FDA limits use of J&J vaccine over rare blood clots

Authors:  PETER SULLIVAN – 05/05/22 THE HILL

The Food and Drug Administration (FDA) on Thursday announced that it is limiting the authorization for the Johnson & Johnson COVID-19 to people who cannot or will not get other versions of the vaccine, citing the risk of rare blood clots.  

The authorization for the J&J vaccine, also known as the Janssen vaccine, is now limited to people for whom the Pfizer or Moderna vaccines “are not accessible or clinically appropriate,” or “who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine.” 

That is, people can still get the J&J vaccine if they are allergic to the mRNA vaccines from Pfizer or Moderna, or if personal concerns with the other vaccines mean they would otherwise go without any inoculation.  

The agency said it was making the decision after “conducting an updated analysis, evaluation and investigation of reported cases” of the blood clots, which “warrants limiting the authorized use of the vaccine.” 

Importantly, the Pfizer and Moderna vaccines do not carry the same risks of blood clots, given they use a different technology than the Johnson & Johnson vaccines.  

Blood clots also remain rare among J&J recipients. The FDA has identified 60 confirmed cases of the blood clots following receipt of the J&J vaccine and nine deaths, it said. That is about three cases of blood clots for every million J&J vaccines administered, and 0.48 deaths per million doses of the J&J vaccine. 

The blood clots are formally known as thrombosis with thrombocytopenia syndrome (TTS).  

This is not the first time that the risk has affected distribution of the vaccine. Regulators caused shockwaves, and some controversy, early last year, when they paused the administration of the J&J vaccine for several days to allow time to investigate the blood clots.  

“Today’s action demonstrates the robustness of our safety surveillance systems and our commitment to ensuring that science and data guide our decisions,” said Peter Marks, a top FDA official. “We’ve been closely monitoring the Janssen COVID-19 Vaccine and occurrence of TTS following its administration and have used updated information from our safety surveillance systems to revise the [authorization].” 

The J&J vaccine already had far lower usage than the Pfizer or Moderna vaccines. About 18 million doses have been administered, according to the Centers for Disease Control and Prevention, compared to more than 200 million for Moderna and more than 300 million for Pfizer.  

In making its decision, the FDA noted the availability of other vaccines from Pfizer and Moderna, “which provide protection from COVID-19 and have not been shown to present a risk for TTS.”

Acute Mesenteric Ischemia in COVID-19 Patients

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

Abstract:

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

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

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

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.

REFERENCES
1 Burch J, Enofe I. Acute mesenteric ischaemia secondary to portal, splenic and superior
mesenteric vein thrombosis. BMJ Case Rep 2019;12:e230145.
2 Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation:
American College of chest physicians evidence-based clinical practice guidelines (8th
edition). Chest 2008;133:546S–92.
3 Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous
thromboembolism: a meta-analysis. Circulation 2008;117:93–102.
4 Fan BE, Shen JY, Lim XR, et al. Cerebral venous thrombosis post BNT162b2 mRNA
SARS-CoV-2 vaccination: a black Swan event. Am J Hematol 2021. doi:10.1002/
ajh.26272. [Epub ahead of print: 16 Jun 2021].
5 Dias L, Soares-Dos-Reis R, Meira J, et al. Cerebral venous thrombosis after BNT162b2
mRNA SARS-CoV-2 vaccine. J Stroke Cerebrovasc Dis 2021;30:105906.
6 Cines DB, Bussel JB. SARS-CoV-2 vaccine-induced immune thrombotic
thrombocytopenia. N Engl J Med 2021;384:2254–6.
7 AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual
blood clots with low blood platelets. Available: https://www.ema.europa.eu/en/news/
astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-bloodclots-low-blood [Accessed Apr 2021].
8 Smadja DM, Yue Q-Y, Chocron R, et al. Vaccination against COVID-19: insight from
arterial and venous thrombosis occurrence using data from VigiBase. Eur Respir J
2021;58:2100956.
9 Wise J. Covid-19: rare immune response may cause clots after AstraZeneca vaccine, say
researchers. BMJ 2021;373:n954.

