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. 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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. 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COVID-19 Can Infect and Harm Digestive Organs

Authors: E.J. Mundell

 The coronavirus isn’t just attacking the lungs: New research shows it’s causing harm to the gastrointestinal tract, especially in more advanced cases of COVID-19.

A variety of imaging scans performed on hospitalized COVID-19 patients showed bowel abnormalities, according to a study published online May 11 in Radiology. Many of the effects were severe and linked with clots and impairment of blood flow.

“Some findings were typical of bowel ischemia, or dying bowel, and in those who had surgery we saw small vessel clots beside areas of dead bowel,” said study lead author Dr. Rajesh Bhayana, who works in the department of radiology at Massachusetts General Hospital in Boston.

“Patients in the ICU can have bowel ischemia for other reasons, but we know COVID-19 can lead to clotting and small vessel injury, so bowel might also be affected by this,” Bhayana explained in a journal news release.

One expert unconnected to the new study said the findings aren’t surprising.

“Our emerging understanding of COVID-19 has found the disease to have multisystem involvement including the nervous, cardiac, vascular [excess clotting] and finally the digestive systems, among others,” said Dr. Sherif Andrawes. He directs endoscopy in the division of gastroenterology and hematology at Staten Island University in New York City.

“It seems that this disease is intricate, in the sense that it can involve multiorgan systems, rather than being a disease of the respiratory system solely,” Andrawes said.

In fact, a study published online May 13 in the journal Science Immunology has found evidence that SARS-CoV-2, the virus behind COVID-19, can infect the human digestive system.

Researchers led by Siyuan Ding of Washington University School of Medicine in St. Louis, said their findings “highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.”

That seems to be borne out by the Boston study.

That research included 412 COVID-19 patients who were hospitalized between March 27 and April 10. They averaged 57 years of age, and 134 of them underwent abdominal imaging, including 137 radiographs, 44 ultrasounds, 42 CT scans, and one MRI.

Extensive thrombosis after COVID-19 vaccine: cause or coincidence

Authors: Luís Lourenço Graça ,1 Maria João Amaral ,2 Marco Serôdio,3 Beatriz Costa2

SUMMARY
A 62-year-old Caucasian female patient presented with abdominal pain, vomiting and fever 1 day after administration of COVID-19 vaccine. Bloodwork revealed anaemia and thrombocytosis. Abdominal CT angiography showed a mural thrombus at the emergence of the coeliac trunk, hepatic and splenic arteries, and extensive thrombosis of the superior and inferior mesenteric veins, splenic and portal veins, and the inferior vena cava, extending to the
left common iliac vein. The spleen displayed extensive areas of infarction. Etiological investigation included assessment of congenital coagulation disorders and acquired causes with no relevant findings. Administration of COVID-19 vaccine was considered a possible cause of the extensive multifocal thrombosis. After reviewing relevant literature, it was considered
that other causes of this event should be further investigated. Thrombosis associated with COVID-19vaccine is rare and an etiological relationship should only be considered in the appropriate context and after investigation of other, more frequent, causes.

BACKGROUND
During the COVID-19 pandemic, the pharmaceutical industry is under immense pressure to develop effective and safe vaccines, and as such clinical trials have been expedited in order to make them available to help fight this health crisis. In this context, timely communication between healthcare institutions and regulatory entities is especially important. Reports of thrombosis due to administration of these vaccines have been causing an important
discussion in the scientific community as well as social alarm. However, it is important to note that this is a rare complication and more frequent causes of extensive arterial and venous thrombosis should be considered and investigated.1

CASE PRESENTATION
A 62-year-old Caucasian female patient, with personal history of obesity (body mass index of
30kg/m2), asthma and rhinitis, presented to the emergency department with abdominal pain,
nausea, vomiting and fever (38°C) 1day after administration of the first dose of COVID-19 vaccine(from AstraZeneca). On physical examination, she presented epigastric and left iliac fossa tenderness as the only abnormal finding. The patient denied recent epistaxis and gastrointestinal or genitourinary blood loss.

INVESTIGATIONS
Blood tests revealed microcytic hypochromic anemia (hemoglobin 7g/L), thrombocytosis (780×109/L),increased levels of inflammatory parameters (leucocytes 13×109/L; C reactive protein 31.07mg/dL) and slightly increased levels of liver enzymes and function (AST 36, ALP 126U/L, GGT 72U/L, LDH 441U/L, total bilirubin 1.3mg/dL, direct bilirubin 0.5mg/dL). The patient was tested for COVID-19 with nasopharyngeal PCR tests at admission and on the fifth day of hospitalization. Both tests were negative. Abdominal CT angiography (CTA) showed a mural thrombus at the emergence of the coeliac trunk, with total occlusion (figure 1), as well as at the hepatic and splenic arteries. There was also extensive thrombosis of the superior and inferior mesenteric veins and its tributaries, splenic and portal veins, including the splenoportal confluent (figure 2). There was a filiform thrombus at the distal portion of the inferior vena cava, extending to the left common iliac vein, non-occlusive (figure 3). Spleen presented extensive areas of infarction (figure 1). Coeliac trunk occlusion due to paradoxical embolism was excluded by transthoracic echocardiogram. No interatrial communication was detected. Re-evaluation CTA 5days after the diagnosis was identical. Etiological investigation included assessment of congenital coagulation disorders and acquired causes. Regarding congenital disorders, personal and family history of important thrombotic events, thrombosis in unusual sites and abortions were assessed with no relevant findings. Molecular testing for factor V Leiden mutation and prothrombin gene20210 G/A mutation were both negative. Acquired causes of a coagulation disorder, such as neoplastic, infectious and autoimmune disorders, like antiphospholipid syndrome (APS), were also investigated. Thorax, abdomen, pelvic and brain CT did not detect any suspicious lesions. Tumor biomarkers—carcinoembryonic antigen, alpha fetoprotein, carbohydrate antigen 19-9, cancer antigen 125, cancer antigen 15-3, neuron-specific enolase and chromogranin A—were negative. The patient refused to undergo upper digestive endoscopy and colonoscopy. Despite increased levels of inflammatory parameters at admission (leukocytosis and C reactive protein), these values decreased during the hospitalization period. Blood and urine cultures were also negative. Anticardiolipin IgG and IgM and antibeta-2-glycoprotein IgG and IgM were negative, excluding APS.

