series of autopsy findings, the incidence of thrombus formation in the pulmonary microvasculature is approximately nine times higher than that seen in influenza [6].

The endothelial damage-derived hypercoagulability

ACE2, the host cellular receptor of SARS-CoV-2, has been identified on the vascular endothelial surface. SARS-CoV-2 uses ACE2 to invade into the cell through the fusion of its membrane to the host cell membrane. As a result, the host cell loses ACE2 activity which subsequently leads to reduced angiotensin II inactivation and decreased conversion to antiotensin1-7. Increased angiotensin II stimulates vascular constriction and decreased antiotensin1-7 suppresses nitric oxide production which triggers increased thrombogenicity due to leucocyte and platelet adhesion and vasoconstriction [23].

The vascular endothelium is coated by a gel-like component known as the glycocalyx, that regulates vascular blood flow by providing an antithrombotic surface via antithrombin binding to the heparan sulfate constituents, a major component of the glycocalyx. Although the circulating antithrombin level has been reported to be in a normal range on presentation in COVID-19 cases [13], if the glycocalyx is disrupted, the local antithrombogenicity of the endothelial surface may be altered. However, little information on the glycocalyx status in COVID-19 is available.

One of the unique features of CAC is the increase in VWF and factor VIII [1324] and it is suggested to be the result of vascular response to SARS-CoV-2 infection. VWF and factor VIII are stored in the Weibel-Palade body of endothelial cells and released in response to infectious stimuli [25] (Fig. 2). The increase in VWF suggests a possible similarity to thrombotic thrombocytopenic purpura, however, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels in COVID-19 although reported to be decreased, may not be severely depleted as in thrombotic thrombocytopenic purpura [26]. The increased VWF levels to 3–4 times normal values seen in patients with COVID-19 may overwhelm the ADAMTS13 activity to degrade the ultra large VWF multimers. The importance of circulating VWF and multimer size in CAC is not established, however, one of the suggested methods to reduce the risk of thrombotic events due to excess ultra large VWF itself is plasma exchange [2728].

figure 2
Fig. 2

Similar to factor VIII and VWF, angiopoietin 2, also stored in Weibel-Palade bodies, is known to be released and its circulating level increases in COVID-19 [29]. Angiopoietin 2 serves as an antagonist of angiopoietin 1 and inhibits anti-inflammatory, anticoagulatory, and antiapoptotic signaling induced by angiopoietin 1 by binding to Tie2 competitively [30] (Fig. 3). Tie2 activation by angiopoietin 1 also normalizes prothrombotic responses by inhibiting endothelial tissue factor and phosphatidylserine exposure in sepsis, and therefore, Tie2 signaling is considered to play a central role in the regulation of thrombus formation in SIC/DIC [31]. Angiotensin 2 is also known to increase endothelial permeability and is considered an important factor in acute respiratory distress syndrome [32]. The role of angiopoietin 2 in CAC has not been studied well and it should be the focus in future studies.

figure 3
Fig. 3

The monitoring of endothelial damage

One of the difficulties in clinical studies of endothelial research is the limited availability of ideal biomarkers. The glycocalyx provides an interface between blood flow and endothelial cells. Since the glycocalyx is fragile, its components are used as biomarkers of endothelial damage in various diseases including infectious diseases [30]. One such biomarker is a hyaluronic acid, a major glycocalyx component. Circulating levels of hyaluronic acid, are elevated in critically ill COVID-19 patients compared with less severe cases [33]. Other than that, the proteins that are released from the Weibel-Palade body i.e., VWF, FVIII, and P-selectin are the potential biomarkers. In addition, sensitive coagulation markers such as thrombin-antithrombin complex (TAT) and prothrombin fragment 1 + 2 can be a marker for the microthrombosis. Goshua et al. [34] reported VWF antigen/antibody, FVIII activity, and TAT levels are significantly higher in the more severe cases.

As previously mentioned, angiopoietin 2 is stored in the endothelial cells and secreted along with the endothelial damage. Reportedly, angiopoietin 2 levels are associated with coagulation disorder, organ damage and death in bacterial sepsis [35]. Smadja et al. [29] measured angiopoietin 2, D-dimer, CRP, and creatinine in consecutive 40 COVID-19 patients treated in ICU, and found angiopoietin 2, cut-off of 5000 pg/mL, as the best predictor for poor outcome (sensitivity: 80.1%, specificity: 70%). It is crucial to find a good biomarker of vascular damage in COVID-19 study.

Therapeutic strategies for endothelial damage

Despite prophylactic anticoagulation in CAC, patients can still develop thrombotic sequela. A recent study reported that despite systematic use of thromboprophylaxis, 31% of the COVID-19 patients treated in ICU developed thrombotic complications [36]. In another study, the cumulative incidence of arterial and venous thromboembolism was 49% [3]. These reports suggest that despite anticoagulation, additional therapy for endothelial injury is necessary to prevent thrombosis. Potential therapies include synthetic serine protease inhibitors such as nafamostat mesylate and camostat mesylate which theoretically prevent SARS-CoV-2 infection. Coronavirus gains entry to the cell using the host TMPRSS2 which cleaves the spike protein resulting in its ability to fuse to the host cellular membrane. These agents inhibit TMPRSS2 thereby abrogating the activating proteolytic processing of virus [37]. Since nafamostat mesylate also has anticoagulatory effects, it has been used for DIC and anticoagulation for extracorporeal circuits in Japan.

Other therapeutic considerations are the physiologic anticoagulants such as protein C and antithrombin. The dual action of protein C/activated protein C to inactivate factor VIIIa and upregulate ACE2 are the advantage of this system which suppress both coagulation and inflammation. Activated protein C can also reduce pulmonary injury by suppressing the macrophage inflammatory protein family chemokine response [38]. Antithrombin is another multifaceted serine protease inhibitor of multiple coagulation factors, but also protects the glycocalyx by binding to heparan sulfate [39]. Bikdeli et al. [40] noted in their recent review of pharmacological therapy targeting thromboinflammation in COVID-19, that antithrombin suppresses excess inflammation by inhibiting nuclear factor-κB, it may be suitable for the treatment of CAC. However, the effects of these agents in COVID-19 haven’t been examined in clinical trials and future study may be warranted.

Arterial thrombosis in COVID-19

Arterial thrombosis is an uncommon event in other infection-associated coagulopathies. In contrast, stroke, ischemic coronary disease, and thrombotic limb ischemia can occur in COVID-19. Lodigiani et al. [41] reported the rate of ischemic stroke and acute coronary syndrome was 2.5% and 1.1%, respectively, in Italy. Kashi et al. [42] reported two cases of floating thrombi in thoracic aorta and such cases are extremely odd in previously described infectious diseases. Antiphospholipid syndrome is known as a disease that result in arterial thrombosis and can occur secondary to infection. Some reports have shown increased lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies, however, the presence of high titer IgG antibody, an important responsible factor, has not proven yet [132443], and the association between antiphospholipid syndrome and CAC is still unclear. The presence of unusually large VWF multimers and subsequent activation of platelets and microthrombi can explain the occurrence of arterial macrothrombosis [44], and Williams et al. [45] reported elevated VWF levels were associated with the increased risk for recurrent stroke. However, a definitive cause and effect relation has not been proven yet. The occurrence of arterial thrombosis is difficult to predict and there are no good prophylactic strategies. Oxley et al. [7] reported five cases of large-vessel stroke in patients younger than 50 years of age. The mechanism of arterial thrombosis in COVID-19 remains a mystery and prediction of the events was not possible in any of the cases; demographic factors, laboratory data, and severity of COVID-19 did not appear to be related to arterial events.

Clot formation in extracorporeal circuits

The high incidence of clot formation during extracorporeal circulation has been recognized. Helms et al. [13] studied 150 COVID-19 patients and reported 28 out of 29 patients (96.6%) receiving continuous renal replacement therapy (CRRT) experienced clotting of the circuit. The median lifespan of an CRRT circuit was 1.5 days which is only half of the recommendation duration. They also reported 12 patients (8%) were treated by extracorporeal membrane oxygenation (ECMO), and among them, thrombotic occlusions of centrifugal pump occurred in 2 patients. Methods to minimize extracorporeal circuit clotting include prefilter infusion of heparin and the use of citrate-based replacement fluid for dialysis are not always successful [46]. The reason for the high incidence of CRRT filter and ECMO oxygenator coagulation is not known, but factors other than endotheliopathy such as hypercoagulability, hypofibrinolysis, and platelet activation must attribute. The elevated VWF activity, increased factor VIII level, and high fibrinogen level may lead to microthrombi formation possibly occluding the filter. Suppressed fibrinolysis may also play a role [47], with excess angiotensin II enhancing the expression of PAI-1 in the endothelium in COVID-19 [48].

Vasculitis in COVID-19

A report from northern Italy observed significantly increased number of patients with Kawasaki disease, an acute self-limiting vasculitis predominantly involving the coronary arteries, with hemodynamically unstable Kawasaki disease shock syndrome (KDSS) during the COVID-19 pandemic [49]. It is also reported that children with COVID-19 are more likely to show MAS that resembles secondary HLH. Varga et al. [50] demonstrated the direct viral infection of the endothelial cell and diffuse endothelial inflammation which are followed by the induction of endothelitis, apoptosis, and pyroptosis in autopsy cases of COVID-19. Of note is the mononuclear cell infiltrations into the vascular intima along the lumen of many vessels also reported in this post-mortem analysis. This finding suggests that the virus can invade into human vasculature and cause vasculitis. Roncati et al. [51] estimated the escalation from type 2 T-helper immune response to type 3 hypersensitivity is involved in the pathophysiology of COVID-19-induced vasculitis. They reported the deposition of immune complexes inside the vascular walls causing more severe inflammatory reaction, and interleukin-6 is the key myokine in this scenario.

Conclusion

The mechanism of coagulopathy in COVID-19 continues to be investigated. However, the predominant role of endotheliopathy due to direct endothelial infection with SARS-COV-2 and the indirect damage caused by inflammation are part of the complex thromboinflammatory process. The elevated circulating levels of clotting factors including fibrinogen, factor VIII, VWF released from the stimulated endothelial cells, and the loss of the thromboprotective function with glycocalyx damage and decreased nitric oxide production also contribute to the coagulopathy and thromboinflammation. SARS-CoV-2 damages not only the luminal surface of the vasculature but also induce vasculitis, contributing to the significant pathology associated with COVID-19.

