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]

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

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.

Better Anticoagulated Than Not! Hypercoagulability in COVID-19

Authors: Dhauna P. Karam, MD1

Incidence of thrombotic complications in patients with COVID-19 who are critically ill is high, with an estimated incidence of 31% for arterial or venous thromboembolism (VTE), acute pulmonary embolism, ischemic stroke, and myocardial infarction. On the basis of the study by Klok et al,1 pulmonary embolism was the most common thrombotic complication in critically ill patients with COVID-19 despite being on standard anticoagulation. Prevention of thromboembolism with anticoagulants is recommended in all critically ill patients with COVID-19.

The American Society of Hematology (ASH) guideline panel (updated April 7, 2021) recommends prophylactic anticoagulation in all critically ill patients with COVID-19 without suspected or confirmed venous thromboembolism (VTE). ASH defines patients with COVID-19 critical illness as someone who is suffering from a life-threatening condition, typically admitted in an intensive care unit. It is recommended that individualized assessment of the patient’s thrombotic and bleeding risk needs to be performed before deciding on anticoagulation.2 What about hospitalized patients with COVID-19 who are not critically ill? What are some clinical parameters that can be used to guide decisions on anticoagulant use in such patients?

The accompanying manuscript by Gaddh et al3 reports guidelines used in a large academic institution, Emory University School of Medicine, Atlanta, Georgia, to determine anticoagulation in hospitalized patients with COVID-19. The guidelines were created by a multidisciplinary panel of experts and were incorporated into frontline care at Emory. The three-tiered algorithm was used to risk stratify patients admitted with a primary diagnosis of COVID-19. It was not recommended for use in patients incidentally found to have COVID-19 during hospitalization for other causes. On the basis of the guidelines, patients with normal D-dimer, no evidence of thromboembolism and not critically ill were given prophylactic anticoagulation (group 1). Patients with elevated D-dimer (> 6 times upper limit normal) with no evidence of thromboembolism and not critically ill were given intermediate-dose anticoagulation. Patients critically ill without any evidence of thromboembolism and without elevation of D-dimer were also given intermediate-dose anticoagulation. Patients with confirmed thromboembolism or those with other markers of possible thromboembolism (worsening hypoxia or pulmonary status without identifiable cause and limb edema) received therapeutic anticoagulation. Anticoagulation was continued for 1 week after discharge in group 1 patients. Group 2 received anticoagulation for 4-6 weeks after discharge. Finally, group 3 received anticoagulation for minimum 3 months postdischarge. Preliminary findings revealed low bleeding complications. Data on type of anticoagulant used, incidence of thromboembolism in the hospitalized group following the above guidelines, and improvement in morbidity and mortality rates were not provided. The algorithm is a simple, practical statement, which can guide frontline caregivers until evidence-based recommendations become available. Group 1 and 3 recommendations are supported by major organizational guidelines such as ASH and International Society on Thrombosis and Haemostasis (ISTH). Preliminary guidelines from these organizations refrain from commenting strongly on intermediate-dose anticoagulation in the absence of supporting data from clinical trials but do support anticoagulant dose escalation on the basis of clinician’s assessment for high-risk patients.2,4

For More Information: https://ascopubs.org/doi/full/10.1200/OP.21.00359

The Impact of COVID-19 Disease on Platelets and Coagulation

Authors: Geoffrey D Wool 1Jonathan L Miller 2

Abstract

Coronavirus disease 2019 (COVID-19) causes a spectrum of disease; some patients develop a severe proinflammatory state which can be associated with a unique coagulopathy and procoagulant endothelial phenotype. Initially, COVID-19 infection produces a prominent elevation of fibrinogen and D-dimer/fibrin(ogen) degradation products. This is associated with systemic hypercoagulability and frequent venous thromboembolic events. The degree of D-dimer elevation positively correlates with mortality in COVID-19 patients. COVID-19 also leads to arterial thrombotic events (including strokes and ischemic limbs) as well as microvascular thrombotic disorders (as frequently documented at autopsy in the pulmonary vascular beds). COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production. Disseminated intravascular coagulopathy (DIC) and severe bleeding events are uncommon in COVID-19 patients. Here, we review the current state of knowledge of COVID-19 and hemostasis.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33049751/

Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition

Authors: Jia YuXuan YuanHang ChenShruti ChaturvediEvan M. BraunsteinRobert A. Brodsky

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein–treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.

For More Information: https://ashpublications.org/blood/article/136/18/2080/463611/Direct-activation-of-the-alternative-complement

What Is the D-Dimer Test?

Authors: Richard N. Fogoros, MD

The D-dimer test is a blood test that indicates whether blood clots are being actively formed somewhere within a person’s vascular system. This test is most often helpful in the diagnosis of pulmonary embolus and deep vein thrombosis, but it can also be useful in diagnosing other medical conditions in which blood clots play a role.

However, there are limitations to the D-dimer test, and it can be tricky to evaluate the results. In order to avoid being misled by it, doctors need to make sure they are using this test at the appropriate times and must take due care in interpreting the results.

For More Information: https://www.verywellhealth.com/d-dimer-test-4173338

Never ignore extremely elevated D-dimer levels: they are specific for serious illness

Authors: T Schutte 1A ThijsY M Smulders

D-dimer is routinely measured as part of the clinical diagnosis algorithms for venous thromboembolism (VTE). In these algorithms, low D- dimer cut-off values are used to generate a dichotomous test result that is sensitive, but very non-specific for VTE. A consequence of any test dichotomisation is loss of information that is hidden in the continuous spectrum of results. For D-dimer, the information conveyed by extremely elevated results may be particularly relevant. Our aim was to assess the differential diagnosis of extremely elevated D-dimer levels in a hospital setting.

For More Information: https://pubmed.ncbi.nlm.nih.gov/27966438/