DIFFERENTIAL DIAGNOSIS
In the presence of venous and arterial thrombosis, the etiological investigation should include

assessment of congenital and acquired coagulation disorders, as well as the presence of interatrial communication that could explain the coeliac trunk occlusion due to paradoxical embolism. As previously stated, these etiological factors were assessed with no specific findings, with the exception of digestive endoscopic study, which was refused by the patient. In this context, and given the fact that the presentation took place 1day after administration of the first dose of COVID-19 vaccine, we hypothesize that the vaccine might be the cause of the extensive arterial and venous thrombosis. This case was immediately reported to INFARMED, the Portuguese authority for drugs and health products. Vaccine-induced thrombotic thrombocytopenia (VITT) was also considered a differential diagnosis. However, the patient did
not present with thrombocytopenia, which is a key criteria for VITT, and therefore the presence of this syndrome was unlikely.COVID-19 tests at admission and on the fifth day of hospitalization were negative; however, she was not tested prior to the onset of the event and therefore it was not possible to exclude

recent COVID-19 infection, which may predispose to thrombosis, even during the convalescent phase.
TREATMENT
At presentation, there were no signs of organ ischemia that required revascularization procedure or intestinal resection. Considering the anemia, the patient was not a candidate for
fibrinolysis. The treatment was empiric endovenous antibiotherapy and transfusion of two units of red blood cells. Anticoagulation with low molecular weight heparin (LMWH) 1mg/kg
two times per day was initiated and maintained during hospitalisation, with monitoring of anti-Xa levels. After hospitalization,in an outpatient setting, the patient was initiated on edoxaban.

OUTCOME AND FOLLOW-UP
Re-evaluation CTA 28 days after presentation revealed a portal vein with a filiform caliber, with a cavernomatous transformation. There was only permeability of the left branch of the portal
vein, with venous collateralization in the hepatic hilum. Coeliac trunk was still occluded, with permeability of the gastroduodenal artery and the right hepatic artery, and apparent occlusion at the emergence of the left hepatic artery, although with distal repermeabilisation. Partial thrombus persisted in the lumen of the left common iliac vein and inferior infrarenal vena cava. At the follow-up consultation, 1month after discharge, the patient was clinically asymptomatic.

DISCUSSION
Venous and arterial thrombotic disorders have long been considered separate pathophysiological entities due to their anatomical differences and distinct clinical presentations. In particular, arterial thrombosis is seen largely as a phenomenon of platelet
activation, whereas venous thrombosis is mostly a matter of activation of the clotting system.2
There is increasing evidence regarding a link between venous and arterial thromboses. These two vascular complications share several risk factors, such as age, obesity, diabetes mellitus, blood Figure 1 CT angiography arterial phase, axial image: a mural thrombus is observed at the coeliac trunk emergence, with total occlusion. Splenic parenchyma without enhancement after contrast administration can also be observed, translating to extensive infarct areas.
Figure 2 CT angiography portal phase, coronal image: portal vein thrombosis (A) extending to the splenoportal confluent (B) can be observed. Figure 3 CT angiography portal phase, coronal image: a non-occlusive filiform thrombus at the distal portion of the inferior vena cava can be observed, extending to the left common iliac vein. on April 13, 2022 by guest. Protected by copyright. http://casereports.bmj.com/ BMJ Case Rep: first published as 10.1136/bcr-2021-244878 on 16 August 2021. Downloaded from Graça LL, et al. BMJ Case Rep 2021;14:e244878. doi:10.1136/bcr-2021-244878 3

Case report hypertension, hypertriglyceridaemia and metabolic syndrome.3 Moreover, there are many examples of conditions accounting for both venous and arterial thromboses, such as APS, hyperhomocysteinaemia, malignancies, infections and use of hormonal treatment.3 In this case, in accordance with the literature, the patient is 62 years old and obese, with no other findings. Hyperhomocysteinaemia and digestive tract malignancies were not excluded. Recent studies have shown that patients with venous thromboembolism are at a higher risk of arterial thrombotic complications than matched control individuals. Therefore, it is speculated that
the two vascular complications may be simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system.3 The modified adenovirus vector COVID-19 vaccines (ChAdOx1nCoV-19 by Oxford/AstraZeneca and Ad26.COV2.S by Johnson & Johnson/Janssen) and mRNA-based COVID-19 vaccines(BNT162b2 mRNA by Pfizer/BioNTech and mRNA-1273 by Moderna) have shown both safety and efficacy against COVID-19 in phase III clinical trials and are now being used in global vaccination programmes.4Rare cases of postvaccine-associated cerebral venous thrombosis(CVT) from use of COVID-19 vaccines which use a viral vector, including the mechanism of VITT, have emerged in real-worldvaccination.4 On the other hand, the incidence and pathogenesis of CVT after mRNA COVID-19 vaccines remain unknown. However Fan et al4
presented three cases and Dias et al5reported two cases of CVT in patients who took an mRNA vaccine (BNT162b2 mRNA by Pfizer/BioNTech). In both cases, causality has not been proven.
In a recent editorial, three independent descriptions of persons with a newly described syndrome, VITT, were highlighted, characterized by thrombosis and thrombocytopenia that developed 5–24 days after initial vaccination with ChAdOx1 nCoV-19 (AstraZeneca), a recombinant adenoviral vector encoding the spike protein of SARS-CoV-2.6VITT is also characterized by the presence of CVT, thrombosis in the portal, splanchnic and hepatic veins, as well as acute arterial thromboses, platelet counts of 20–30×109 /L, high levels of D-dimers and low levels of fibrinogen, suggesting systemic activation of coagulation.6 In our case, similarities were found with VITT regarding thrombosis in the portal, splanchnic and hepatic veins, as well as acute arterial thromboses and high levels of D-dimers. On the other hand, timing of the event (1day after vaccination), high levels of fibrinogen and absence of thrombocytopenia, which is a key criteria for VITT, point to a different direction. Moreover, the
presence of thrombocytosis allowed for a safe use of LMWH for anticoagulation, with monitoring of anti-Xa levels. Most of the cases reported so far of venous and arterial thrombosis as a complication of AstraZeneca’s COVID-19 vaccine have occurred in women under the age of 60 years, associated with thrombocytopenia, within 2weeks of receiving their first dose of the vaccine.7As for the mechanism, it is thought that the vaccine may trigger an immune response leading to an atypical heparin-induced thrombocytopenia-like disorder. In contrast with the literature, our patient presented with thrombocytosis, not thrombocytopaenia.7 Smadja et al8reported that between 13 December 2020 and
16 March 2021 (94 days), 361734967 people in the international COVID-19 vaccination data set received vaccination and795 venous and 1374 arterial thrombotic events were reported in
Vigibase on 16 March 2021. Spontaneous reports of thrombotic events are shared in 1197 for Pfizer/BioNtech’s COVID-19 vaccine,325 for Moderna’s COVID-19 vaccine and 639 for AstraZeneca’sCOVID-19 vaccine.7 The reporting rate for cases of venous (VTE) and arterial (ATE) thrombotic events during this time period among the total number of people vaccinated was 0.21 cases of thrombotic events per 1million person vaccinated-days.7For VTE and ATE, the rates were 0.075 and 0.13 cases per 1million persons vaccinated, respectively, and the timeframe between vaccinationand ATE is the same for the three vaccines (median of 2days),
although a significant difference in terms of VTE was identified between AstraZeneca’s COVID-19 vaccine (median of 6days) and both mRNA vaccines (median of 4days).8 The first paper addressing this issue was published in the New England Journal of Medicine and described 11 patients, 9 of themwomen.9 Nine patients had cerebral venous thrombosis, three had
splanchnic vein thrombosis, three had pulmonary embolism and four had other thromboses. All 11 patients, as well as another 17 for whom the researchers had blood samples, tested positive for antibodies against platelet factor 4 (PF4). These antibodies are also observed in people who develop heparin-induced thrombocytopenia. However, none of the patients had received heparin before their symptoms started.9Our patient did not present thrombocytopenia, so anti-PF4 antibodies were not tested. Thus, considering the anemia, thrombocytosis and thrombosis diagnosed 1day after the first dose ofCOVID-19 vaccine, it seems prudent to continue investigation for other causes of this event, such as hematological malignancies or others.