References

  1. 1.Han H, Yang L, Liu R. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020. https://doi.org/10.1515/cclm-2020-0188.Article PubMed Google Scholar 
  2. 2.Ren B, Yan F, Deng Z, Zhang S, Xiao L, Wu M, Cai L. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation. 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.047407.Article PubMed Google Scholar 
  3. 3.Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, Clark C, Iba T. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023–6.CAS Article Google Scholar 
  4. 4.Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020:blood.2020006000.
  5. 5.Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;S0049–3848(20):30157–62.Google Scholar 
  6. 6.Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2015432.Article PubMed Google Scholar 
  7. 7.Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fifi JT. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;382(20):e60.Article Google Scholar 
  8. 8.Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7(6):e438–e440440.Article Google Scholar 
  9. 9.Iba T, Levy JH. Sepsis-induced coagulopathy and disseminated intravascular coagulation. Anesthesiology. 2020;132(5):1238–45.Article Google Scholar 
  10. 10.McGonagle D, et al. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020. https://doi.org/10.1016/S2665-9913(20)30121-1.Article PubMed PubMed Central Google Scholar 
  11. 11.Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020;28:1–4. https://doi.org/10.1007/s00134-020-06059-6.CAS Article Google Scholar 
  12. 12.Opoka-Winiarska V, Grywalska E, Roliński J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BMC Med. 2020;18(1):214.CAS Article Google Scholar 
  13. 13.Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Anglés-Cano E, Sattler L, Mertes PM, Meziani F, CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020:1–10.
  14. 14.Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li T, Zhang F, Zhao Y, Li Y, Zhang S. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38.Article Google Scholar 
  15. 15.Nougier C, Benoit R, Simon M, Desmurs-Clavel H, Marcotte G, Argaud L, David JS, Bonnet A, Negrier C, Dargaud Y. Hypofibrinolytic state and high thrombin generation may play a major role in sars-cov2 associated thrombosis. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.15016.Article PubMed PubMed Central Google Scholar 
  16. 16.Maatman TK, Jalali F, Feizpour C, Douglas A 2nd, McGuire SP, Kinnaman G, Hartwell JL, Maatman BT, Kreutz RP, Kapoor R, Rahman O, Zyromski NJ, Meagher AD. Routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease 2019. Crit Care Med. 2020. https://doi.org/10.1097/CCM.0000000000004466.Article PubMed PubMed Central Google Scholar 
  17. 17.Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, Resta M, Falco M, Albano G, Menicanti L. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14854.Article PubMed PubMed Central Google Scholar 
  18. 18.Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, Pesenti A, Peyvandi F, Tripodi A. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14850.Article PubMed Google Scholar 
  19. 19.Scala E, Coutaz C, Gomez F, Alberio L, Marcucci C. Comparison of ROTEM sigma to standard laboratory tests and development of an algorithm for the management of coagulopathic bleeding in a tertiary center. J Cardiothorac Vasc Anesth. 2020;34(3):640–9.CAS Article Google Scholar 
  20. 20.Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, Heinrich F, Mushumba H, Kniep I, Schröder AS, Burdelski C, de Heer G, Nierhaus A, Frings D, Pfefferle S, Becker H, Bredereke-Wiedling H, de Weerth A, Paschen HR, Sheikhzadeh-Eggers S, Stang A, Schmiedel S, Bokemeyer C, Addo MM, Aepfelbacher M, Püschel K, Kluge S. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. 2020;6:M20–2003. https://doi.org/10.7326/M20-2003.Article Google Scholar 
  21. 21.Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LFF, de Oliveira EP, Nascimento Saldiva PH, Mauad T, Marcia NE. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14844.Article PubMed PubMed Central Google Scholar 
  22. 22.Lax SF, Skok K, Zechner P, Kessler HH, Kaufmann N, Koelblinger C, Vander K, Bargfrieder U, Trauner M. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med. 2020. https://doi.org/10.7326/M20-2566.Article PubMed PubMed Central Google Scholar 
  23. 23.Verdecchia P, Cavallini C, Spanevello A, Angeli F. COVID-19: ACE2 centric infective disease? Hypertension. 2020. https://doi.org/10.1161/HYPERTENSIONAHA.120.15353.Article PubMed Google Scholar 
  24. 24.Escher R, Breakey N, Lämmle B. ADAMTS13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients. Thromb Res. 2020;192:174–5.CAS Article Google Scholar 
  25. 25.Streetley J, Fonseca AV, Turner J, Kiskin NI, Knipe L, Rosenthal PB, Carter T. Stimulated release of intraluminal vesicles from Weibel–Palade bodies. Blood. 2019;133(25):2707–17.CAS Article Google Scholar 
  26. 26.Huisman A, Beun R, Sikma M, Westerink J, Kusadasi N. Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2. Int J Lab Hematol. 2020. https://doi.org/10.1111/ijlh.13244.Article PubMed PubMed Central Google Scholar 
  27. 27.Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Version 2. Crit Care. 2020;24(1):128.Article Google Scholar 
  28. 28.Zachariah U, Nair SC, Goel A, Balasubramanian KA, Mackie I, Elias E, Eapen CE. Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: consider low volume plasma exchange and low dose steroid. Thromb Res. 2020;192:2.CAS Article Google Scholar 
  29. 29.Smadja DM, Guerin CL, Chocron R, Yatim N, Boussier J, Gendron N, Khider L, Hadjadj J, Goudot G, Debuc B, Juvin P, Hauw-Berlemont C, Augy JL, Peron N, Messas E, Planquette B, Sanchez O, Charbit B, Gaussem P, Duffy D, Terrier B, Mirault T, Diehl JL. Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients. Angiogenesis. 2020;27:1–10. https://doi.org/10.1007/s10456-020-09730-0.CAS Article Google Scholar 
  30. 30.Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23(1):16.Article Google Scholar 
  31. 31.Higgins SJ, De Ceunynck K, Kellum JA, Chen X, Gu X, Chaudhry SA, Schulman S, Libermann TA, Lu S, Shapiro NI, Christiani DC, Flaumenhaft R, Parikh SM. Tie2 protects the vasculature against thrombus formation in systemic inflammation. J Clin Invest. 2018;128(4):1471–84.Article Google Scholar 
  32. 32.Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, Karumanchi SA, Sukhatme VP. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. Version 2. PLoS Med. 2006;3(3):e46.Article Google Scholar 
  33. 33.Ding M, Zhang Q, Li Q, Wu T, Huang YZ. Correlation analysis of the severity and clinical prognosis of 32 cases of patients with COVID-19. Respir Med. 2020;167:105981.Article Google Scholar 
  34. 34.Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, Baluha A, Bar N, Bona RD, Burns AJ, Dela Cruz CS, Dumont A, Halene S, Hwa J, Koff J, Menninger H, Neparidze N, Price C, Siner JM, Tormey C, Rinder HM, Chun HJ, Lee AI. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575–e582582.Article Google Scholar 
  35. 35.Fisher J, Douglas JJ, Linder A, Boyd JH, Walley KR, Russell JA. Elevated plasma angiopoietin-2 levels are associated with fluid overload, organ dysfunction, and mortality in human septic shock. Crit Care Med. 2016;44(11):2018–27.CAS Article Google Scholar 
  36. 36.Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020:S0049-3848(20)30120-1.
  37. 37.Yamaya M, Nishimura H, Deng X, Kikuchi A, Nagatomi R. Protease inhibitors: candidate drugs to inhibit severe acute respiratory syndrome coronavirus 2 replication. Tohoku J Exp Med. 2020;251(1):27–30.CAS Article Google Scholar 
  38. 38.Richardson MA, Gupta A, O’Brien LA, Berg DT, Gerlitz B, Syed S, Sharma GR, Cramer MS, Heuer JG, Galbreath EJ, Grinnell BW. Treatment of sepsis-induced acquired protein C deficiency reverses Angiotensin-converting enzyme-2 inhibition and decreases pulmonary inflammatory response. J Pharmacol Exp Ther. 2008;325(1):17–26.CAS Article Google Scholar 
  39. 39.Iba T, Levy JH, Hirota T, et al. Protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis. Thromb Res. 2018;171:1–6.CAS Article Google Scholar 
  40. 40.Bikdeli B, Madhavan MV, Gupta A, Jimenez D, Burton JR, Der Nigoghossian C, Chuich T, Nouri SN, Dreyfus I, Driggin E, Sethi S, Sehgal K, Chatterjee S, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Bertoletti L, Giri J, Cushman M, Quéré I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Tafur AJ, Francese DP, Batra J, Falanga A, Clerkin KJ, Uriel N, Kirtane A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Leon MB, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH, Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost. 2020. https://doi.org/10.1055/s-0040-1713152.Article PubMed PubMed Central Google Scholar 
  41. 41.Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, Kucher N, Studt JD, Sacco C, Alexia B, Sandri MT, Barco S, Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.CAS Article Google Scholar 
  42. 42.Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020;190:62.CAS Article Google Scholar 
  43. 43.Connell NT, Battinelli EM, Connors JM. Coagulopathy of COVID-19 and antiphospholipid antibodies. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14893.Article PubMed PubMed Central Google Scholar 
  44. 44.Chang JC. Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis. Clin Appl Thromb Hemost. 2019;25:1076029619887437.CAS Article Google Scholar 
  45. 45.Williams SR, Hsu FC, Keene KL, Chen WM, Dzhivhuho G, Rowles JL 3rd, Southerland AM, Furie KL, Rich SS, Worrall BB, Sale MM. Genetic drivers of von Willebrand factor levels in an ischemic stroke population and association with risk for recurrent stroke. Stroke. 2017;48(6):1444–500.CAS Article Google Scholar 
  46. 46.Sise ME, Baggett MV, Shepard JO, Stevens JS, Rhee EP. Case 17–2020: a 68-year-old man with Covid-19 and acute kidney injury. N Engl J Med. 2020;382(22):2147–56.Article Google Scholar 
  47. 47.Wright FL, Vogler TO, Moore EE, Moore HB, Wohlauer MV, Urban S, Nydam TL, Moore PK, McIntyre RC Jr. Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection. J Am Coll Surg. 2020;S1072–7515(20):30400–2.Google Scholar 
  48. 48.Kwaan HC. Coronavirus disease 2019: the role of the fibrinolytic system from transmission to organ injury and sequelae. Semin Thromb Hemost. 2020. https://doi.org/10.1055/s-0040-1709996.Article PubMed PubMed Central Google Scholar 
  49. 49.Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, Bonanomi E, D’Antiga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)31103-X.Article PubMed PubMed Central Google Scholar 
  50. 50.Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8.CAS Article Google Scholar 
  51. 51.Roncati L, Ligabue G, Fabbiani L, Malagoli C, Gallo G, Lusenti B, Nasillo V, Manenti A, Maiorana A. Type 3 hypersensitivity in COVID-19 vasculitis. Clin Immunol. 2020;29:108487. https://doi.org/10.1016/j.clim.2020.108487.CAS Article Google Scholar 

Download references

Funding

This work was supported in part by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan.

Author information

Affiliations

  1. Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, JapanToshiaki Iba
  2. Hematology Division Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAJean Marie Connors
  3. Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USAJerrold H. Levy

COVID-19-associated coagulopathy: An exploration of mechanisms

Authors: Meaghan E Colling 1Yogendra Kanthi 2 PMID: 32558620

PMCID: PMC7306998 OI: 10.1177/1358863X20932640

Abstract

An ongoing global pandemic of viral pneumonia (coronavirus disease [COVID-19]), due to the virus SARS-CoV-2, has infected millions of people and remains a threat to many more. Most critically ill patients have respiratory failure and there is an international effort to understand mechanisms and predictors of disease severity. Coagulopathy, characterized by elevations in D-dimer and fibrin(ogen) degradation products (FDPs), is associated with critical illness and mortality in patients with COVID-19. Furthermore, increasing reports of microvascular and macrovascular thrombi suggest that hemostatic imbalances may contribute to the pathophysiology of SARS-CoV-2 infection. We review the laboratory and clinical findings of patients with COVID–19-associated coagulopathy, and prior studies of hemostasis in other viral infections and acute respiratory distress syndrome. We hypothesize that an imbalance between coagulation and inflammation may result in a hypercoagulable state. Although thrombosis initiated by the innate immune system is hypothesized to limit SARS-CoV-2 dissemination, aberrant activation of this system can cause endothelial injury resulting in loss of thromboprotective mechanisms, excess thrombin generation, and dysregulation of fibrinolysis and thrombosis. The role various components including neutrophils, neutrophil extracellular traps, activated platelets, microparticles, clotting factors, inflammatory cytokines, and complement play in this process remains an area of active investigation and ongoing clinical trials target these different pathways in COVID-19.Keywords anticoagulationantiplateletCOVID-19inflammationneutrophilsthrombosisvascular endotheliumvenous thromboembolism (VTE)

Introduction

In December 2019, a new betacoronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), thought to originate in Wuhan, China, emerged as a novel human pathogen for viral pneumonia (coronavirus disease [COVID-19]), resulting in an ongoing pandemic.1,2 The number of cases worldwide now exceeds five million, with more than 350,000 associated deaths, triggering a global effort to understand the predictors of disease severity for rapid triage, and the pathology of disease for rational therapeutic development and clinical trials. A consistent finding in early case series in China and New York City is an association between elevations in D-dimer and fibrin(ogen) degradation products (FDPs) and increasing COVID-19 severity and mortality.37 We aim to review the available data on the coagulopathy observed in COVID-19 and draw from studies of prior viral epidemics to explore possible mechanisms and therapies.

Coronaviruses are enveloped, non-segmented, positive-sense RNA viruses of the Nidovirales order within the Coronaviridae family. Different strains are infectious to a broad range of animals including humans, bats, cats, racoon dogs, rabbits, pigs, and cattle.8 In general, coronavirus infections in humans are mild; however, two recent epidemics of betacoronaviruses – SARS in 2003911 and Middle East Respiratory Syndrome (MERS) in 201212,13 – were associated with significant mortality with death rates around 10% and 35%, respectively.14,15 While the observed case fatality rate for the COVID-19 pandemic is lower,16,17 the population at risk is much higher due to the global spread of the disease and the infectivity of the virus,18 and worldwide fatalities already exceed those in the prior epidemics.

Common clinical manifestations of patients with COVID-19 include fever and cough, and less commonly fatigue, dyspnea, headache, sore throat, anosmia, nausea, vomiting, or diarrhea.6 In the largest case series to date of over 44,000 patients with COVID-19, > 75% of cases were mild, 14% were severe, and 5% were critical, with an overall case fatality rate of 2–2.5%. All deaths occurred in patients with critical disease (in which the case fatality rate was almost 50%).19 While the majority of critically ill patients with COVID-19 have isolated respiratory failure, often acute respiratory distress syndrome (ARDS), multiple organ dysfunction occurs in 20–30% of patients with critical illness and more often in fatal cases.16 Hematologic findings, such as mild to moderate thrombocytopenia and lymphopenia, are associated with COVID-19;20,21 however, the most significant and concerning vascular aspect of this disease is coagulopathy. We have attempted to summarize the data on the pathogenesis, epidemiology and outcomes related to COVID-19-coagulopathy and thrombotic disease using PubMed as well as the pre-print server https://medrxiv.org (date of last search April 23, 2020).

Coagulopathy of SARS-CoV-2 and other infections

There is particular interest in the coagulopathy in patients with COVID-19 as abnormal coagulation parameters, most consistently elevations in D-dimer and FDPs, are associated with disease severity.22,23 An elevated D-dimer, the most common coagulation abnormality in COVID-19 (found in up to 45% of patients), is an independent risk factor for death,6,22,24,25 and patients with D-dimer greater than 1000 ng/mL are almost 20 times more likely to die from their infection than patients with lower D-dimer values.25 In contrast, most patients with COVID-19 have a normal or mildly prolonged prothrombin time (PT) and a normal or shortened activated partial thromboplastin time (aPTT) on presentation and these labs are not reliably associated with disease severity.5,17,22,24,25 Both initial and longitudinal monitoring of coagulation parameters can predict disease severity, as elevated D-dimer and FDP levels on admission and decreased levels of fibrinogen and antithrombin III during the admission are associated with death.23 Although changes in plasminogen activator inhibitor-1 (PAI-1) levels and activity have not been studied, an increase in the PAI-1/tissue plasminogen activator (t-PA) ratio would not be unexpected. These findings may be due to uncontrolled activation of coagulation with ongoing consumption and widespread microvascular thrombosis.

While early descriptions of the coagulopathy identified it as disseminated intravascular coagulation (DIC), in DIC, unlike in severe COVID-19, platelet count and PT prolongation correlate with sepsis severity and mortality, while fibrinogen and FDPs levels do not.26,27 And while the majority of patients who die from COVID-19 develop some laboratory evidence of DIC during their admission, elevations in D-dimer and prolonged PT with mild thrombocytopenia and normal fibrinogen are commonly seen.23 Thromboelastography in patients with COVID-19 in the ICU shows a hypercoagulable state.28 These observations suggest the underlying pathophysiology in at least a subset of critically ill patients with COVID-19 is distinct from traditional systemic DIC and may be due to a unique coagulopathy.