Intestinal Damage in COVID-19: SARS-CoV-2 Infection and Intestinal Thrombosis

Authors: Xiaoming Wu1Haijiao Jing1Chengyue Wang1Yufeng Wang1Nan Zuo1Tao Jiang2*Valerie A. Novakovic3 and Jialan Shi1,3,4* Front. Microbiol., 22 March 2022 | https://doi.org/10.3389/fmicb.2022.860931

The intestinal tract, with high expression of angiotensin-converting enzyme 2 (ACE2), is a major site of extrapulmonary infection in COVID-19. During pulmonary infection, the virus enters the bloodstream forming viremia, which infects and damages extrapulmonary organs. Uncontrolled viral infection induces cytokine storm and promotes a hypercoagulable state, leading to systemic microthrombi. Both viral infection and microthrombi can damage the gut–blood barrier, resulting in malabsorption, malnutrition, and intestinal flora entering the blood, ultimately increasing disease severity and mortality. Early prophylactic antithrombotic therapy can prevent these damages, thereby reducing mortality. In this review, we discuss the effects of SARS-CoV-2 infection and intestinal thrombosis on intestinal injury and disease severity, as well as corresponding treatment strategies.

Introduction

COVID-19 has become a worldwide pandemic causing widespread illness and mortality. SARS-CoV-2 mainly infects the respiratory tract through attachment to angiotensin-converting enzyme 2 (ACE2) receptors (Lan et al., 2020). ACE2 is also highly expressed on intestinal epithelial cells, allowing SARS-CoV-2 to infect the intestinal tract (Xiao et al., 2020a). Recent meta-analyses show that 48%–54% of fecal samples from COVID-19 patients have tested positive for viral RNA, and 15%–17% of patients have gastrointestinal (GI) symptoms (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). Additionally, live virus can be isolated from fecal samples of COVID-19 patients (Wang et al., 2020). Some studies have proposed fecal–oral transmission as the cause of intestinal infection (Guo et al., 2021). However, direct evidence for fecal–oral transmission is still lacking. Meanwhile, the virus has been detected in the blood of both symptomatic and asymptomatic patients (Chang et al., 2020), and disseminated virus could infect extrapulmonary organs (Jacobs and Mellors, 2020). Thus, the potential that intestinal infection occurs via blood transmission should be carefully considered.

Pulmonary infection triggers cytokine storm and induces a prothrombotic state (McFadyen et al., 2020Moore and June, 2020). Venous and arterial thrombosis are common in COVID-19 (Moore and June, 2020). Systematic reviews estimate that 14%–31% of in-hospital patients develop a clinically apparent thrombotic event (Suh et al., 2021Tan et al., 2021), while autopsy reports show a high prevalence of microthrombi in multiple organs, including lung, heart, liver, kidney, and gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). A cohort study showed that COVID-19 patients with intestinal ischemia had markedly elevated D-dimer levels and poor outcomes (Norsa et al., 2020). Additionally, recent studies have shown that mesenteric thrombosis often results in intestinal resection and significantly increases mortality (Bhayana et al., 2020El Moheb et al., 2020). Therefore, it is essential to outline the mechanisms of intestinal thrombosis and its contribution to intestinal damage and disease progression.

In this review, we discuss blood transmission as a potential route for intestinal infection. We then summarize the characteristics and mechanism of intestinal thrombosis formation in COVID-19. Next, we focus on the effects of intestinal infection and thrombosis on intestinal damage and disease severity. Finally, we discuss therapeutic strategies to prevent intestinal damage.

Gastrointestinal Symptoms and SARS-CoV-2 Infection

Multiple studies have reported GI symptoms in COVID-19 patients, including diarrhea, nausea, vomiting, anorexia, and abdominal pain (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). According to a meta-analysis comprising 10,890 COVID-19 patients, the pooled prevalence estimates of GI symptoms were: diarrhea (7.7%), nausea or vomiting (7.8%), and abdominal pain (2.7%; Sultan et al., 2020) with 10% of these patients reporting GI symptoms as being their initial symptoms (Cheung et al., 2020). These data indicate potential gastrointestinal infection by SARS-CoV-2, which is reported to infect and replicate in epithelial cells of human small intestinal organoids (Zang et al., 2020). Both viral nucleocapsid proteins and viral particles have been detected in infected patient intestinal biopsies (Livanos et al., 2021). Additionally, SARS-CoV-2 RNA and live virus can be found in the stool of patients (Wang et al., 2020). More importantly, SARS-CoV-2 subgenomic mRNA is transcribed in actively replicating cells and has been detected in fecal samples (Wölfel et al., 2020). Further, rectal viral shedding persists for longer than that of the respiratory system (Zhao et al., 2020). All these data demonstrate that SARS-CoV-2 directly infects and replicates in intestinal epithelial cells of patients.