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Review of Mesenteric Ischemia in COVID-19 Patients

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

Abstract

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

Introduction

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

Case summary

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

figure 1
Fig. 1
figure 2
Fig. 2

Pathophysiology

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

figure 3
Fig. 3

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

Clinical Presentation

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

Investigations

Blood investigations

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

Radiological imaging

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

Computed tomography

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

Management

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

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

Prognosis

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

Conclusion

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

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

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

Abstract

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

1 INTRODUCTION

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

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

2 METHODS

2.1 Study population and design

2.1.1 COVID-19 cases

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

2.1.2 Contemporaneous control cases

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

2.1.3 Historical control cases

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

2.2 Determination of clinical variables

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

2.3 Determination of laboratory variables

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

2.4 Coagulation factor assay methods

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

2.5 APTT waveform analyses

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

2.6 Statistical methods

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

3 RESULTS

3.1 A cohort of patients with severe COVID-19

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

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

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

TABLE 2. Clinical outcomes and features

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

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

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

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

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

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

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

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

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

3.4 Factor V activity relationships in COVID-19

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

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

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

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

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

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

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

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

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

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

4 DISCUSSION

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

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

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

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

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

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

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

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

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

ACKNOWLEDGEMENTS

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

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

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

ABSTRACT

Introduction

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

Methods

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

Conclusion

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

Introduction

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

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

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

Prevalence

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

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

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

Pathogenesis

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

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

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

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

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

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

Manifestations

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

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

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

Diagnosis

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

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

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

Treatment

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

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

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

Table 1.

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

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

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Table 2.

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

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

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Table 3.

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

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

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How should biomarkers be used to guide management?

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

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

What are the preferred prophylactic anticoagulation regimens?

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

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

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

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

When to increase intensity of anticoagulation

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

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

What is the preferred therapeutic anticoagulation regimens?

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

When are thrombolytics recommended?

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

When to hold anticoagulation?

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

What is the utility of mechanical thromboprophylaxis?

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

What is the appropriate method of monitoring anticoagulation?

Monitoring of patients receiving therapeutic anticoagulation with LMWH

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

Monitoring of patients receiving therapeutic anticoagulation with UFH

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

Heparin resistance

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

What is the recommended approach to control active bleeding?

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

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

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

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

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

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

Conclusion

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

Acknowledgments

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

Declaration of funding

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

Declaration of financial/other relationships

No potential conflict of interest was reported by the author.

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

Authors contributions

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

Take home message

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

COVID-19: Coronavirus disease 2019

WHO: World Health Organization

CAC: COVID-19 associated coagulopathy

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

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

ASH: American Society of Hematology (ASH)

ACCP: American College of Chest Physicians

SCC-ISTH: Scientific and Standardization Committee of ISTH

ACF: Anticoagulation Forum

ACC: American College of Cardiology

vWF: von Willebrand Factor

ICU: Intensive Care Unit

TEG: Thromboelastography

ROTEM: Rotational thromboelastometry

DIC: Disseminated intravascular coagulation

PT: Prothrombin time

PTT: Partial thromboplastin time

AT: Antithrombin

MA: Maximum amplitude

INR: International normalized ratio

VTE: Venous thromboembolism

HIT: Heparin-induced thrombocytopenia

SRA: Serotonin release assay

PE: Pulmonary embolism

CTPA: Computed tomography pulmonary angiogram (CTPA)

LMWH: Low molecular weight heparin

UFH: Unfractionated heparin

RCT: Randomized control trial

DOAC: Direct oral anticoagulants

PPE: Personal protective equipment

CRRT: Continuous renal replacement therapyGo to:

Declaration of interest

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

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Whole genome sequencing reveals host factors underlying critical Covid-19

Authors: Athanasios KousathanasErola Pairo-CastineiraJ. Kenneth BaillieArticle

Published:  nature  articles  article

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

Abstract

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

Author information

Author notes

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

Affiliations

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

Consortia

GenOMICC Investigators

23andMe

Covid-19 Human Genetics Initiative

Corresponding authors

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

Supplementary information

Supplementary Information

This file contains Supplementary Figures; Supplementary Tables and Supplementary References

OPINION

Here’s how to detox from the COVID spike protein – from the jab or the virus


Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs, but the World Council for Health has compiled a list of medications to prevent this.

Thu Dec 23, 2021 – 10:38 am EST

Note: This article is an opinion and the treatments that are recommended in it have not been proven as an effective means to eliminate the spike protein from COVID or mRNA vaccines. Damage to endothelial linings of vessels and organs by the COVID-19 spike protein and how to reverse it requires new research and randomized clinical trials to determine if any treatment can detox the body of the spike protein that causes Long-haul diseases.