Elevations in D-dimer are common in critical illness and are associated with disease severity and mortality in many severe infections.2931 Patients with influenza, SARS, HIV, hantavirus, Ebola virus, and dengue have elevations in D-dimer, prothrombin fragments, thrombin–antithrombin complexes, and/or plasmin-α2-antiplasmin complexes.32 Similar to patients with SARS-CoV-2 infections, there is an association between elevated D-dimer and mortality in patients with H1N1 and H5N1, which is not seen in SARS.3335

Additionally, in the H1N1 pandemic, patients with severe disease had high rates of venous thromboembolism (VTE) and many patients with thromboembolism did not have evidence of systemic DIC.3639 Patients with ARDS from H1N1 infection had a greater than 20-fold increase in risk of pulmonary embolism compared to patients with ARDS unrelated to H1N1.39 Empiric therapeutic anticoagulation in patients with ARDS was associated with decreased rates of VTE in patients with ARDS from H1N1, but had no effect on VTE rates in patients with ARDS unrelated to H1N1 infection. There are reports of VTE in patients with COVID-19, despite concerns regarding underdiagnosis given baseline elevations in D-dimer, as well as pragmatic challenges in diagnostic imaging while in isolation, including use of personal protective equipment and longer duration of exposure of health care workers.40,41 Although data remain scarce, there are increasing reports of arterial thrombotic events including ischemic strokes in patients with COVID-19.4143 Myocardial injury, defined by elevations in cardiac troponin levels, is common in patients hospitalized with COVID-19 and is associated with severe disease and high risk of mortality.44,45 Myocardial injury may result from systemic inflammatory response syndrome (SIRS) and inflammation as well as due to acute thrombotic events.46,47 Similar observations of myocardial injury have been found in patients with other viral infections.48,49

Pathologic findings in SARS-CoV-2 infection

Although there are only a few published pathologic reports of patients with COVID-19, histopathology of lung specimens from patients with early disease shows characteristic findings of ARDS and evidence of small vessel occlusion.50,51 There are several mechanisms by which SARS-CoV-2 infection may result in microvascular and macrovascular thrombosis, including cytokine storm with activation of leukocytes, endothelium and platelets resulting in upregulation of tissue factor, activation of coagulation, thrombin generation and fibrin formation,52 deranged coagulation with imbalances in PAI-1, tissue factor pathway inhibitor, and activated protein C that promotes fibrin generation and limits fibrinolysis,53,54 hypoxic vaso-occlusion, and direct viral effects with cell activation (Figure 1). It remains an active area of investigation whether these are specific to SARS-CoV-2 infection or a final common pathway in the thromboinflammatory response to viral infections and a marker of disease severity. Early COVID-19 autopsy reports have also identified a possible role for neutrophils as microvascular thrombi contained numerous neutrophils, which in some cases were partially degenerated, consistent with neutrophil extracellular traps (NETs).55,56 NETs are tangles of DNA released from neutrophils, and are decorated with antimicrobial and nuclear proteins that propagate intravascular thrombosis.57,58 NETs initiate both the extrinsic and contact pathways by augmenting presentation of tissue factor, activation of factor XII (FXII), as well as trapping and activating platelets.5962 Consistent with these observations, patients with severe COVID-19 have elevated serum markers of neutrophil activation and NET formation.63 In one study, neutrophil activation measured in serum correlated with, and sometimes preceded, VTE in patients with COVID-19.64

Figure 1. Immune activation and mechanisms of coagulopathy in patients with coronavirus disease 2019 (COVID-19).

Multiple processes may contribute to COVID-19-associated coagulopathy including direct infection of type II pneumocytes and endothelial cells, leading to barrier dysfunction and increased permeability; inflammatory responses characterized by activation of T cells, neutrophils, monocytes, macrophages, and platelets resulting in exuberant inflammatory cytokine release (including IL-1, IL-6, IL-10, TNF-α), monocyte-derived TF and PAI-1 expression; and culminating in the development of microvascular and macrovascular thrombi composed of fibrin, NETs, and platelets.

IL, interleukin; NETs, neutrophil extracellular traps; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; TNF-α, tumor necrosis factor-alpha.

Dysregulation of hemostasis and coagulopathy in acute respiratory distress syndrome (ARDS)

Thrombi in the pulmonary micro- and macrovasculature are observed in patients with ARDS with or without overt DIC, and changes consistent with a prothrombotic state have been found both in blood and in alveolar fluid studies of these patients.65,66 Higher levels of FDPs and D-dimer are seen in patients who developed ARDS as compared to patients with similar predisposing conditions that did not develop ARDS.67 Lower levels of protein C and higher levels of soluble thrombomodulin and PAI-1 are also associated with multiple organ failure, disease severity, and mortality in ARDS in some studies.53,6872 Finally, plasma and alveolar levels of tissue factor are higher in patients with ARDS than patients with pulmonary edema.73 Mechanistically, there is increased thrombin generation by tissue factor coupled with an impaired fibrinolytic response due to elevations in PAI-1. Elevations in D-dimer, a breakdown product of crosslinked fibrin, may result from residual t-PA/plasmin activity, as well as from alternative fibrinolytic pathways such as human neutrophil elastase activity.74,75

As patients with COVID-19 frequently have isolated pulmonary findings, the initial hemostatic dysregulation may be localized to the lungs as a consequence of the bidirectional relationship between the innate immune system and thrombosis. Activated platelets through degranulation and coordinated interactions with monocytes, dendritic cells, and neutrophils, as well as activated T cells, NETs, tissue factor-bearing microparticles, and coagulation proteases may facilitate this crosstalk.54,76,77 In this model, immune cells, inflammatory cytokines, and pathogen-associated molecular patterns induce thrombi consisting of fibrin, monocytes, neutrophils, and platelets.57,58,78 These immunothrombi initially serve a protective purpose, promoting pathogen recognition and creating a sterile barrier against further pathogen invasion, but can become maladaptive and injurious to tissue and organ perfusion.57,79,80 During this process, there is abundant intra- and extra-vascular fibrin deposition and impaired fibrinolysis, which has been well described in ARDS.81,82 In postmortem studies, both macro- and microvascular thrombi are common in patients in ARDS (observed in up to 95% of patients).82,83 In COVID-19, the alveolar immunothrombotic response may be an attempt to limit dissemination of SARS-CoV-2 outside the alveoli.

Findings from the SARS epidemic provide possible viral-specific mechanisms for ARDS and uncontrolled coagulation. Autopsy studies of patients who died of SARS pneumonia, identified the SARS-CoV spike (S) protein in cells expressing the receptor angiotensin-converting enzyme 2 (ACE2),8487 the leading candidate receptor for SARS-CoV-2.88,89 Binding of the S protein to ACE2 induces expression of a nuclear factor kappa B (NFκB)-driven inflammatory module, resulting in production of proinflammatory cytokines including monocyte chemoattractant protein 1 (MCP-1), transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6, which have been implicated in thrombogenesis.90 Although inflammatory responses are important in host-defense, hyperinflammatory responses result in tissue damage, disruption of the endothelial barrier, and uncontrolled activation of coagulation.54 Overall, these findings are consistent with a model in which SARS-CoV and SARS-CoV-2 directly infect endothelial and epithelial cells, increasing levels of proinflammatory cytokines, causing immune-mediated damage to the vasculature and surrounding tissue, with exposure of tissue factor and associated thromboinflammatory changes.91 While these changes appear to be predominantly in the lungs, endotheliitis in COVID-19 has been observed in kidneys, liver, heart, and intestine.91

Additional studies in SARS-CoV and influenza found dysregulation of urokinase, coagulation, and fibrinolysis pathways contributed to the severity of lung injury, possibly through altering the hemostatic balance with subsequent coagulation-induced ischemic injury.92 Plasminogen was protective against severe influenza A, H5N1, and H1N1 infections.93 These groups hypothesized that increased fibrinolysis led to a positive feedback loop of vascular permeability, leukocyte recruitment, and fibrin generation. Interestingly, one hypothesis suggests that elevated plasminogen may be a risk factor for SARS-CoV-2 infection because plasmin may cleave the S protein of the virus and increase its infectivity.94 These findings highlight the delicate balance between corralling infection and uncontrolled inflammation and thrombosis.

Therapeutic considerations

Markers of hypercoagulability and higher inflammatory mediators are consistently associated with worse outcomes in patients with ARDS and sepsis. These observations have led to numerous clinical trials targeting various components of inflammatory and coagulation pathways in acute lung injury, ARDS or sepsis. Studies with heparin, steroids, non-steroidal anti-inflammatory drugs, and TNF-α inhibitors have been disappointing.95100

Given the laboratory and clinical findings in patients with severe COVID-19, several repurposed and novel therapies are under investigation in clinical trials to prevent the hyperinflammatory response or mitigate uncontrolled coagulation. As elevations in D-dimer and FDPs likely reflect ongoing lung injury and microvascular thrombi, possible therapeutic targets include inflammatory cytokines, activated platelets, neutrophils, or microparticles that may propagate thrombosis; or anticoagulants and fibrinolytics that could limit thrombosis. Supporting this enthusiasm was a recent retrospective study in China in which VTE prophylaxic dose heparin was associated with a survival benefit in patients with severe COVID-19 and evidence of sepsis-induced coagulopathy.101 The study found no benefit among patients with milder COVID-19 illness; however, the study did not control for other markers of disease severity nor other therapies, such as antivirals. The study raises the possibility that prophylactic or therapeutic anticoagulation may benefit patients with severe infection. Heparin may alter the biology of the disease not only through its anticoagulant properties, but also due to its anti-inflammatory effects that promote a quiescent endothelium.

Current expert recommendations, including interim guidelines from the International Society on Thrombosis and Haemostasis (ISTH) and the American College of Cardiology (ACC), recommend use of prophylactic dose LMWH or unfractionated heparin in all COVID-19 patients requiring hospital admission; for patients with a contraindication to pharmacologic prophylaxis, mechanical prophylaxis should be used.102,103 While a number of VTE risk stratification tools exist for hospitalized medical patients, these have not been validated in patients with COVID-19. Extended VTE prophylaxis with LMWH or direct oral anticoagulants after hospitalization for acute medical illness reduces the risk of VTE with an associated increased risk of bleeding.104106 There are currently no data regarding extended prophylaxis in patients with COVID-19; however, the ACC expert opinion statement recommends consideration of extended prophylaxis in patients with elevated risk of VTE, such as patients with cancer or prolonged immobility who have low bleeding risk. Given early reports and ongoing concerns of high rates of VTE, randomized trials of empiric therapeutic anticoagulation or antifibrinolytics are ongoing, and there are reports of empiric therapeutic anticoagulation in patients with significantly elevated D-dimer both in Italy and in the US. While heparin offers both anti-inflammatory and anticoagulant effects, the benefit of therapeutic anticoagulation remains uncertain, with a risk of bleeding complications in critically ill patients with respiratory failure.95,107 Clinical trials will help define the role of heparin in the treatment of hospitalized patients with COVID-19. Outside of a trial setting, we advocate universal standard-dose pharmacologic VTE prophylaxis in patients without a contraindication. In patients with a high suspicion of VTE where access to confirmatory or serial imaging is limited, clinicians may consider empiric anticoagulation, although there is a paucity of evidence to provide guidance in this context. There are currently no randomized data to recommend empiric therapeutic or intermediate-dose anticoagulation in patients without documented VTE, or an other indication for anticoagulation, or outside the context of a clinical trial. A recent retrospective, observational study in New York City showed therapeutic anticoagulation was associated with decreased mortality in patients with COVID-19 who required mechanical ventilation, but not in all hospitalized patients with COVID-19. Although these findings are provocative, interpretation is limited by their observational nature.108

There are over 300 trials ongoing for patients with COVID-19, many of which aim to simultaneously reduce inflammation and thrombosis, including cytokine-directed therapies (against IL-1, IL-6, interferon gamma), corticosteroids, Janus kinase inhibitors, TLR ligands, complement inhibitors, N-acetylcysteine, serine protease inhibitors, DNAse enzymes, and anti-viral agents. However, suppressing the cytokine storm or hypercoagulability may be insufficient once initiated, and targeting upstream pathways to prevent activation of this self-amplifying feedback loop may be more effective.

One therapeutic candidate to treat COVID-19 is dipyridamole, an adenosinergic drug indicated for use as an arterial thromboembolic prophylaxis agent in combination with aspirin or warfarin.109 Dipyridamole has recently been shown to suppress human neutrophil and T-cell activation, upstream of cytokine effectors.58,110 Dipyridamole induces a type I interferon response, which is necessary for physiologic anti-viral activity, and inhibits SARS-CoV-2 replication in vitro by inhibiting a critical viral replication complex.111,112 Administered orally, dipyridamole has a favorable safety profile, and a small clinical trial in patients with COVID-19 suggests it may improve D-dimer levels.113 Randomized clinical trials of agents active at the intersection of inflammation and coagulation in COVID-19, such as dipyridamole, t-PA, and heparin are necessary to determine if these therapeutics can restore the balance of inflammation and coagulation without dampening early or late physiologic anti-viral responses. The heterogenous response to the SARS-CoV-2 infection and the various time-dependent pathways driving pathology make universal therapies challenging. The temporal and mechanistic role each pathway plays in severe SARS-CoV-2 infection remains uncertain and requires further exploration for treatment opportunities as efforts to control this pandemic continue.