Intestinal Infection and Transmission Routes

With the deepening understanding of COVID-19, GI symptoms have been recognized as early signs of the disease. The high expression of ACE2 in the GI tract, isolation of live virus from fecal samples, and a subset of patients presenting with only GI symptoms seem to suggest fecal–oral transmission. However, problems with the feasibility of this mode of transmission remain. First, studies have shown that SARS-CoV-2 loses infectivity in simulated gastric acid within 10 min (Chan et al., 2020Zang et al., 2020Zhong et al., 2020). Secondly, SARS-CoV-2, as an enveloped virus, is largely unable to withstand the detergent effect of bile salts and the activity of digestive enzymes in the duodenum (Figure 1). Although some studies have suggested that highly viscous mucus in the gastrointestinal tract protects SARS-CoV-2, allowing the virus to retain its infectivity (Guo et al., 2021Zhang H. et al., 2021), there is still a lack of direct evidence. Bushman et al. (2019) had previously investigated the links between the structures of viruses and routes of transmission and found a strong association between fecal–oral transmission and the absence of a lipid envelope. Lastly, although some studies have isolated intact viruses from feces (Wang et al., 2020Zhang Y. et al., 2020Zhou et al., 2020Xiao et al., 2020b), most of them have not further confirmed the infectivity of these viruses (Wang et al., 2020Zhang Y. et al., 2020Xiao et al., 2020b). Zhou et al. (2020) confirmed viral propagation by RT-PCR, but only in a single fecal sample. Previous research has shown that SARS-CoV-2 is completely inactivated in simulated human colonic fluid over the course of 24 h, which may explain the sporadic detection of infection-active SARS-CoV-2 from feces samples.FIGURE 1

Figure 1. Intestinal infection and transmission routes. ① Direct evidence for fecal–oral transmission is still lacking. SARS-CoV-2 may be unable to enter the small intestine from the stomach due to gastric acid, bile and digestive enzymes. ② SARS-CoV-2 released from type II alveolar cells infects alveolar capillary endothelial cells (ECs). The virus replicates in ECs and is released into the blood to form viremia. ③ SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation. ④ Blood transmission after alveolar or nasal infection is a potential route of intestinal infection. Eventually, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract. ⑤ SARS-CoV-2 in the gut can also enter the capillaries and cause viremia, leading to recurrence of disease.

Several lines of evidence suggest that SARS-CoV-2 may infect the intestinal tract via the bloodstream. Deng et al. (2020) detected SARS-CoV-2 RNA in anal swabs from intratracheally but not intragastrically infected rhesus macaques, suggesting blood transmission. Indeed, SARS-CoV-2 RNA has been detected in blood and urine samples of patients (Wang et al., 2020). The virus can also be detected in multiple organs (including heart, brain, and kidney) and is associated with organ injury, indicating that the virus can reach and infect extrapulmonary organs (Puelles et al., 2020). Another study showed that SARS-CoV-2 viremia was associated with intestinal damage, independent of disease severity (Li Y. et al., 2021). Thus, blood transmission could be the cause of intestinal infection. Specifically, SARS-CoV-2 replicating in alveolar epithelial cells and capillary ECs is released into the bloodstream and infects new vascular ECs. The capillary network is then the main route by which the virus enters and infects extrapulmonary organs. The extensive surface area of intestinal capillaries makes intestinal epithelial cells more susceptible to infection than other extrapulmonary organs. Following infection of intestinal capillaries, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract (Figure 1). Once established in the gut, SARS-CoV-2 can also reenter the capillaries, potentially leading to recurrence of disease. Consistent with this, in patients who experienced recurrence, the phylogenetic analysis of infection samples has shown that recurrent virus evolves from the original parent virus (Hu et al., 2020).