STORY AT-A-GLANCE

  • If you had COVID-19 or received a COVID-19 injection, you may have dangerous spike proteins circulating in your body
  • Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs
  • The World Council for Health has released a spike protein detox guide, which provides straightforward steps you can take to potentially lessen the effects of toxic spike protein in your body
  • Spike protein inhibitors and neutralizers include pine needles, ivermectin, neem, N-acetylcysteine (NAC) and glutathione
  • The top 10 spike protein detox essentials include vitamin D, vitamin C, nigella seed, quercetin, zinc, curcumin, milk thistle extract, NAC, ivermectin and magnesium

(Mercola) – Have you had COVID-19 or received a COVID-19 injection? Then you likely have dangerous spike proteins circulating in your body. While a spike protein is naturally found in SARS-CoV-2, no matter the variant, it’s also produced in your body when you receive a COVID-19 shot. In its native form in SARS-CoV-2, the spike protein is responsible for the pathologies of the viral infection.

In its wild form it’s known to open the blood-brain barrier, cause cell damage (cytotoxicity) and, as Dr. Robert Malone – the inventor of the mRNA and DNA vaccine core platform technology – said in a commentary on News Voice, the protein “is active in manipulating the biology of the cells that coat the inside of your blood vessels — vascular endothelial cells, in part through its interaction with ACE2, which controls contraction in the blood vessels, blood pressure and other things.”

It’s also been revealed that the spike protein on its own is enough to cause inflammation and damage to the vascular system, even independent of a virus.

Now, the World Council for Health (WCH) – a worldwide coalition of health-focused organizations and civil society groups that seek to broaden public health knowledge – has released a spike protein detox guide, which provides straightforward steps you can take to potentially lessen the effects of toxic spike protein. You can view their full guide of natural remedies, including dosages, at the end of this article.

Why should you consider a spike protein detox?

Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs. “Spike protein is a deadly protein,” Dr. Peter McCullough, an internist, cardiologist and trained epidemiologist, says in a video. It may cause inflammation and clotting in any tissue in which it accumulates.

For instance, Pfizer’s biodistribution study, which was used to determine where the injected substances end up in the body, showed the COVID spike protein from the shots accumulated in “quite high concentrations” in the ovaries.

Further, a Japanese biodistribution study for Pfizer’s jab found that vaccine particles move from the injection site to the blood, after which circulating spike proteins are free to travel throughout the body, including to the ovaries, liver, neurological tissues and other organs. WCH noted:

“The virus spike protein has been linked to adverse effects, such as: blood clots, brain fog, organizing pneumonia, and myocarditis. It is probably responsible for many of the Covid-19 [injection] side effects … Even if you have not had any symptoms, tested positive for Covid-19, or experienced adverse side effects after a jab, there may still be lingering spike proteins inside your body.

In order to clear these after the jab or an infection, doctors and holistic practitioners are suggesting a few simple actions. It is thought that cleansing the body of spike protein … as soon as possible after an infection or jab may protect against damage from remaining or circulating spike proteins.”

Spike protein inhibitors and neutralizers

A group of international doctors and holistic practitioners who have experience helping people recover from COVID-19 and post-injection illness compiled natural options for helping to reduce your body’s spike protein load. The following are spike protein inhibitors, which means they inhibit the binding of the spike protein to human cells:

Prunella vulgarisPine needles
EmodinNeem
Dandelion leaf extractIvermectin

Ivermectin, for example, docks to the SARS-CoV-2 spike receptor-bending domain attached to ACE2, which may interfere with its ability to attach to the human cell membrane. They also compiled a list of spike protein neutralizers, which render it unable to cause further damage to cells. This includes:

N-acetylcysteine (NAC)Glutathione
Fennel teaStar anise tea
Pine needle teaSt. John’s wort
Comfrey leafVitamin C

The plant compounds in the table above contain shikimic acid, which may counteract blood clot formation and reduce some of the spike protein’s toxic effects. Nattokinase, a form of fermented soy, may also help to reduce the occurrence of blood clots.

How to protect your ACE2 receptors and detox IL-6

Spike protein attaches to your cells’ ACE2 receptors, impairing the receptors’ normal functioning. This blockage may alter tissue functioning and could be responsible for triggering autoimmune disease or causing abnormal bleeding or clotting, including vaccine-induced thrombotic thrombocytopenia.

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Ivermectin, hydroxychloroquine (with zinc), quercetin (with zinc) and fisetin (a flavonoid) are examples of substances that may naturally protect your ACE2 receptors. Ivermectin works in this regard by binding to ACE2 receptors, preventing the spike protein from doing so.

Interleukin 6 (IL-6) is a proinflammatory cytokine that is expressed post-injection, and its levels increase in people with COVID-19. It’s for this reason that the World Health Organization recommends IL-6 inhibitors for people who are severely ill with COVID-19. Many natural IL-6 inhibitors, or anti-inflammatories, exist and may be useful for those seeking to detox from COVID-19 or COVID-19 injections:

Boswellia serrata (frankincense)Dandelion leaf extract
Black cumin (Nigella sativa)Curcumin
Krill oil and other fatty acidsCinnamon
FisetinApigenin
QuercetinResveratrol
LuteolinVitamin D3 (with vitamin K)
ZincMagnesium
Jasmine teaSpices
Bay leavesBlack pepper
NutmegSage

How to detox from Furin and Serine Protease

To gain entry into your cells, SARS-CoV-2 must first bind to an ACE2 or CD147 receptor on the cell. Next, the spike protein subunit must be proteolytically cleaved (cut). Without this protein cleavage, the virus would simply attach to the receptor and not get any further.

“The furin site is why the virus is so transmissible, and why it invades the heart, the brain and the blood vessels,” Dr. Steven Quay, a physician and scientist, explained at a GOP House Oversight and Reform Subcommittee on Select Coronavirus Crisis hearing.

The existence of a novel furin cleavage site on SARS-CoV-2, while other coronaviruses do not contain a single example of a furin cleavage site, is a significant reason why many believe SARS-CoV-2 was created through gain-of-function (GOF) research in a laboratory. Natural furin inhibitors, which prevent cleavage of the spike protein, can help you detox from furin and include:

  • Rutin
  • Limonene
  • Baicalein
  • Hesperidin

Serine protease is another enzyme that’s “responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus.” Inhibiting serine protease may therefore prevent spike protein activation and viral entry into cells. WCH compiled several natural serine protease inhibitors, which include:

Green teaPotato tubers
Blue green algaeSoybeans
N-acetyl cysteine (NAC)Boswellia

Time-restricted eating and healthy diet for all

In addition to the targeted substances mentioned above, WCH was wise to note that a healthy diet is the first step to a healthy immune system. Reducing your consumption of processed foods and other proinflammatory foods, including vegetable (seed) oils, is essential for an optimal immune response.