Conclusions

In conclusion, in patients with COVID-19, the presence of coagulopathy, characterized by elevations in D-dimer and FDPs, is consistently associated with more severe illness and mortality. Laboratory, clinical, and early histopathologic findings suggest this coagulopathy is distinct from sepsis-induced DIC and may reflect dysregulated hemostasis. Similar findings have been associated with several other viral infections, and it remains uncertain if this coagulopathy is specific to SARS-CoV-2 or the end common pathway of the thrombo-inflammatory response to severe viral infections. There are efforts to target numerous components of the thrombo-inflammatory pathway to improve outcomes in patients with severe COVID-19. The optimal management for these patients including strategies to diagnose VTE, appropriate anticoagulation doses and duration, and effectiveness of novel therapies are under active investigation in the current pandemic.

Acknowledgements

The authors would like to thank Charles Bolan, MD and Jason Knight, MD, PhD for guidance and review of the manuscript, and all members of the ‘NETwork to Target Neutrophils in COVID-19’ and the SVM Next Generation Committee for their helpful advice and encouragement. The authors credit Alan Hoofring for the illustration.

Declaration of conflicting interests
Yogen Kanthi has served as a consultant for Surface Oncology and has a pending patent on use of biogases in vascular disease. Meaghan E. Colling has nothing to disclose.

Funding
Meaghan E. Colling is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Yogen Kanthi is supported by grant funding from the NIH-NHLBI (K08HL131993, R01HL150392), A. Alfred Taubman Medical Research Institute, Michigan Medicine Frankel COVID-19 Cardiovascular Impact Research Ignitor Program, Falk Medical Research Trust Catalyst Award, American Venous Forum-JOBST Award, University of Michigan BioInterfaces Institute, and Bo Schembechler Heart of A Champion Foundation.

ORCID iD
Yogendra Kanthi  https://orcid.org/0000-0002-5660-5194

References

1.World Health Organization . Pneumonia of unknown cause – China. Disease outbreak news, 5 January, https://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/ (2020, accessed 25 March 2020).
Google Scholar
2.Zhu, N, Zhang, D, Wang, W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727–733.
Google Scholar | Crossref | Medline
3.Gao, Y, Li, T, Han, M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol. 2020; 92: 791–796.
Google Scholar | Crossref | Medline
4.Wan, S, Xiang, Y, Fang, W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol. 2020; 92: 797–806.
Google Scholar | Crossref | Medline
5.Huang, C, Wang, Y, Li, X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.
Google Scholar | Crossref | Medline
6.Guan, WJ, Ni, ZY, Hu, Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382: 1708–1720.
Google Scholar | Crossref | Medline
7.Petrilli, CM, Jones, SA, Yang, J, et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. BMJ 2020; 369: m1966.
Google Scholar | Crossref | Medline
8.Saif, LJ. Animal coronavirus vaccines: lessons for SARS. Dev Biol (Basel) 2004; 119: 129–140.
Google Scholar | Medline
9.Kuiken, T, Fouchier, RA, Schutten, M, et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 2003; 362: 263–270.
Google Scholar | Crossref | Medline | ISI
10.Drosten, C, Gunther, S, Preiser, W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1967–1976.
Google Scholar | Crossref | Medline | ISI
11.Ksiazek, TG, Erdman, D, Goldsmith, CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1953–1966.
Google Scholar | Crossref | Medline | ISI
12.De Groot, RJ, Baker, SC, Baric, RS, et al. Middle East respiratory syndrome coronavirus (MERS-CoV): Announcement of the Coronavirus Study Group. J Virol 2013; 87: 7790–7792.
Google Scholar | Crossref | Medline | ISI
13.Zaki, AM, van Boheemen, S, Bestebroer, TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367: 1814–1820.
Google Scholar | Crossref | Medline | ISI
14.World Health Organization . Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003, https://www.who.int/csr/sars/country/table2004_04_21/en/ (2003, accessed 28 March 2020).
Google Scholar
15.World Health Organization . Middle East respiratory syndrome coronavirus (MERS-CoV). MERS Monthly Summary, November 2019, http://www.who.int/emergencies/mers-cov/en/ (2019, accessed 27 March 2020).
Google Scholar
16.Yang, X, Yu, Y, Xu, J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020; 8: 475–481.
Google Scholar | Crossref | Medline
17.Wang, D, Hu, B, Hu, C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323: 1061–1069.
Google Scholar | Crossref | Medline
18.Petrosillo, N, Viceconte, G, Ergonul, O, et al. COVID-19, SARS and MERS: Are they closely related? Clin Microbiol Infect 2020; 26:729–734.
Google Scholar | Crossref | Medline
19.Wu, Z, McGoogan, JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323: 1239–1242.
Google Scholar | Crossref | Medline
20.Zhou, P, Yang, XL, Wang, XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270–273.
Google Scholar | Crossref | Medline
21.Lippi, G, Plebani, M, Henry, BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020; 506: 145–148.
Google Scholar | Crossref | Medline
22.Wu, C, Chen, X, Cai, Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180: 1–11.
Google Scholar | Crossref
23.Tang, N, Li, D, Wang, X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 844–847.
Google Scholar | Crossref | Medline
24.Chen, N, Zhou, M, Dong, X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020; 395: 507–513.
Google Scholar | Crossref | Medline
25.Zhou, F, Yu, T, Du, R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020; 395: 1054–1062.
Google Scholar | Crossref | Medline
26.Iba, T, Levy, JH, Warkentin, TE, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019; 17: 1989–1994.
Google Scholar | Crossref | Medline
27.Iba, T, Di Nisio, M, Thachil, J, et al. A proposal of the modification of Japanese Society on Thrombosis and Hemostasis (JSTH) Disseminated Intravascular Coagulation (DIC) diagnostic criteria for sepsis-associated DIC. Clin Appl Thromb Hemost 2018; 24: 439–445.
Google Scholar | SAGE Journals
28.Panigada, M, Bottino, N, Tagliabue, P, et al. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18: 1738–1742.
Google Scholar | Crossref | Medline
29.Shorr, AF, Thomas, SJ, Alkins, SA, et al. D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients. Chest 2002; 121: 1262–1268.
Google Scholar | Crossref | Medline | ISI
30.Rodelo, JR, De la Rosa, G, Valencia, ML, et al. D-dimer is a significant prognostic factor in patients with suspected infection and sepsis. Am J Emerg Med 2012; 30: 1991–1999.
Google Scholar | Crossref | Medline
31.Wan, J, Yang, X, He, W, et al. Serum D-dimer levels at admission for prediction of outcomes in acute pancreatitis. BMC Gastroenterol 2019; 19: 67.
Google Scholar | Crossref | Medline
32.Goeijenbier, M, van Wissen, M, van de Weg, C, et al. Review: Viral infections and mechanisms of thrombosis and bleeding. J Med Virol 2012; 84: 1680–1696.
Google Scholar | Crossref | Medline
33.Wong, RS, Wu, A, To, KF, et al. Haematological manifestations in patients with severe acute respiratory syndrome: Retrospective analysis. BMJ 2003; 326: 1358–1362.
Google Scholar | Crossref | Medline
34.Soepandi, PZ, Burhan, E, Mangunnegoro, H, et al. Clinical course of avian influenza A(H5N1) in patients at the Persahabatan Hospital, Jakarta, Indonesia, 2005–2008. Chest 2010; 138: 665–673.
Google Scholar | Crossref | Medline
35.Wang, ZF, Su, F, Lin, XJ, et al. Serum D-dimer changes and prognostic implication in 2009 novel influenza A(H1N1). Thromb Res 2011; 127: 198–201.
Google Scholar | Crossref | Medline
36.Centers for Disease Control and Prevention . Intensive-care patients with severe novel influenza A (H1N1) virus infection – Michigan, June 2009. MMWR Morb Mortal Wkly Rep 2009; 58: 749–752.
Google Scholar | Medline
37.Avnon, LS, Munteanu, D, Smoliakov, A, et al. Thromboembolic events in patients with severe pandemic influenza A/H1N1. Eur J Intern Med 2015; 26: 596–598.
Google Scholar | Crossref | Medline
38.Bunce, PE, High, SM, Nadjafi, M, et al. Pandemic H1N1 influenza infection and vascular thrombosis. Clin Infect Dis 2011; 52: e14–17.
Google Scholar | Crossref | Medline
39.Obi, AT, Tignanelli, CJ, Jacobs, BN, et al. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord 2019; 7: 317–324.
Google Scholar | Crossref | Medline
40.Cui, S, Chen, S, Li, X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Epub ahead of print 6 May 2020. DOI: 10.1111/jth.14830.
Google Scholar | Crossref
41.Klok, FA, Kruip, M, van der Meer, NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 141–147.
Google Scholar
42.Lodigiani, C, Iapichino, G, Carenzo, L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9–14.
Google Scholar | Crossref | Medline
43.Oxley, TJ, Mocco, J, Majidi, S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med 2020; 382: e60.
Google Scholar | Crossref | Medline
44.Guo, T, Fan, Y, Chen, M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5: 811–818.
Google Scholar | Crossref | Medline
45.Shi, S, Qin, M, Shen, B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020; 5: 802–810.
Google Scholar | Crossref | Medline
46.Lacour, T, Semaan, C, Genet, T, et al. Insights for increased risk of failed fibrinolytic therapy and stent thrombosis associated with COVID-19 in ST-segment elevation myocardial infarction patients. Catheter Cardiovasc Interv. Epub ahead of print 30 April 2020. DOI: 10.1002/ccd.28948.
Google Scholar | Crossref
47.Corrales-Medina, VF, Madjid, M, Musher, DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: 83–92.
Google Scholar | Crossref | Medline | ISI
48.Madjid, M, Aboshady, I, Awan, I, et al. Influenza and cardiovascular disease: Is there a causal relationship? Tex Heart Inst J 2004; 31: 4–13.
Google Scholar | Medline | ISI
49.Kwong, JC, Schwartz, KL, Campitelli, MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018; 378: 345–353.
Google Scholar | Crossref | Medline
50.Tian, S, Hu, W, Niu, L, et al. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020; 15: 700–704.
Google Scholar | Crossref | Medline
51.Xu, Z, Shi, L, Wang, Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8: 420–422.
Google Scholar | Crossref | Medline
52.Sebag, SC, Bastarache, JA, Ware, LB. Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome. Curr Pharm Biotechnol 2011; 12: 1481–1496.
Google Scholar | Crossref | Medline
53.Ware, LB, Fang, X, Matthay, MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285: L514–521.
Google Scholar | Crossref | Medline | ISI
54.Frantzeskaki, F, Armaganidis, A, Orfanos, SE. Immunothrombosis in acute respiratory distress syndrome: Cross talks between inflammation and coagulation. Respiration 2017; 93: 212–225.
Google Scholar | Crossref | Medline
55.Fox, SE, Akmatbekov, A, Harbert, JL, et al. Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series from New Orleans. Lancet Respir Med 2020; 8: 681–686.
Google Scholar | Crossref | Medline
56.Barnes, BJ, Adrover, JM, Baxter-Stoltzfus, A, et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med 2020; 217: e20200652.
Google Scholar | Crossref | Medline
57.Yadav, V, Chi, L, Zhao, R, et al. Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1beta-driven venous thrombosis. J Clin Invest 2019; 129: 2872–2877.
Google Scholar | Crossref | Medline
58.Ali, RA, Gandhi, AA, Meng, H, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat Commun 2019; 10: 1916.
Google Scholar | Crossref
59.Kambas, K, Mitroulis, I, Ritis, K. The emerging role of neutrophils in thrombosis—The journey of TF through NETs. Front Immunol 2012; 3: 385.
Google Scholar | Crossref | Medline
60.Liberale, L, Holy, EW, Akhmedov, A, et al. Interleukin-1β mediates arterial thrombus formation via NET-associated tissue factor. J Clin Med 2019; 8: 2072.
Google Scholar | Crossref
61.Noubouossie, DF, Reeves, BN, Strahl, BD, et al. Neutrophils: Back in the thrombosis spotlight. Blood 2019; 133: 2186–2197.
Google Scholar | Crossref | Medline
62.Thalin, C, Hisada, Y, Lundstrom, S, et al. Neutrophil extracellular traps: Villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler Thromb Vasc Biol 2019; 39: 1724–1738.
Google Scholar | Crossref | Medline
63.Zuo, Y, Yalavarthi, S, Shi, H, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. Epub ahead of print 24 April 2020. DOI: 10.1172/jci.insight.138999.
Google Scholar | Crossref
64.Zuo, Y, Zuo, M, Yalavarthi, S, et al. Neutrophil extracellular traps and thrombosis in COVID-19. medRxiv. Preprint 5 May 2020. DOI: 10.1101/2020.04.30.20086736.
Google Scholar | Crossref
65.Bone, RC, Francis, PB, Pierce, AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61: 585–589.
Google Scholar | Crossref | Medline | ISI
66.Blondonnet, R, Constantin, JM, Sapin, V, et al. A pathophysiologic approach to biomarkers in acute respiratory distress syndrome. Dis Markers 2016; 2016: 3501373.
Google Scholar | Crossref | Medline
67.Haynes, JB, Hyers, TM, Giclas, PC, et al. Elevated fibrin(ogen) degradation products in the adult respiratory distress syndrome. Am Rev Respir Dis 1980; 122: 841–847.
Google Scholar | Medline
68.Sapru, A, Calfee, CS, Liu, KD, et al. Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome. Int Care Med 2015; 41: 470–478.
Google Scholar | Crossref | Medline
69.Ware, LB, Matthay, MA, Parsons, PE, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35: 1821–1828.
Google Scholar | Medline | ISI
70.Thompson, BT, Chambers, RC, Liu, KD. Acute respiratory distress syndrome. N Engl J Med 2017; 377: 1904–1905.
Google Scholar | Crossref | Medline
71.Prabhakaran, P, Ware, LB, White, KE, et al. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003; 285: L20–28.
Google Scholar | Crossref | Medline
72.Agrawal, A, Zhuo, H, Brady, S, et al. Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: Results from two clinical trials. Am J Physiol Lung Cell Mol Physiol 2012; 303: L634–639.
Google Scholar | Crossref | Medline
73.Bastarache, JA, Wang, L, Geiser, T, et al. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax 2007; 62: 608–616.
Google Scholar | Crossref | Medline
74.Bach-Gansmo, ET, Halvorsen, S, Godal, HC, et al. D-dimers are degraded by human neutrophil elastase. Thromb Res 1996; 82: 177–186.
Google Scholar | Crossref | Medline
75.Gando, S, Hayakawa, M, Sawamura, A, et al. The activation of neutrophil elastase-mediated fibrinolysis is not sufficient to overcome the fibrinolytic shutdown of disseminated intravascular coagulation associated with systemic inflammation. Thromb Res 2007; 121: 67–73.
Google Scholar | Crossref | Medline
76.Koupenova, M, Clancy, L, Corkrey, HA, et al. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res 2018; 122: 337–351.
Google Scholar | Crossref | Medline
77.Mackman, N. The many faces of tissue factor. J Thromb Haemost 2009; 7(suppl 1): 136–139.
Google Scholar | Crossref | Medline
78.Chang, JC. Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: Based on hemostatic theory and endothelial molecular pathogenesis. Clin Appl Thromb Hemost 2019; 25: 1076029619887437.
Google Scholar | SAGE Journals
79.Van der Poll, T, Herwald, H. The coagulation system and its function in early immune defense. Thromb Haemost 2014; 112: 640–648.
Google Scholar | Crossref | Medline
80.Lefrancais, E, Mallavia, B, Zhuo, H, et al. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 2018; 3: e98178.
Google Scholar | Crossref | Medline
81.Glas, GJ, Van Der Sluijs, KF, Schultz, MJ, et al. Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome. J Thromb Haemost 2013; 11: 17–25.
Google Scholar | Crossref | Medline
82.Tomashefski, JF Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med 2000; 21: 435–466.
Google Scholar | Crossref | Medline | ISI
83.Vesconi, S, Rossi, GP, Pesenti, A, et al. Pulmonary microthrombosis in severe adult respiratory distress syndrome. Crit Care Med 1988; 16: 111–113.
Google Scholar | Crossref | Medline | ISI
84.He, Y, Zhou, Y, Liu, S, et al. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: Implication for developing subunit vaccine. Biochem Biophys Res Commun 2004; 324: 773–781.
Google Scholar | Crossref | Medline
85.Li, W, Greenough, TC, Moore, MJ, et al. Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin-converting enzyme 2. J Virol 2004; 78: 11429–11433.
Google Scholar | Crossref | Medline
86.Li, W, Moore, MJ, Vasilieva, N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426: 450–454.
Google Scholar | Crossref | Medline | ISI
87.Xiao, X, Chakraborti, S, Dimitrov, AS, et al. The SARS-CoV S glycoprotein: Expression and functional characterization. Biochem Biophys Res Commun 2003; 312: 1159–1164.
Google Scholar | Crossref | Medline | ISI
88.Hoffmann, M, Kleine-Weber, H, Schroeder, S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271–280.e8.
Google Scholar | Crossref | Medline
89.Wrapp, D, Wang, N, Corbett, KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367: 1260–1263.
Google Scholar | Crossref | Medline
90.He, L, Ding, Y, Zhang, Q, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: Relation to the acute lung injury and pathogenesis of SARS. J Pathol 2006; 210: 288–297.
Google Scholar | Crossref | Medline | ISI
91.Varga, Z, Flammer, AJ, Steiger, P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395: 1417–1418.
Google Scholar | Crossref | Medline
92.Gralinski, LE, Bankhead, A, Jeng, S, et al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio 2013; 4: e00271-13.
Google Scholar | Crossref | Medline
93.Berri, F, Rimmelzwaan, GF, Hanss, M, et al. Plasminogen controls inflammation and pathogenesis of influenza virus infections via fibrinolysis. PLoS Pathog 2013; 9: e1003229.
Google Scholar | Crossref | Medline
94.Ji, HL, Zhao, R, Matalon, S, et al. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev 2020; 100: 1065–1075.
Google Scholar | Crossref | Medline
95.Jaimes, F, De La Rosa, G, Morales, C, et al. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med 2009; 37: 1185–1196.
Google Scholar | Crossref | Medline
96.Abraham, E, Anzueto, A, Gutierrez, G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 1998; 351: 929–933.
Google Scholar | Crossref | Medline | ISI
97.Abraham, E, Wunderink, R, Silverman, H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273: 934–941.
Google Scholar | Crossref | Medline | ISI
98.National Heart, Lung, and Blood Institute ARDS Clinical Trials Network , Truwit, JD, Bernard, GR, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014; 370: 2191–2200.
Google Scholar | Crossref | Medline | ISI
99.Bernard, GR, Wheeler, AP, Russell, JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997; 336: 912–918.
Google Scholar | Crossref | Medline | ISI
100.Steinberg, KP, Hudson, LD, Goodman, RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354: 1671–1684.
Google Scholar | Crossref | Medline | ISI
101.Tang, N, Bai, H, Chen, X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18: 1094–1099.
Google Scholar | Crossref | Medline
102.Thachil, J, Tang, N, Gando, S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18: 1023–1026.
Google Scholar | Crossref | Medline
103.Bikdeli, B, Madhavan, MV, Jimenez, D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020; S0735-1097(20): 35008-7.
Google Scholar | Crossref
104.Cohen, AT, Harrington, RA, Goldhaber, SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375: 534–544.
Google Scholar | Crossref | Medline | ISI
105.Cohen, AT, Spiro, TE, Spyropoulos, AC; MAGELLAN Steering Committee . Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368: 1945–1946.
Google Scholar | Crossref | Medline
106.Dentali, F, Mumoli, N, Prisco, D, et al. Efficacy and safety of extended thromboprophylaxis for medically ill patients. A meta-analysis of randomised controlled trials. Thromb Haemost 2017; 117: 606–617.
Google Scholar | Crossref | Medline
107.Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330: 377–381.
Google Scholar | Crossref | Medline | ISI
108.Paranjpe, I, Fuster, V, Lala, A, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; S0735-1097(20): 35218-9.
Google Scholar | Crossref
109.Persantine (dipyridamole) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. December 2019.
Google Scholar
110.Macatangay, BJC, Jackson, EK, Abebe, KZ, et al. A randomized, placebo-controlled, pilot clinical trial of dipyridamole to decrease HIV-associated chronic inflammation. J Infect Dis 2020; 221: 1598–1606.
Google Scholar | Crossref | Medline
111.Li, Z, Li, X, Huang, Y-Y, et al. FEP-based screening prompts drug repositioning against COVID-19. bioRxiv. Preprint 25 March 2020. DOI: https://doi.org/10.1101/2020.03.23.004580.
Google Scholar
112.Galabov, AS, Mastikova, M. Dipyridamole induces interferon in man. Biomed Pharmacother. 1984; 38: 412–413.
Google Scholar | Medline
113.Liu, X, Li, Z, Liu, S, et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharm Sin B 2020; 10: 1205–1215.
Google Scholar | Crossref | Medline

Role of von Willebrand Factor in COVID-19 Associated Coagulopathy

Authors: Zhen W MeiXander M R van WijkHuy P PhamMaximo J Marin

The Journal of Applied Laboratory Medicine, Volume 6, Issue 5, September 2021, Pages 1305–1315,  https://doi.org/10.1093/jalm/jfab042Published: 13 June 2021

Abstract

Background

COVID-19, the disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can present with symptoms ranging from none to severe. Thrombotic events occur in a significant number of patients with COVID-19, especially in critically ill patients. This apparent novel form of coagulopathy is termed COVID-19-associated coagulopathy (CAC), and endothelial derived von Willebrand factor (vWF) may play an important role in its pathogenesis.Content

vWF is a multimeric glycoprotein molecule that is involved in inflammation, primary and secondary hemostasis. Studies have shown that patients with COVID-19 have significantly elevated levels of vWF antigen and activity, likely contributing to an increased risk of thrombosis seen in CAC. The high levels of both vWF antigen and activity have been clinically correlated with worse outcomes. Furthermore, the severity of a COVID-19 infection appears to reduce molecules that regulate vWF level and activity such as ADAMTS-13 and high-density lipoproteins (HDL). Finally, studies have suggested that patients with group O blood (a blood group with lower baseline levels of vWF) have a lower risk of infection and disease severity compared to other ABO blood groups; however, more studies are needed to elucidate the role of vWF.Summary

CAC is a significant contributor to morbidity and mortality. Endothelial dysfunction with the release of prothrombotic factors, such as vWF, needs further examination as a possible important component in the pathogenesis of CAC.von Willebrand FactorCOVID-19coagulopathyendothelial injurythrombosisIssue Section: Mini-review

Introduction and Background

COVID-19 Pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in Wuhan, China in 2019. COVID-19, the disease caused by SARS-CoV-2, quickly evolved into a global pandemic. According to the Johns Hopkins COVID-19 Dashboard, there were more than 20 million confirmed cases and almost 350,000 deaths in the US alone, by the end of 2020. Although COVID-19 may present with a variety of symptoms, a large majority of infected individuals may have none to only mild symptoms (1). However, the mortality rate is dominated by a subset of patients with severe respiratory failure that meet the criteria for acute respiratory distress syndrome (ARDS) and require respiratory support (12). The development of severe disease is related to interstitial viral pneumonia, systemic inflammation, respiratory failure, and multiorgan dysfunction (3).Impact Statement

COVID-19 is a global pandemic with no current effective treatment. COVID-19-associated coagulopathy contributes to patient morbidity and mortality. von Willebrand factor (vWF) may play an important role in the pathogenesis of this coagulopathy. Currently, available studies have demonstrated that patients with COVID-19 have significantly elevated levels of vWF antigen and activity as well as reduced regulatory molecules, which could contribute to an increased risk of thrombosis seen in patients who develop coagulopathy. Elucidation of vWF role in patients with COVID-19 may offer additional insights into developing novel therapies for this disease.

Viral Pathophysiology

SARS-CoV-2 preferentially binds to host cells that express the angiotensin-converting enzyme-2 receptor (ACE2) through the viral spike protein structure. The initiation and progression of the SARS-CoV-2 infection is likely dependent on a combination of factors, including, but not limited to, host cell expression of ACE2, anatomic contiguity with the environment, inoculation dose at the time of exposure, and the host immune response to the infection. In general, the initial infection by the SARS-CoV-2 virus targets the cells of the respiratory system such as nasal or bronchial epithelial cells and pneumocytes. However, if the severity of the infection progresses to a systemic inflammatory phase, the mechanism is likely a complex combination of the virus entering the blood stream, infection of other cells expressing ACE2 receptors, tissue/organ specificity, and the inflammatory milieu. However, the extent to which each factor contributes to the systemic severity remains unclear. Additionally, in severe COVID-19 cases, endothelial cells (ECs), which also express ACE2 receptors, are activated, leading to endothelial dysfunction and possible injury that parallels clinical manifestations, such as coagulopathy and prothrombotic tendency (4).

COVID-19 Associated Coagulopathy

It is clear that a significant component of the observed morbidity and mortality is directly related to lung injury as supported by COVID-19 related autopsies (56). The predominant pattern of injury was found to be diffuse alveolar damage, which includes hyaline membrane formation, capillary congestion, inflammation, and pneumocyte necrosis. In addition, the study also identified platelet-fibrin thrombi in small arterial vessels in 87% of their cases (6). A more recent, albeit small, series showed that all COVID-19 related autopsies demonstrated platelet-fibrin thrombi in multiple organs, including the liver, kidney, heart, and lungs (5). Another autopsy case series compared lung tissue from equally severe, age-matched patients with ARDS with either COVID-19 or influenza A (H1N1) and found that alveolar capillary microthrombi were more prevalent in COVID-19 than influenza (7). This study also observed that COVID-19 lung tissue showed significant EC injury associated with intracellular SARS-CoV-2 infection (7). Furthermore, there is some evidence to suggest that COVID-19 associated coagulopathy (CAC) might be different from other coagulopathic conditions, such as disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA), which are associated with other underlying causes such as infections, malignancy, autoimmune, and hereditary diseases (Table 1) (8). Taken together, the data indicate that a distinct coagulopathy may be occurring in COVID-19 patients, particularly those with severe symptoms.

Table 1

Laboratory data in COVID-19 and other coagulopathies.