Time-restricted eating, which means condensing your meals into a six- to eight-hour window, is also beneficial. This will improve your health in a variety of ways, primarily by improving your mitochondrial health and metabolic flexibility. It can also increase autophagy, which helps your body clear out damaged cells. As noted by WCH:

“This method … is used to induce autophagy, which is essentially a recycling process that takes place in human cells, where cells degrade and recycle components. Autophagy is used by the body to eliminate damaged cell proteins and can destroy harmful viruses and bacteria post-infection.”

Another strategy to boost your health and longevity, and possibly to help detox spike protein, is regular sauna usage. As your body is subjected to reasonable amounts of heat stress, it gradually becomes acclimated to the heat, prompting a number of beneficial changes to occur in your body.

These adaptations include increased plasma volume and blood flow to your heart and muscles (which increase athletic endurance) along with increased muscle mass due to greater levels of heat-shock proteins and growth hormone. It’s a powerful detoxification method due to the sweating it promotes.

Top 10 spike protein detox essentials and the full guide

Below you can find WCH’s full guide of useful substances to detox from toxic spike proteins, including recommended doses, which you can confirm with your holistic health care practitioner. If you’re not sure where to start, the following 10 compounds are the “essentials” when it comes to spike protein detox. This is a good place to begin as you work out a more comprehensive health strategy:

Vitamin DVitamin C
NACIvermectin
Nigella seedQuercetin
ZincMagnesium
CurcuminMilk thistle extract

World Council for Health’s spike protein detox guide

SubstanceNatural Source(s)Where to GetRecommended Dose
IvermectinSoil bacteria (avermectin)On prescription0.4 mg/kg weekly for 4 weeks, then monthly
*Check package instructions to determine if there are contraindications prior to use
HydroxychloroquineOn prescription200 mg weekly for 4 weeks
*Check package instructions to determine if there are contraindications prior to use
Vitamin CCitrus fruits (e.g. oranges) and vegetables (broccoli, cauliflower, brussels sprouts)Supplement: health food stores, pharmacies, dietary supplement stores, online6-12 g daily (divided evenly between sodium ascorbate (several grams), liposomal vitamin C (3-6 g) & ascorbyl palmitate (1–3 g)
Prunella Vulgaris (commonly known as self-heal)Self-heal plantSupplement: health food stores, pharmacies, dietary supplement stores, online7 ounces (207 ml) daily
Pine NeedlesPine treeSupplement: health food stores, pharmacies, dietary supplement stores, onlineConsume tea 3 x daily (consume oil/resin that accumulates in the tea also)
NeemNeem treeSupplement: health food stores, pharmacies, dietary supplement stores, onlineAs per your practitioner’s or preparation instructions
Dandelion Leaf ExtractDandelion plantSupplement (dandelion tea, dandelion coffee, leaf tincture): natural food stores, pharmacies, dietary supplement stores, onlineTincture as per your practitioner’s or preparation instructions
N-Acetyl Cysteine (NAC)High-protein foods (beans, lentils, spinach, bananas, salmon, tuna)Supplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 1,200 mg daily (in divided doses)
Fennel TeaFennel plantSupplement: health food stores, pharmacies, dietary supplement stores, onlineNo upper limit. Start with 1 cup and monitor body’s reaction
Star Anise TeaChinese evergreen tree (Illicium verum)Supplement: health food stores, pharmacies, dietary supplement stores, onlineNo upper limit. Start with 1 cup and monitor body’s reaction
St John’s WortSt John’s wort plantSupplement: health food stores, pharmacies, dietary supplement stores, onlineAs directed on supplement
Comfrey LeafSymphytum plant genusSupplement: health food stores, pharmacies, dietary supplement stores, onlineAs directed on supplement
Lumbrokinase
Serrapeptidase
Or Nattokinase
Natto (Japanese soybean dish)Supplement: health food stores, pharmacies, dietary supplement stores, online2-6 capsules 3-4 times a day on empty stomach one hour before or two hours after a meal
Boswellia serrataBoswellia serrata treeSupplement: health food stores, pharmacies, dietary supplement stores, onlineAs directed on supplement
Black Cumin (Nigella Sativa)Buttercup plant familyGrocery stores, health food stores
CurcuminTurmericGrocery stores, health food stores
Fish OilFatty/oily fishGrocery stores, health food storesUp to 2,000 mg daily
CinnamonCinnamomum tree genusGrocery store
Fisetin (Flavonoid)Fruits: strawberries, apples, mangoes Vegetables: onions, nuts, wineSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 100 mg daily Consume with fats
ApigeninFruits, veg & herbs parsley, chamomile, vine-spinach, celery, artichokes, oreganoSupplement: health food stores, pharmacies, dietary supplement stores, online50 mg daily
Quercetin (Flavonoid)Citrus fruits, onions, parsley, red wineSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 500 mg twice daily, Consume with zinc
ResveratrolPeanuts, grapes, wine, blueberries, cocoaSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 1,500 mg daily for up to 3 months
LuteolinVegetables: celery, parsley, onion leaves
Fruits: apple skins, chrysanthemum flowers
Supplement: health food stores, pharmacies, dietary supplement stores, online100-300 mg daily (Typical manufacturer recommendations)
Vitamin D3Fatty fish, fish liver oilsSupplement: health food stores, pharmacies, dietary supplement stores, online5,000–10,000 IU daily or whatever it takes to get to 60-80 ng/ml as tested in your blood
Vitamin KGreen leafy vegetablesSupplement: health food stores, pharmacies, dietary supplement stores, online90-120 mg daily (90 for women, 120 for men)
ZincRed meat, poultry, oysters, whole grains, milk productsSupplement: health food stores, pharmacies, dietary supplement stores, online11-40 mg daily
MagnesiumGreens, whole grains, nutsSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 350 mg daily
Jasmine TeaLeaves of common jasmine or Sampaguita plantsGrocery store, health food storesUp to 8 cups per day
SpicesGrocery store
Bay LeavesBay leaf plantsGrocery store
Black PepperPiper nigrum plantGrocery store
NutmegMyristica fragrans tree seedGrocery store
SageSage plantGrocery store
RutinBuckwheat, asparagus, apricots, cherries, black tea, green tea, elderflower teaSupplement: health food stores, pharmacies, dietary supplement stores, online500-4,000 mg daily (consult health care provider before taking higher-end doses)
LimoneneRind of citrus fruits such as lemons, oranges, and limesSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 2,000 mg daily
BaicaleinScutellaria plant genusSupplement: health food stores, pharmacies, dietary supplement stores, online100-2,800 mg
HesperidinCitrus fruitSupplement: health food stores, pharmacies, dietary supplement stores, onlineUp to 150 mg twice daily
Green TeaCamellia sinensis plant leavesGrocery storeUp to 8 cups of tea a day or as directed on supplement
Potatoes tubersPotatoesGrocery store
Blue Green AlgaeCyanobacteriaSupplement: health food stores, pharmacies, dietary supplement stores, online1-10 grams daily
Andrographis PaniculataGreen chiretta plantSupplement: health food stores, pharmacies, dietary supplement stores, online400 mg x 2 daily
*Check for contraindications
Milk Thistle ExtractSilymarinSupplement; Health food stores, pharmacies, dietary supplement stores, online200 mg x 3 daily
Soybeans (organic)SoybeansGrocery store, health food stores