Platelet countD-dimerPT/INR; aPTTFibrinogenAntithrombin activityComplement activationInflammatory cytokinesADAMTS-13vWF antigen
Normal within reference range within reference range within reference range within reference range within reference range within reference range within reference range within reference range within reference range 
COVID-19 generally, mildly elevated early and decreases as severity increases elevated no change to mildly elevated elevated no change increased activation, may result in lower antigen levels due to consumption elevated mildly decreased elevated 
DIC/SIC decreased elevated elevated no change to decreased decreased no increase elevated normal decreased 
TTP Severely decreased no change to elevated no change to elevated no change no change normal to mildly increased decreased severely decreased normal to mildly elevated 
HUS decreased no change to elevated no change to elevated no change no change usually mildly increased but may be normal decreased normal normal to mildly elevated 
Atypical HUS decreased no change to elevated no change to elevated no change no change moderate to severely increased decreased normal to moderately decreased normal to mildly elevated 

Normal values will vary among laboratories due to varying methodologies and reagents. Given that there are multiple markers for complement activation, inflammation, and acute phase reactants, reference ranges for these (patho)-physiological events are not provided. Of note, ADAMTS13 measurement is generally the reliable biomarker distinguishing TTP from HUS/atypical HUS. HUS can be distinguished from aHUS if the patient has history of Shiga-toxin or Streptococcus exposure. Other biomarkers may be overlapping in the spectrum from DIC/SIC to TTP/HUS/aHUS. DIC: disseminated intravascular coagulation, SIC: sepsis-induced coagulopathy, TMA: thrombotic microangiopathy, TTP: thrombotic thrombocytopenia purpura, aHUS: atypical hemolytic uremic syndrome, PT: prothrombin time, aPTT: activated partial thromboplastin time, vWF: von Willebrand factor. Adapted from Iba et al. (8).Open in new tab

Incidence of CAC, especially in severe COVID-19 cases, was apparent from early reports in Wuhan (9). A number of studies have shown that the development of CAC is an important prognostic indicator of poor outcomes (10–12). One study evaluated the rate of arterial and venous thrombotic events in COVID-19 pneumonia patients admitted into the intensive care unit (ICU) and found that the incidence of thrombotic events in 184 patients was 49% (after adjustment for competing risk of death) despite receiving routine pharmacologic thromboprophylaxis; not surprisingly, these thrombotic complications led to a higher risk of death (13). Additional studies have shown similar incidence rates of thrombotic events in COVID-19 ICU patients (1415). Collectively, clinical studies suggest that CAC leads to a prothrombotic state even with standard pharmacologic thromboprophylaxis treatment.

Laboratory Patterns

In general, CAC is characterized by mild thrombocytopenia, slight prolongation of the prothrombin time (PT), high levels of D-dimer, and elevated fibrinogen (81216) (Table 1). Recent International Society for Thrombosis and Hemostasis (ISTH) interim guidance recommends monitoring these 4 parameters in the management of patients with CAC. D-dimer was designated the highest level of priority as many studies have shown that elevated levels are associated with increasing severity of disease and mortality risk (3101117–20). These studies reported a range of associations of higher D-dimer levels in COVID patients, including greater risk of mortality (31118), increased disease severity (1011), increased incidence of pulmonary emboli (17), and need for intensive care (20). Based on this data, clinical services can order a baseline D-dimer level to determine the current morbidity and mortality risk that a COVID-19 patient carries and can follow a D-dimer level to predict progression to more severe disease.

D-dimer is a breakdown product of mature clots (cross-linked fibrin mesh) that undergoes fibrinolysis. Though some studies reported data where the association with D-dimer and death may not be as compelling (2122), D-dimer levels do play a role during the follow-up and treatment of patients with CAC. There is, however, another biomarker, von Willebrand factor (vWF), which may also play an important role in the evaluation of CAC patients due to its direct relationship to hemostasis, inflammation, and EC activation/injury, which are all important aspects of COVID-19 pathogenesis. The biological role of vWF and its association with CAC will be the focus of the remainder of this review.

vWF Physiology and Laboratory Testing

vWF Biology

vWF is a multimeric glycoprotein ranging from 2 to >60 prepropolypeptide units that are each 2138 amino acids in length. The vWF propeptide sequence serves to align 2 units together to allow proper cross-linking during the multimerization process. Further post-translational modification leads to removal of the propeptide sequence as well as glycosylation, including the addition of blood group determinants. This addition of an A or B blood group determinant only occurs during EC glycosylation. Following these processes, a heterogenous mix of ultra-large-vWF (UL-vWF) molecules are synthesized and stored in megakaryocytes and ECs, respectively, in alpha granules and Weibel–Palade bodies (WPB). Additionally, other processing components such as vWF propeptides are found in the WPB of ECs. Although platelets do play an important role in both storage and secretion of vWF, this review will focus on ECs.

When ECs are activated, UL-vWF molecules are released and can either remain free-floating in the plasma or localized on endothelial surfaces. UL-vWF have greater prothrombotic activity than smaller vWF multimers. Therefore, as UL-vWF molecules are secreted, ADAMTS-13 (a disintegrase and metalloproteinase with a thrombospondin type 1 motif, member 13), cleaves vWF into smaller multimers to mitigate unwanted thrombus formation and leads to a variation in the sizes of vWF found both in the plasma and on endothelial surfaces. Elevated vWF activity levels depend on the presence of the largest vWF multimers and activation by shear stress in the circulatory system. vWF responds to shear stress by unfolding and exposing sites for activity such as self-association, platelet binding, and ADAMTS-13 cleavage. Accordingly, the imbalance of these components may lead to a prothrombotic state.

Role in Primary Hemostasis

Primary hemostasis is the process of the platelet clot formation at the site of blood vessel injury. For proper primary hemostasis to occur, platelet adhesion and aggregation must occur. During platelet adhesion at the site of blood vessel injury, platelets can bind directly to the exposed subendothelial collagen (via GPIa-IIa or GPVI receptors) or indirectly via vWF. In the latter case, platelets bind to the vWF molecule via the platelet glycoprotein Ib-V-IX receptor (GPIb) while vWF is bound to subendothelial collagen. Additionally, vWF also promotes platelet aggregation (platelet–platelet interaction) by binding to platelet surface receptor GPIIb/IIIa. Although GPIIb/IIIa is better known as a fibrinogen receptor, it can bind to both fibrinogen and vWF. In summary, vWF plays a vital role in platelet adhesion and aggregation in clot formation.

Role in Secondary Hemostasis

vWF also performs an important role in secondary hemostasis. Secondary hemostasis involves coagulation factors and the coagulation cascade to produce a fibrin meshwork at the site of vessel injury. vWF facilitates the secondary hemostasis process in two ways. First, vWF serves as a carrier protein for Factor VIII, extending Factor VIII’s half-life in the plasma. Although this may initially seem trivial, the vWF carrier activity stabilizes Factor VIII and significantly extends its half-life 4 to 6-fold. Second, it releases and concentrates Factor VIII at the site of injury. Factor VIII is a clotting factor that, when activated, complexes with other factors to ultimately produce fibrin. To highlight the significance of vWF in this process, mutations affecting the vWF binding site for Factor VIII leads to decreased levels of Factor VIII, known as Type 2N von Willebrand disease (vWD), resulting in a clinical presentation similar to hemophilia A, which is a bleeding disorder that occurs when an individual lacks the ability to produce adequate amounts of Factor VIII for proper clotting.

vWF, Inflammation, and Endothelial Activation/Injury

During the inflammatory process, various chemical mediators are released. These inflammatory molecules activate ECs to release their WPB contents, including vWF and other molecules such as P-selectin, which has been directly linked to leukocyte recruitment (2324). In addition, UL-vWF molecules that remain bound to EC surface will subsequently bind platelets and may have the ability to act as a molecular surface for leukocyte interaction (25). With increased release of vWF, the inflammatory process is expected to induce a prothrombotic state. Studies show that inflammation enhances vWF self-association, which may lead to increased adhesiveness of platelets while decreasing ADAMTS-13 cleavage (24). Additionally, high-density lipoprotein (HDL) decreases during inflammation in both chronic and acute phases. HDL may play a vital role in preventing shear stress-induced vWF self-association, thus decreasing prothrombotic risk under normal circumstances (24). This concept will become a point of discussion later in the review. In summary, the data indicate that during the inflammatory process there is an increased thrombotic risk due to the imbalance of increased vWF and activity levels via EC activation and reduced ADAMTS-13 activity.

Laboratory Testing of vWF

To understand the studies that will be mentioned in connection with CAC, it is important to briefly discuss basic vWF laboratory testing. There are 3 basic tests performed to assess vWF; the exact methods may vary between manufacturers for those that are highly automated but the fundamental parameters rest on testing vWF quantity, activity, and multimer size.

The quantity of the vWF level in a specimen is commonly referred to as antigenic testing (vWF:Ag). An immunoturbidimetric method is commonly used for vWF:Ag measurement. However, the details of the assays vary by manufacturer. This allows for quantitative determination of the physical presence of the molecule without assessment of function. ABO blood typing and Factor VIII levels are also performed concurrently; it is well documented that individuals of blood group O have physiologically lower levels of vWF, and therefore Factor VIII (since vWF binds and stabilizes it) levels are also slightly lower than individuals of non-O blood groups (see the “vWF Association with Blood Type” section).

The quality of present vWF is known as functional or activity testing; this involves testing the ability of vWF to bind to platelet receptor GPIb, collagen, and Factor VIII (vWF:RCo). There are a number of assays and methods that revolve around testing the ability of vWF to bind its natural physiologic substrates (with or without ristocetin). Depending on the substrate used to assess its binding function, these tests will often carry an acronym such as vWF:Ac, vWF:RCo, vWF:Co, or vWF:VIII. It is important to note that there are important and distinct differences amongst these tests; however, this is beyond the scope of the review.

Additionally, the qualitative variation of vWF multimers is performed to visualize the presence and size distribution of vWF located in the plasma using gel electrophoresis and vWF labeling. This assessment is important since multimer presence and size is directly correlated to the function and activity level of the vWF molecule.

Finally, although not a laboratory test, the results of the activity and antigenic assays may be juxtaposed to obtain the ratio of vWF activity to antigen (RCo:Ag ratio). A ratio that is less than 0.5–0.7 would indicate that a qualitative defect in the vWF molecules is likely and this helps categorize the pattern and subtypes of vWD, if present.

Examination of vWF in COVID-19 Associated Coagulopathy

Endothelial Activation and vWF

As a molecule present in ECs that plays a fundamental role in hemostasis and thrombosis, vWF is a reasonable candidate marker to consider when monitoring clinical issues related to endothelial injury and coagulopathy in COVID-19. Early studies duly noted that D-dimer levels were an important prognostic marker in COVID-19. However, studies also began to recognize and demonstrate that significantly elevated levels of vWF were also present (14161926). Further, studies then recognized that vWF activity is also increased and that ADAMTS-13 activity levels are relatively mild to moderately reduced, leading to an imbalance favoring thrombosis (2728). Similarly, in a well-recognized pathological entity, thrombotic thrombocytopenic purpura (TTP) is associated with reduced activity levels of ADAMTS-13. TTP is generally due to an extremely hindered or absent ADAMTS-13 activity by either an acquired inhibitor or congenital absence. The decreased activity levels of ADAMTS-13 result in an excess of overactive UL-vWF multimers that promote microthrombi formation.

However, in contrast to TTP, the mild to moderately decreased ADAMTS-13 activity levels observed in CAC may not lead to excessive UL-vWF. Thus, it is important to distinguish that activity levels of ADAMTS-13 may not be low enough in CAC cases to detect an excessive increase in UL-vWF as seen in severe deficiency such as in TTP. In line with this, a recent study showed decreased activity levels of ADAMTS-13 in patients with severe COVID-19 but found no evidence of UL-vWF multimers in the plasma (29). Further, the authors of this study emphasized the significance of the elevated vWF:Ag to ADAMTS-13 activity ratio in association with increasing severity of disease. This suggests that an increased risk of thrombosis seen in patients with COVID-19 may, in part, be due to a relative decrease of ADAMTS-13 activity rather than an absolute decrease as seen in TTP.

The high levels of both vWF antigen and activity have been correlated clinically with increased thrombotic events (14), increased likelihood for treatment in ICUs (19), and increased need for oxygen support (26), as well as correlated with other laboratory testing such as decreased clotting times, increased clot formation velocities as demonstrated by whole blood viscoelastic testing (16) and increased levels of other markers of platelet and endothelial activation, such as Factor VIII and thrombomodulin (161926–2830). As new biomarkers to assess CAC severity emerge, reexamining the synthetic pathway of vWF may have some utility. One promising avenue is to examine levels of vWF propeptide; its physiologic role in the multimerization process would suggest that elevated levels of vWF propeptide indicate elevated vWF release. In addition, a greater level of increase in vWF and propeptide in comparison to an increase in Factor VIII suggest that this is due to release of vWF from pulmonary ECs involved in the COVID-19 pathophysiologic process (31). The ratio of propeptide levels to vWF levels can also examined; this ratio seems to decrease with disease progression suggesting that while the propeptide is cleared normally, levels of vWF may stay elevated due to decreased clearance (29). Further examination of propeptide levels in patients with COVID-19 are indicated to elucidate these possible relationships.

High-Density Lipoprotein and vWF

Aside from endothelial activation and injury, a more indirect mechanism may contribute to increased vWF activity levels. In general, infection leads to an inflammatory state and, as mentioned previously, this decreases HDL levels. Although most commonly known for its important role in preventing atherosclerotic disease, additional physiologic functions include activity as an antiinflammatory, antiapoptotic, and antioxidant agent. However, lesser-known roles include preventing thrombosis through binding to ECs to ramp up nitric oxide (a vasodilatory molecule) production and preventing shear stress-induced vWF self-association, thus decreasing prothrombotic risk (2432). Interestingly, a retrospective analysis of total cholesterol, LDL and HDL levels of patients in Changsha, China showed that HDL levels were lower in patients with COVID-19 than normal and patients with severe disease had lower HDL levels than patients with mild disease (33). Beyond the general infectious inflammatory state that may reduce HDL levels, a study showed that patients with COVID-19 had reduced apolipoprotein A1 (ApoA1) levels, which is a major protein component of HDL molecules (34). The study also showed that as patients went from nonsevere to severe disease, apolipoprotein decreased. Indeed, it has been shown, both in vivo and vitro models, that ApoA1 prevents vWF self-association and binding to vessel walls (32). Additional studies in the future could shed light on the role of HDL in CAC patients and possibly lead to novel treatment options.

vWF Association with Blood Type and COVID-19 Susceptibility

If increased levels of vWF can be monitored as a marker of endothelial damage and used to predict prognosis in patients with COVID-19, then decreased levels of vWF may be protective. One naturally existing population of patients who have baseline lower levels of vWF are patients of blood group O. Group O individuals naturally have a baseline level of vWF ∼25% less than the non-group O cohort (blood groups A and B). Although the exact molecular mechanism by which group O individuals have lower vWF levels is not fully elucidated, it has been hypothesized that perhaps theadditional glycosylation status, which occurs within ECs, by non-group O individuals prevents the activity of ADAMTS-13 to cleave vWF. This leads to reduced clearance and an increased half-life that is demonstrated by baseline higher levels of vWF when compared to group O individuals (31).

Initial data from China found a greater than expected proportion of group A and a smaller than expected proportion of group O individuals among patients with COVID-19. However, this involved a small cohort of patients with limited analysis due to lack of available clinical information (35). Following this, a genome-wide association study on patients in Italy and Spain also found group O individuals to have a lower relative risk than non-group O individuals (36). Another study showed a similar pattern of this phenomenon in a cohort of patients treated at the New York Presbyterian Hospital System (37). However, conflicting information is reported among these and other studies with some reporting no significant difference in severity and some reporting contradicting patterns in terms of need for mechanical ventilation. Preliminary data from these studies do potentially suggest that the lower vWF levels may be associated with decreased severity of disease in group O patients but more data is needed to clarify this relationship.

Conclusion

CAC is a significant contributor to patient morbidity and mortality. We highlight the role of vWF in CAC and compare and contrast it to the normal physiological response, mild and severe COVID-19 disease, and TTP (Fig. 1). Direct infection of ECs with SARS-CoV-2 and/or activation of ECs due to high levels of inflammatory mediators results in release of prothrombotic factors such as vWF. vWF, bound to the ECs or in plasma, promotes platelet aggregation and thrombus formation. It is likely that multiple mechanisms contribute to an imbalance of the vWF-ADAMTS-13 axis, pushing patients with CAC toward a more prothrombotic tendency. For example, in this review we discussed HDL and role it plays in reducing vWF activity, in which little discussion has been seen in other review articles of CAC and vWF. Nevertheless, the range of clinical presentation may be a reflection of the severity of this imbalance since reports show that though vWF is elevated in patients who are both critically ill and noncritically ill (19), there is a significant difference in vWF and ADAMTS-13 levels in patients who suffer thrombotic events versus those that do not (38). Multiple biomarkers, including vWF-associated proteins such as vWF propeptide and P-selectin, may help demonstrate the level of imbalance, as well as the mechanisms causing the imbalance. This would clarify the roles of therapies that would counter the actions of these prothrombotic molecules, whether by mitigating their release by reducing inflammation, such as N-acetylcysteine (39), or by inhibiting their activity once released or activated, such as caplacizumab (anti-vWF) or crizanlizumab (anti-P-selectin). Regardless, vWF has clearly demonstrated that it plays a role in the progression of CAC in patients with COVID-19, however, to what extent remains unclear. Further studies are needed to elucidate the many roles of vWF and the mechanism by which it becomes imbalanced.Fig. 1Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.Open in new tabDownload slide

Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.

Proposed mechanism and distinguishing characteristics in mild and severe cases of COVID-19 associated coagulopathy and a comparison to a normal physiological response and thrombotic thrombocytopenic purpura. (A), Normal physiological response to stress and or injury. After endothelial activation, vWF multimers are bound to the endothelial surface, ADAMTS-13 actively cleaves large multimers and HDL assists in the regulation of vWF self-association resulting in well-controlled thrombus formation during a physiologic response. (B), COVID-19 associated coagulopathy in mild disease. Localized infection and minimal systemic inflammation lead to a higher level of endothelial cell activation. Regardless, in this scenario, infection and inflammation remains fairly well regulated. Furthermore, the HDL and ADAMTS-13 mechanisms are mostly intact, leading to only a slight increase of pathologic thrombotic events. (C), COVID-19 associated coagulopathy in severe disease. Infection and or inflammation becomes overwhelmingly dysregulated, leading to an extremely elevated level of endothelial activation. Additionally, both HDL and ADAMTS-13 levels are decreased, leading to a much higher increase risk of pathologic thrombotic events. (D), Thrombotic thrombocytopenia purpura (TTP). In TTP, ADAMTS-13 activity levels are significantly lower than observed in COVID-19 coagulopathy. TTP leads to increased levels of ultralarge and large multimers of vWF. Subsequently, there are increased levels of platelet binding, which leads to highly increased thrombotic risk.

Author Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and(d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors’ Disclosures or Potential Conflicts of Interest:Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:Employment or Leadership: H.P. Pham, University of Southern California. Consultant or Advisory Role: H.P. Pham, Sanofi Genzyme. Stock Ownership: None declared. Honoraria: H.P. Pham, Alexion. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.

REFERENCES

1Wu Z , McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239.

Google ScholarCrossrefPubMed2Bhatraju PK , Ghassemieh BJ , Nichols M , Kim R , Jerome KR , Nalla AK , et al.  COVID-19 in critically ill patients in the Seattle region – case series. N Engl J Med 2020;382:2012–22.

Google ScholarCrossrefPubMed3Zhou F , Yu T , Du R , Fan G , Liu Y , Liu Z , et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054–62.

Google ScholarCrossrefPubMed4Libby P , Luscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020;41:3038–44.

Google ScholarCrossrefPubMed5Amy V , Rapkiewicz XM , Carsons SE , Pittaluga S , Kleiner DE , Berger JS , Thomas S , et al.  Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020;24:100434.

Google ScholarPubMed6Carsana L , Sonzogni A , Nasr A , Rossi RS , Pellegrinelli A , Zerbi P , et al.  Pulmonary post-mortem findings in a series of COVID-19 cases from Northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 21: 1135–1140.

Google Scholar7Ackermann M , Verleden SE , Kuehnel M , Haverich A , Welte T , Laenger F , et al.  Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med 2020;383:120–8.

Google ScholarCrossrefPubMed8Iba T , Levy JH , Connors JM , Warkentin TE , Thachil J , Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020;24:360.

Google ScholarCrossrefPubMed9Wu C , Chen X , Cai Y , Xia J , Zhou X , Xu S , et al.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934.

Google ScholarCrossrefPubMed10Liao D , Zhou F , Luo L , Xu M , Wang H , Xia J , et al.  Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study. Lancet Haematol 2020;7:e671–79.

Google ScholarCrossrefPubMed11Yao Y , Cao J , Wang Q , Shi Q , Liu K , Luo Z , et al.  D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care 2020;8:49.

Google ScholarCrossrefPubMed12Tang N , Li D , Wang X , Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844–7.

Google ScholarCrossrefPubMed13Klok FA , Kruip M , van der Meer NJM , Arbous MS , Gommers D , Kant KM , et al.  Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020;191:148–50.

Google ScholarCrossrefPubMed14Helms J , Tacquard C , Severac F , Leonard-Lorant I , Ohana M , Delabranche X , et al. ; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020;46:1089–98.

Google ScholarCrossrefPubMed15Lodigiani C , Iapichino G , Carenzo L , Cecconi M , Ferrazzi P , Sebastian T , et al. ; Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020;191:9–14.

Google ScholarCrossrefPubMed16Panigada M , Bottino N , Tagliabue P , Grasselli G , Novembrino C , Chantarangkul V , et al.  Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020;18:1738–42.

Google ScholarCrossrefPubMed17Leonard-Lorant I , Delabranche X , Severac F , Helms J , Pauzet C , Collange O , et al.  Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to D-dimer levels. Radiology 2020;296:E189–E91.

Google ScholarCrossrefPubMed18Zhang L , Yan X , Fan Q , Liu H , Liu X , Liu Z , Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with COVID-19. J Thromb Haemost 2020;18:1324–9.

Google ScholarCrossrefPubMed19Goshua G , Pine AB , Meizlish ML , Chang CH , Zhang H , Bahel P , et al.  Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol 2020;7:e575–e82.

Google ScholarCrossrefPubMed20Huang C , Wang Y , Li X , Ren L , Zhao J , Hu Y , et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.

Google ScholarCrossrefPubMed21Martin-Rojas RM , Perez-Rus G , Delgado-Pinos VE , Domingo-Gonzalez A , Regalado-Artamendi I , Alba-Urdiales N , et al.  COVID-19 coagulopathy: an in-depth analysis of the coagulation system. Eur J Haematol 2020;105:741–750.

Google ScholarCrossrefPubMed22Cummings MJ , Baldwin MR , Abrams D , Jacobson SD , Meyer BJ , Balough EM , et al.  Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet 2020;395:1763–70.

Google ScholarCrossrefPubMed23Kawecki C , Lenting PJ , Denis CV. von Willebrand factor and inflammation. J Thromb Haemost 2017;15:1285–94.

Google ScholarCrossrefPubMed24Chen J , Chung DW. Inflammation, von Willebrand factor, and ADAMTS13. Blood 2018;132:141–7.

Google ScholarCrossrefPubMed25Bernardo A , Ball C , Nolasco L , Choi H , Moake JL , Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost 2005;3:562–70.

Google ScholarCrossrefPubMed26Rauch A , Labreuche J , Lassalle F , Goutay J , Caplan M , Charbonnier L , et al.  Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19. J Thromb Haemost 2020;18:2942–2953.

Google ScholarCrossrefPubMed27Escher R , Breakey N , Lammle B. ADAMTS13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients. Thromb Res 2020;192:174–5.

Google ScholarCrossrefPubMed28Escher R , Breakey N , Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res 2020;190:62.

Google ScholarCrossrefPubMed29Mancini I , Baronciani L , Artoni A , Colpani P , Biganzoli M , Cozzi G , et al.  The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost 2021:19;513-521

Google Scholar30Ladikou EE , Sivaloganathan H , Milne KM , Arter WE , Ramasamy R , Saad R , et al.  von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clin Med (Lond) 2020;20:e178–e82.

Google ScholarCrossrefPubMed31Ward SE , O’Sullivan JM , O’Donnell JS. The relationship between abo blood group, von Willebrand factor and primary hemostasis. Blood 2020;136:2864–74.

Google ScholarCrossrefPubMed32Chung DW , Chen J , Ling M , Fu X , Blevins T , Parsons S , et al.  High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion. Blood 2016;127:637–45.

Google ScholarCrossrefPubMed33Wang G , Zhang Q , Zhao X , Dong H , Wu C , Wu F , et al.  Low high-density lipoprotein level is correlated with the severity of COVID-19 patients: an observational study. Lipids Health Dis 2020;19:204.

Google ScholarCrossrefPubMed34Shen B , Yi X , Sun Y , Bi X , Du J , Zhang C , et al.  Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 2020;182:59–72.e15.

Google ScholarCrossrefPubMed35Zhao J , Yang Y , Huang H , Li D , Gu D , Lu X , et al.  Relationship between the ABO blood group and the COVID-19 susceptibility. Clin Infect Dis 2020:ciaa1150.

Google Scholar36Ellinghaus D , Degenhardt F , Bujanda L , Buti M , Albillos A , Invernizzi P , et al.  Genomewide association study of severe COVID-19 with respiratory failure. N Engl J Med 2020;383:1522–34.

Google ScholarPubMed37Zietz M , Zucker J , Tatonetti NP. Associations between blood type and COVID-19 infection, intubation, and death. Nat Commun 2020;11:5761.

Google ScholarCrossrefPubMed38Delrue M , Siguret V , Neuwirth M , Joly B , Beranger N , Sene D , et al.  Von Willebrand factor/ADAMTS13 axis and venous thromboembolism in moderate-to-severe COVID-19 patients. Br J Haematol 2021;192:1097–100.

Google ScholarCrossrefPubMed39Shi Z , Puyo CA. N-acetylcysteine to combat COVID-19: an evidence review. Ther Clin Risk Manag 2020;16:1047–55.

Google ScholarCrossrefPubMed © American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Elevated P-Selectin in Severe Covid-19: Considerations for Therapeutic Options

Authors: Chiara Agrati,1Veronica Bordoni,1Alessandra Sacchi,1Nicola Petrosillo,1Emanuele Nicastri,1Franca Del Nonno,1Gianpiero D’Offizi,1Fabrizio Palmieri,1Luisa Marchioni,1Maria Rosaria Capobianchi,1Andrea Antinori,1Giuseppe Ippolito,1 and Michele Bibas1

Mediterr J Hematol Infect Dis. 2021; 13(1): e2021016.Published online 2021 Mar 1.  doi:  10.4084/MJHID.2021.016

Abstract

Background

Coronavirus disease 2019 (COVID-19) is mainly a respiratory tract disease and acute respiratory failure with diffuse microvascular pulmonary thrombosis are critical aspects of the morbidity and mortality of this new syndrome.

Purpose

The aim of our study was to investigate, in severe COVID-19 hospitalized patients, the P-selectin plasma concentration as a biomarker of endothelial dysfunction and platelet activation.

Methods

46 patients with severe or critical SARS-CoV-2 infection were included in the study. Age-matched patients then were divided in those requiring admission to the intensive care unit (ICU, ICU cases) vs those not requiring ICU hospitalization (non-ICU cases). Blood samples of severe COVID-19 patients were collected at the time of hospital admission. The quantification of soluble P-selectin was performed by ELI, assay.

Results

Our study showed a higher P-selectin plasma concentration in patients with Covid-19, regardless of ICU admission, compared to the normal reference values and compared to ten contextually sampled healthy donors (HD); (COVID-19): median 65.2 (IQRs: 45.1–81.1) vs. HD: 40.3 (IQRs: 24.3–48.7), p=0023. Moreover, results showed a significant reduction of P-sele din after platelets removal in HD, in contrast, both ICU and non-ICU COVID-19 patients showed similar high levels of P-selectin with and without platelets.