Reprinted with permission from Mercola

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Authors.Maximilian Ackermann, M.D., Stijn E. Verleden, Ph.D., Mark Kuehnel, Ph.D., Axel Haverich, M.D., Tobias Welte, M.D., Florian Laenger, M.D., Arno Vanstapel, Ph.D., Christopher Werlein, M.D., Helge Stark, Ph.D., Alexandar Tzankov, M.D., William W. Li, M.D., Vincent W. Li, M.D., et al.

July 9, 2020 N Engl J Med 2020; 383:120-128 DOI: 10.1056/NEJMoa2015432

Abstract

BACKGROUND

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.

METHODS

We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.

RESULTS

In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).

CONCLUSIONS

In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans is associated with a broad spectrum of clinical respiratory syndromes, ranging from mild upper airway symptoms to progressive life-threatening viral pneumonia.1,2 Clinically, patients with severe coronavirus disease 2019 (Covid-19) have labored breathing and progressive hypoxemia and often receive mechanical ventilatory support. Radiographically, peripheral lung ground-glass opacities on computed tomographic (CT) imaging of the chest fulfill the Berlin criteria for acute respiratory distress syndrome (ARDS).3,4 Histologically, the hallmark of the early phase of ARDS is diffuse alveolar damage with edema, hemorrhage, and intraalveolar fibrin deposition, as described by Katzenstein et al.5 Diffuse alveolar damage is a nonspecific finding, since it may have noninfectious or infectious causes, including Middle East respiratory syndrome coronavirus (MERS-CoV),6 SARS-CoV,7 SARS-CoV-2,8-10 and influenza viruses.11

Among the distinctive features of Covid-19 are the vascular changes associated with the disease. With respect to diffuse alveolar damage in SARS-CoV7 and SARS-CoV-2 infection,8,12 the formation of fibrin thrombi has been observed anecdotally but not studied systematically. Clinically, many patients have elevated d-dimer levels, as well as cutaneous changes in their extremities suggesting thrombotic microangiopathy.13 Diffuse intravascular coagulation and large-vessel thrombosis have been linked to multisystem organ failure.14-16 Peripheral pulmonary vascular changes are less well characterized; however, vasculopathy in the gas-exchange networks, depending on its effect on the matching of ventilation and perfusion that results, could potentially contribute to hypoxemia and the effects of posture (e.g., prone positioning) on oxygenation.17

Despite previous experience with SARS-CoV18 and early experience with SARS-CoV-2, the morphologic and molecular changes associated with these infections in the peripheral lung are not well documented. Here, we examine the morphologic and molecular features of lungs obtained during autopsy from patients who died from Covid-19, as compared with those of lungs from patients who died from influenza and age-matched, uninfected control lungs.

Methods

PATIENT SELECTION AND WORKFLOW

We analyzed pulmonary autopsy specimens from seven patients who died from respiratory failure caused by SARS-CoV-2 infection and compared them with lungs from seven patients who died from pneumonia caused by influenza A virus subtype H1N1 (A[H1N1]) — a strain associated with the 1918 and 2009 influenza pandemics. The lungs from patients with influenza were archived tissue from the 2009 pandemic and were chosen for the best possible match with respect to age, sex, and disease severity from among the autopsies performed at the Hannover Medical School. Ten lungs that had been donated but not used for transplantation served as uninfected control specimens. The Covid-19 group consisted of lungs from two female and five male patients with mean (±SD) ages of 68±9.2 years and 80±11.5 years, respectively (clinical data are provided in Table S1A in the Supplementary Appendix, available with the full text of this article at NEJM.org). The influenza group consisted of lungs from two female and five male patients with mean ages of 62.5±4.9 years and 55.4±10.9 years, respectively. Five of the uninfected lungs were from female donors (mean age, 68.2±6.9 years), and five were from male donors (mean age, 79.2±3.3 years) (clinical data are provided in Table S1B). The study was approved by and conducted according to requirements of the ethics committees at the Hannover Medical School and the University of Leuven. There was no commercial support for this study.

All lungs were comprehensively analyzed with the use of microCT, histopathological, and multiplexed immunohistochemical analysis, transmission and scanning electron microscopy, corrosion casting, and direct multiplexed gene-expression analysis, as described in detail in the Methods section of the Supplementary Appendix.

STATISTICAL ANALYSIS

All comparisons of numeric variables (including those in the gene-expression analysis) were conducted with Student’s t-test familywise error rates due to multiplicity set at 0.05 with the use of the Benjamini–Hochberg method of controlling false discovery rates. Original P values are reported only for the tests that met the criteria for false discovery rates. All confidence intervals have been calculated on the basis of the t-distribution, as well. Additional details are provided in the Methods section of the Supplementary Appendix.

Results

GROSS EXAMINATION

The mean (±SE) weight of the lungs from patients with proven influenza pneumonia was significantly higher than that from patients with proven Covid-19 (2404±560 g vs. 1681±49 g; P=0.04). The mean weight of the uninfected control lungs (1045±91 g) was significantly lower than those in the influenza group (P=0.003) and the Covid-19 group (P<0.001).

ANGIOCENTRIC INFLAMMATION

Figure 1. Lymphocytic Inflammation in a Lung from a Patient Who Died from Covid-19.

All lung specimens from the Covid-19 group had diffuse alveolar damage with necrosis of alveolar lining cells, pneumocyte type 2 hyperplasia, and linear intraalveolar fibrin deposition (Figure 1). In four of seven cases, the changes were focal, with only mild interstitial edema. The remaining three cases had homogeneous fibrin deposits and marked interstitial edema with early intraalveolar organization. The specimens in the influenza group had florid diffuse alveolar damage with massive interstitial edema and extensive fibrin deposition in all cases. In addition, three specimens in the influenza group had focal organizing and resorptive inflammation (Fig. S2). These changes were reflected in the much higher weight of the lungs from patients with influenza.

Immunohistochemical analysis of angiotensin-converting enzyme 2 (ACE2) expression, measured as mean (±SD) relative counts of ACE2-positive cells per field of view, in uninfected control lungs showed scarce expression of ACE2 in alveolar epithelial cells (0.053±0.03) and capillary endothelial cells (0.066±0.03). In lungs from patients with Covid-19 and lungs from patients with influenza, the relative counts of ACE2-positive cells per field of view were 0.25±0.14 and 0.35±0.15, respectively, for alveolar epithelial cells and 0.49±0.28 and 0.55±0.11, respectively, for endothelial cells. Furthermore, ACE2-positive lymphocytes were not seen in perivascular tissue or in the alveoli of the control lungs but were present in the lungs in the Covid-19 group and the influenza group (relative counts of 0.22±0.18 and 0.15±0.09, respectively). (Details of counting are provided in Table S2.)

In the lungs from patients with Covid-19 and patients with influenza, similar mean (±SD) numbers of CD3-positive T cells were found within a 200-μm radius of precapillary and postcapillary vessel walls in 20 fields of examination per patient (26.2±13.1 for Covid-19 and 14.8±10.8 for influenza). With the same field size used for examination, CD4-positive T cells were more numerous in lungs from patients with Covid-19 than in lungs from patients with influenza (13.6±6.0 vs. 5.8±2.5, P=0.04), whereas CD8-positive T cells were less numerous (5.3±4.3 vs. 11.6±4.9, P=0.008). Neutrophils (CD15 positive) were significantly less numerous adjacent to the alveolar epithelial lining in the Covid-19 group than in the influenza group (0.4±0.5 vs. 4.8±5.2, P=0.002).

A multiplexed analysis of inflammation-related gene expression examining 249 genes from the nCounter Inflammation Panel (NanoString Technologies) revealed similarities and differences between the specimens in the Covid-19 group and those in the influenza group. A total of 79 inflammation-related genes were differentially regulated only in specimens from patients with Covid-19, whereas 2 genes were differentially regulated only in specimens from patients with influenza; a shared expression pattern was found for 7 genes (Fig. S1).

THROMBOSIS AND MICROANGIOPATHY

Figure 2. Microthrombi in the Interalveolar Septa of a Lung from a Patient Who Died from Covid-19.

The pulmonary vasculature of the lungs in the Covid-19 group and the influenza group was analyzed with hematoxylin–eosin, trichrome, and immunohistochemical staining (as described in the Methods section of the Supplementary Appendix). Analysis of precapillary vessels showed that in four of the seven lungs from patients with Covid-19 and four of the seven lungs from the patients with influenza, thrombi were consistently present in pulmonary arteries with a diameter of 1 mm to 2 mm, without complete luminal obstruction (Figs. S3 and S5). Fibrin thrombi of the alveolar capillaries could be seen in all the lungs from both groups of patients (Figure 2). Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (mean [±SD] number of distinct thrombi per square centimeter of vascular lumen area, 159±73 and 16±16, respectively; P=0.002). Intravascular thrombi in postcapillary venules of less than 1 mm diameter were seen in lower numbers in the lungs from patients with Covid-19 than in those from patients with influenza (12±14 vs. 35±16, P=0.02). Two lungs in the Covid-19 group had involvement of all segments of the vasculature, as compared with four of the lungs in the influenza group; in three of the lungs in the Covid-19 group and three of the lungs in the influenza group, combined capillary and venous thrombi were found without arterial thrombi.

The histologic findings were supported by three-dimensional microCT of the pulmonary specimens: the lungs from patients with Covid-19 and from patients with influenza showed nearly total occlusions of precapillary and postcapillary vessels.

ANGIOGENESIS

Figure 3. Microvascular Alterations in Lungs from Patients Who Died from Covid-19

.

We examined the microvascular architecture of the lungs from patients with Covid-19, lungs from patients with influenza, and uninfected control lungs with the use of scanning electron microscopy and microvascular corrosion casting. The lungs in the Covid-19 group had a distorted vascularity with structurally deformed capillaries (Figure 3). Elongated capillaries in the lungs from patients with Covid-19 showed sudden changes in caliber and the presence of intussusceptive pillars within the capillaries (Figure 3C). Transmission electron microscopy of the Covid-19 endothelium showed ultrastructural damage to the endothelium, as well as the presence of intracellular SARS-CoV-2 (Figure 3D). The virus could also be identified in the extracellular space.

Figure 4.Numeric Density of Features of Intussusceptive and Sprouting Angiogenesis in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).

In the lungs from patients with Covid-19, the density of intussusceptive angiogenic features (mean [±SE], 60.7±11.8 features per field) was significantly higher than that in lungs from patients with influenza (22.5±6.9) or in uninfected control lungs (2.1±0.6) (P<0.001 for both comparisons) (Figure 4A). The density of features of conventional sprouting angiogenesis was also higher in the Covid-19 group than in the influenza group (Figure 4B). When the pulmonary angiogenic feature count was plotted as a function of the length of hospital stay, the degree of intussusceptive angiogenesis was found to increase significantly with increasing duration of hospitalization (P<0.001) (Figure 4C). In contrast, the lungs from patients with influenza had less intussusceptive angiogenesis and no increase over time (Figure 4C). A similar pattern was seen for sprouting angiogenesis (Figure 4D).Figure 5.elative Expression Analysis of Angiogenesis-Associated Genes in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).