Conclusion

Elevation of P-selectin suggests a central role of platelet endothelium interaction as part of the multifaced pathogenic mechanism of COVID-19 leading to the local activation of hemostatic system forming pulmonary thrombi. Further work is necessary to determine the therapeutic role of antiplatelets agents or of the anti P-selectin antibody Crizanlizumab.Keywords: P-selectin, Covid-19, Endothelium, PlateletsGo to:

Introduction

Despite a worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection approaching, in January 2021, one hundred million cases and two million deaths, this disease’s pathophysiology remains inadequately defined and largely ununderstood.

COVID-19 is mainly a respiratory tract disease, and acute respiratory failure and diffuse microvascular pulmonary thrombosis are critical aspects of the morbidity and mortality of the coronavirus disease 2019 (Covid-19).1 However, both autopsy findings and clinical observations have described vascular damages and thrombotic complications in a wide range of organs.

Available published data suggest that from one-third to one-half of patients hospitalized with COVID-19 have hemostatic laboratory parameters suggestive of a pro-thrombotic state leading to a coagulopathy. These patients also manifest a hyperinflammatory state characterized by elevated inflammatory markers, strongly associated with severe pneumonia and a high mortality rate.3

SARS-CoV-2 enters human cells by binding to the angiotensin-converting-enzyme 2 (ACE2) receptor, expressed on respiratory epithelial cells and other cell types, including endothelial cells.2

Direct infection of endothelial cells, as well as the inflammatory environment, might result in an endothelial activation that drives the expression of P-selectin and tissue factor (TF), thus promoting platelet recruitment and aggregation.4 Subsequent accumulation of mononuclear cells provides a platform for the initiation of plasma coagulation by triggering prothrombin’s cleavage to thrombin and fibrin formation.5

The molecular interaction between P-selectin expressed in platelets and endothelial cells rapidly triggers TF exposure on monocytes,6 and this may represent a mechanism by which platelets and mononuclear cells contribute to disproportionate intravascular micro-thrombosis in SARS-CoV-2.

The aim of our study was to investigate, in COVID-19 hospitalized patients compared to healthy adult human controls, the ex-vivo P-selectin plasma concentration as a biomarker of endothelial dysfunction and platelet activation. The association between this parameter at the time of hospital admission and the severity and the outcomes of the disease with subsequent admittance into the intensive care unit (ICU) was finally assessed.

Study Population

A group of 46 patients with confirmed SARS-CoV-2 infection, admitted to our Institute between March and April 2020, was included in the study. All enrolled patients had severe illness (respiratory rate >30, SpO2 <93% on room air at sea level, PaO2/FiO2 <300, or lung infiltrates >50%), or critical illness (association of acute respiratory distress syndrome (ARDS), septic shock, cardiac dysfunction, cytokine storm and/or exacerbation of underlying comorbidities. Age-matched patients were then divided into those requiring admission to the intensive care unit (ICU, ICU cases) vs. those non requiring ICU hospitalization (non-ICU cases). A significant effort was made to exclude from the study population those with prior administration of anti-platelet agents or anticoagulant drugs.

A group of ten age-matched healthy donors (HD) were enrolled in the study as controls. Characteristics of enrolled patients are described in Figure 1.

An external file that holds a picture, illustration, etc.
Object name is mjhid-13-1-e2021016f1.jpg

Figure 1

The expression of P-selectin and Annexin V on platelet surface was evaluated in plasma samples by flow cytometry (A). The removal of platelets/vescicles in EV-free plasma samples was confirmed by flow cytometry (B).

Material and Methods

Blood samples of severe COVID-19 patients were collected at the time of hospital admission. Heparin peripheral blood was centrifuged at 1200 rpm for 10 minutes at room temperature to obtain plasma samples containing extracellular vesicles and platelets (Plasma). After that, 500 ul of plasma samples were further centrifuged at 5000 rpm for 5 minutes at room temperature to eliminate platelets and extracellular vesicles (EV-free plasma). To verify the removal of platelets/vesicles in EV-free plasma, we performed a flow cytometry analysis. Specifically, plasma and EV-free plasma were stained with P-selectin and Annex V for 15 minutes at room temperature and then acquired to a FACS Canto II cytometer (Figure 2). The quantification of soluble P-selectin was performed by ELISA assay (R&D system; average value in heparin plasma: mean 39 ng/ml (range: 25–53).

An external file that holds a picture, illustration, etc.
Object name is mjhid-13-1-e2021016f2.jpg

Open in a separate windowFigure 2

Clinical features of enrolled COVID-19 patients (A). Soluble P-selectin was quantified in plasma samples (B–C) and in extracellular-free plasma samples (EV-free, C) from healthy donors (HD, n=10), ICU (n=27) and in non-ICU (n=19) COVID-19 patients by ELISA assay. Data were compared by Mann-Whitney test. * p<0.05 was considered significant.

Results

Our study showed a higher P-selectin plasma concentration in patients with Covid-19, regardless of ICU admission, compared to the normal reference values and compared to contextually sample healthy donors; (COVID-19): median 65.2 (IQRs: 45.1–81.1) vs. HD: 40.3 (IQRs: 24.3–48.7), p=0.0023). Moreover, results showed a significant reduction of P-selectin after platelet removal in HD, suggesting that most of this molecule was trapped in the platelets. In contrast, both ICU and non-ICU COVID-19 patients showed similar P-selectin levels with and without platelets, suggesting that Covid-19 induced a release of these molecules from activated platelets/cells (Figure 1C). A similar platelet count has been observed in the two groups ranging within the standard value (150–400/mmc). More significantly lower lymphocyte count was observed in ICU patients, confirming an association between lymphocytopenia and disease severity.6,7

Discussion

Our results suggest a central role of platelet endothelium interaction as part of the multifaced pathogenic mechanism of COVID-19, leading to the local activation of the hemostatic system forming pulmonary thrombi. More, these interactions amplify the leukocyte recruitment, increasing chemokine expression on the endothelial surface with extensive adhesion, activation, and leukocyte trafficking across the endothelial wall.8

It will be interesting to examine whether therapies inhibiting platelet-endothelium interaction or inhibiting platelet function might improve microvascular perfusion, reduce thrombo-inflammation, and finally reduce COVID-19 morbidity and mortality.

In this perspective, we suggest studying, in the early phases of COVID-19 disease, the role of anti-platelet agents, acetylsalicylic acid, GPIIb, GPIIIa antagonists, and P2Y12 antagonists, not only in de novo therapy initiation but also in patients previously in prophylaxis or in treatment for cardiovascular disorders. The suggested mechanism to study is not only the direct P-selectin/platelet interaction but also the neutrophil extracellular trap (NET) production as described in sepsis and transfusion-related acute lung injury (TRALI).9,10,11 Further, Crizanlizumab-tmca, a selectin blocker humanized IgG2 kappa monoclonal antibody that binds to P-selectin, and approved to reduce the frequency of vaso-occlusive crises (VOCs) in adult and pediatric patients, might be evaluated in severe cases not responding or in combination to anti-platelet therapy.12,13

Acknowledgements

Supported by The Italian Ministry of Health (Ricerca Corrente Linea 1, COVID-2020-12371735 and COVID-2020-12371817). All Authors have reviewed and approved the manuscript. All authors have reviewed the authorship policy. No author has any conflicts of interest related to this work.

We gratefully acknowledge the Collaborators Members of INMI COVID-19 study group: Maria Alessandra Abbonizio, Amina Abdeddaim, Chiara Agrati, Fabrizio Albarello, Gioia Amadei, Alessandra Amendola, Mario Antonini, Tommaso Ascoli Bartoli, Francesco Baldini, Raffaella Barbaro, Bardhi Dorian, Barbara Bartolini, Rita Bellagamba, Martina Benigni, Nazario Bevilacqua, Gianlugi Biava, Michele Bibas, Licia Bordi, Veronica Bordoni, Evangelo Boumis, Marta Branca, Donatella Busso, Marta Camici, Paolo Campioni, Maria Rosaria Capobianchi, Alessandro Capone, Cinzia Caporale, Emanuela Caraffa, Ilaria Caravella, Fabrizio Carletti, Concetta Castilletti, Adriana Cataldo, Stefano Cerilli, Carlotta Cerva, Roberta Chiappini, Pierangelo Chinello, Carmine Ciaralli, Stefania Cicalini, Francesca Colavita, Angela Corpolongo, Massimo Cristofaro, Salvatore Curiale, Alessandra D’Abramo, Cristina Dantimi, Alessia De Angelis, Giada De Angelis, Maria Grazia De Palo, Federico De Zottis, Virginia Di Bari, Rachele Di Lorenzo, Federica Di Stefano, Gianpiero D’Offizi, Davide Donno, Francesca Faraglia, Federica Ferraro, Lorena Fiorentini, Andrea Frustaci, Matteo Fusetti, Vincenzo Galati, Roberta Gagliardini, Paola Gallì, Gabriele Garotto, Saba Gebremeskel Tekle, Maria Letizia Giancola, Filippo Giansante, Emanuela Giombini, Guido Granata, Maria Cristina Greci, Elisabetta Grilli, Susanna Grisetti, Gina Gualano, Fabio Iacomi, Giuseppina Iannicelli, Giuseppe Ippolito, Eleonora Lalle, Simone Lanini, Daniele Lapa, Luciana Lepore, Raffaella Libertone, Raffaella Lionetti, Giuseppina Liuzzi, Laura Loiacono, Andrea Lucia, Franco Lufrani, Manuela Macchione, Gaetano Maffongelli, Alessandra Marani, Luisa Marchioni, Raffaella Marconi, Andrea Mariano, Maria Cristina Marini, Micaela Maritti, Alessandra Mastrobattista, Giulia Matusali, Valentina Mazzotta, Paola Mencarini, Silvia Meschi, Francesco Messina, Annalisa Mondi, Marzia Montalbano, Chiara Montaldo, Silvia Mosti, Silvia Murachelli, Maria Musso, Emanuele Nicastri, Pasquale Noto, Roberto Noto, Alessandra Oliva, Sandrine Ottou, Claudia Palazzolo, Emanuele Pallini, Fabrizio Palmieri, Carlo Pareo, Virgilio Passeri, Federico Pelliccioni, Antonella Petrecchia, Ada Petrone, Nicola Petrosillo, Elisa Pianura, Carmela Pinnetti, Maria Pisciotta, Silvia Pittalis, Agostina Pontarelli, Costanza Proietti, Vincenzo Puro, Paolo Migliorisi Ramazzini, Alessia Rianda, Gabriele Rinonapoli, Silvia Rosati, Martina Rueca, Alessandra Sacchi, Alessandro Sampaolesi, Francesco Sanasi, Carmen Santagata, Alessandra Scarabello, Silvana Scarcia, Vincenzo Schininà, Paola Scognamiglio, Laura Scorzolini, Giulia Stazi, Fabrizio Taglietti, Chiara Taibi, Roberto Tonnarini, Simone Topino, Francesco Vaia, Francesco Vairo, Maria Beatrice Valli, Alessandra Vergori, Laura Vincenzi, Ubaldo Visco-Comandini, Pietro Vittozzi, Mauro Zaccarelli.

Footnotes

Competing interests: The authors declare no conflict of Interest.

References

1. Guan WJ, Ni ZY, Hu Y, Liang WH, et al. :Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708–1720. doi: 10.1056/NEJMoa2002032. [PMC free article] [PubMed] [CrossRef] [Google Scholar]2. Hamming I, Timens W, Bulthuis ML, Lely AT, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631–7. doi: 10.1002/path.1570. [PMC free article] [PubMed] [CrossRef] [Google Scholar]3. Kreidieh F, Temraz S. SARS-CoV-2: infected patient: from a hematologist’s perspective. Mediterr J Hematol Infect Dis. 2020;12(1):e2020078. doi: 10.4084/mjhid.2020.078. [PMC free article] [PubMed] [CrossRef] [Google Scholar]4. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 May 2; doi: 10.1016/S0140-6736(20)30937-5395(10234)1417-1418. Epub 2020 Apr 21. [PMC free article] [PubMed] [CrossRef] [Google Scholar]5. Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019 Feb 28;133(9):906–918. doi: 10.1182/blood-2018-11-882993. [PubMed] [CrossRef] [Google Scholar]6. Ivanov II, Apta BHR, Bonna AM, Harper MT. Platelet P-selectin triggers rapid surface exposure of tissue factor in monocytes. Sci Rep. 2019 Sep 16;9(1):13397. doi: 10.1038/s41598-019-49635-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]7. Li Tan, Qi Wang, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020 Mar 27;5(1):33. doi: 10.1038/s41392-020-0148-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2020 Nov;19:1–16. doi: 10.1038/s41569-020-00469-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]9. Zuo Y, Yalavarthi S, Shi H, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020 Apr 24; doi: 10.1172/jci.insight.138999. pii: 138999. [PMC free article] [PubMed] [CrossRef] [Google Scholar]10. Du F, Jiang P, He S, Song D, Xu F. Antiplatelet Therapy for Critically Ill Patients: A Pairwise and Bayesian Network Meta-Analysis. Shock. 2018 Jun;49(6):616–624. doi: 10.1097/SHK.0000000000001057. [PubMed] [CrossRef] [Google Scholar]11. Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusion-related acute lung injury. Blood. 2019 Apr 25;133(17):1840–1853. doi: 10.1182/blood-2018-10-860809. [PubMed] [CrossRef] [Google Scholar]12. Blair HA. Crizanlizumab: First Approval. Drugs. 2020 Jan;80(1):79–84. doi: 10.1007/s40265-019-01254-2. [PubMed] [CrossRef] [Google Scholar]13. Neri T, Nieri D, Celi A. P-selectin blockade in COVID-19-related ARDS. Am J Physiol Lung Cell Mol Physiol. 2020 Jun 1;318(6):L1237–L1238. doi: 10.1152/ajplung.00202.2020. [PMC free article] [PubMed] [CrossRef] [Google Scholar]