A multiplexed analysis of angiogenesis-related gene expression examining 323 genes from the nCounter PanCancer Progression Panel (NanoString Technologies) revealed differences between the specimens from patients with Covid-19 and those from patients with influenza. A total of 69 angiogenesis-related genes were differentially regulated only in the Covid-19 group, as compared with 26 genes differentially regulated only in the influenza group; 45 genes had shared changes in expression (Figure 5).

Discussion

In this study, we examined the morphologic and molecular features of seven lungs obtained during autopsy from patients who died from SARS-CoV-2 infection. The lungs from these patients were compared with those obtained during autopsy from patients who had died from ARDS secondary to influenza A(H1N1) infection and from uninfected controls. The lungs from the patients with Covid-19 and the patients with influenza shared a common morphologic pattern of diffuse alveolar damage and infiltrating perivascular lymphocytes. There were three distinctive angiocentric features of Covid-19. The first feature was severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes. Second, the lungs from patients with Covid-19 had widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries.12,19 Third, the lungs from patients with Covid-19 had significant new vessel growth through a mechanism of intussusceptive angiogenesis. Although our sample was small, the vascular features we identified are consistent with the presence of distinctive pulmonary vascular pathobiologic features in some cases of Covid-19.

Our finding of enhanced intussusceptive angiogenesis in the lungs from patients with Covid-19 as compared with the lungs from patients with influenza was unexpected. New vessel growth can occur by conventional sprouting or intussusceptive (nonsprouting) angiogenesis. The characteristic feature of intussusceptive angiogenesis is the presence of a pillar or post spanning the lumen of the vessel.20 Typically referred to as an intussusceptive pillar, this endothelial-lined intravascular structure is not seen by light microscopy but is readily identifiable by corrosion casting and scanning electron microscopy.21 Although tissue hypoxia was probably a common feature in the lungs from both these groups of patients, we speculate that the greater degree of endothelialitis and thrombosis in the lungs from patients with Covid-19 may contribute to the relative frequency of sprouting and intussusceptive angiogenesis observed in these patients. The relationship of these findings to the clinical course of Covid-19 requires further research to elucidate.

A major limitation of our study is that the sample was small; we studied only 7 patients among the more than 320,000 people who have died from Covid-19, and the autopsy data also represent static information. On the basis of the available data, we cannot reconstruct the timing of death in the context of an evolving disease process. Moreover, there could be other factors that account for the differences we observed between patients with Covid-19 and those with influenza. For example, none of the patients in our study who died from Covid-19 had been treated with standard mechanical ventilation, whereas five of the seven patients who died from influenza had received pressure-controlled ventilation. Similarly, it is possible that differences in detectable intussusceptive angiogenesis could be due to the different time courses of Covid-19 and influenza. These and other unknown factors must be considered when evaluating our data.22 Nonetheless, our analysis suggests that this possibility is unlikely, particularly since the degree of intussusceptive angiogenesis in the patients with Covid-19 increased significantly with increasing length of hospitalization, whereas in the patients with influenza it remained stable at a significantly lower level. Moreover, we have shown intussusceptive angiogenesis to be the predominant angiogenic mechanism even in late stages of chronic lung injury.21

ACE2 is an integral membrane protein that appears to be the host-cell receptor for SARS-CoV-2.23,24 Our data showed significantly greater numbers of ACE2-positive cells in the lungs from patients with Covid-19 and from patients with influenza than in those from uninfected controls. We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of Covid-19. Endothelial cells in the specimens from patients with Covid-19 showed disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane. The presence of SARS-CoV-2 virus within the endothelial cells, a finding consistent with other studies,25 suggests that direct viral effects as well as perivascular inflammation may contribute to the endothelial injury.

We report the presence of pulmonary intussusceptive angiogenesis and other pulmonary vascular features in the lungs of seven patients who died from Covid-19. Additional work is needed to relate our findings to the clinical course in these patients. To aid others in their research, our full data set is available on the Vivli platform (https://vivli.org/. opens in new tab) and can be requested with the use of the following digital object identifier: https://doi.org/10.25934/00005576. opens in new tab.

Supported by grants (HL94567 and HL134229, to Drs. Ackermann and Mentzer) from the National Institutes of Health, a grant from the Botnar Research Centre for Child Health (to Dr. Tzankov), a European Research Council Consolidator Grant (XHale) (771883, to Dr. Jonigk), and a grant (KFO311, to Dr. Jonigk) from Deutsche Forschungsgemeinschaft (Project Z2).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on May 21, 2020, at NEJM.org.

We thank Kerstin Bahr, Jan Hinrich Braesen, Peter Braubach, Emily Brouwer, Annette Mueller Brechlin, Regina Engelhardt, Jasmin Haslbauer, Anne Hoefer, Nicole Kroenke, Thomas Menter, Mahtab Taleb Naghsh, Christina Petzold, Vincent Schmidt, and Pauline Tittmann for technical support; Peter Boor of the German Covid-19 registry; and Lynnette Sholl, Hans Kreipe, Hans Michael Kvasnicka, and Jean Connors for helpful comments. Dr. Jonigk thanks Anita Swiatlak for her continued support.

Author Affiliations

From the Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten–Herdecke, Wuppertal (M.A.), the Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz (M.A.), the Institute of Pathology (M.K., F.L., C.W., H.S., D.J.), the Department of Cardiothoracic, Transplantation, and Vascular Surgery (A.H.), and the Clinic of Pneumology (T.W.), Hannover Medical School, and the German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) (M.K., A.H., T.W., F.L., C.W., H.S., D.J.), Hannover — all in Germany; the Laboratory of Respiratory Diseases, BREATH, Department of Chronic Diseases, Metabolism, and Aging, KU Leuven, Leuven, Belgium (S.E.V., A.V.); the Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland (A.T.); and the Angiogenesis Foundation, Cambridge (W.W.L., V.W.L.), and the Laboratory of Adaptive and Regenerative Biology and the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston (S.J.M.) — all in Massachusetts.

Address reprint requests to Dr. Mentzer at the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, or at smentzer@bwh.harvard.edu.

Supplementary Material

Supplementary AppendixPDF1523KB
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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Authors: Juan Pablo Robles 1Magdalena Zamora 1Elva Adan-CastroLourdes Siqueiros-MarquezGonzalo Martinez de la EscaleraCarmen Clapp

Open AccessDOI:https://doi.org/10.1016/j.jbc.2022.101695

Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNF⍺, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

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https://www.jbc.org/action/showPdf?pii=S0021-9258%2822%2900135-1