Additionally, SARS-CoV-2 RNA can also be detected in the blood and urine of asymptomatic patients, suggesting a second pathway to viremia through the nasal cavity (Chang et al., 2020Hasanoglu et al., 2021). The abundant blood vessels, thin mucous membrane, and higher levels of ACE2 (Huang et al., 2021) make it possible for the virus to initiate viremia from the nasal cavity. Specifically, SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation (Figure 1). Blood transmission after nasal infection is therefore another potential route of intestinal infection.

Intestinal Damage, Malnutrition, and Poor Outcomes

A recent study has shown that a fecal sample positive for SARS-CoV-2 RNA at any time during hospitalization was associated with higher mortality [HR: 3.4 (1.2–9.9); Das Adhikari et al., 2021]. Similarly, another study showed that small-bowel thickening on CT was strongly associated with ICU admission (Wölfel et al., 2020). This relationship did not hold for colon or rectal thickening. These data indicates that small-bowel damage contributes to poor outcomes. As the main organ for nutrient absorption, damage to the small intestine will result in malabsorption and malnutrition, both of which commonly occur in COVID-19 patients (Di Filippo et al., 2021Lv et al., 2021) and are associated with disease severity (Luo et al., 2020Zhang P. et al., 2021). A fecal metabolome study showed that feces of COVID-19 patients were enriched with important nutrients that should be metabolized or absorbed, consistent with malabsorption (Lv et al., 2021). A prospective study showed that 29% of COVID-19 patients (31% of hospitalization patients and 21% of patients quarantined at home) had lost >5% of body weight [median weight loss, 6.5 (5.0–9.0) kg or 8.1 (6.1–10.9) %; Di Filippo et al., 2021]. Those patients with weight loss had greater systemic inflammation, impaired renal function and longer disease duration. A large, multicenter study (including 3,229 patients with GI symptoms) showed that 23% of patients had malnutrition, of whom 56.4% were unable to gain weight after 6 months follow-up (Rizvi et al., 2021). Studies also showed that malnutrition was associated with higher incidences of acute respiratory distress syndrome, acute myocardial injury, secondary infection, shock, and 28-day ICU mortality (Luo et al., 2020Zhang P. et al., 2021). Overall, malabsorption and malnutrition due to damaged small intestine increased disease severity and mortality.

Nutrient absorption in the small intestine is mainly through ATP-dependent active transport. Intestinal infection, hypoxemia, and intestinal ischemia contribute to malabsorption. SARS-CoV-2 adhesion depletes ACE2 levels on intestinal epithelial cells, which alters the expression of the neutral amino acid transporter B0AT1, reducing the intake of tryptophan and the production of nicotinamide (D’Amico et al., 2020). Meanwhile, uncontrolled viral replication consumes large amounts of ATP and nutrients, resulting in decreased nutrients entering the bloodstream. More importantly, anaerobic glycolysis caused by hypoxemia and intestinal ischemia significantly decreases ATP and active transport, leading to malabsorption. Additionally, hypoxemia and intestinal ischemia can also cause anorexia, nausea, vomiting, and enteral nutrition intolerance, reducing food intake. A prospective multicenter study showed that reduced food intake was associated with higher ICU admission and mortality (Caccialanza et al., 2021).

Intestinal Ischemia and Thrombosis

Intestinal ischemia is a common manifestation in COVID-19 patients. Autopsy results have shown that 31.6% of deceased patients had focal ischemic intestinal changes (Chiu et al., 2020). In a separate imaging study, bowel wall thickening and pneumatosis intestinalis, which indicate intestinal ischemia, were found on 38.1% (16 of 42) of abdominal CT images (Bhayana et al., 2020). Of these, 4 (9.5%) patients with pneumatosis intestinalis developed severe intestinal necrosis and needed resection. In another cohort study, 55.8% (58/104) of ICU patients developed an ileus (Kaafarani et al., 2020). Although mechanical factors cannot be ruled out, insufficient intestinal motility due to intestinal ischemia was more likely to be the cause of ileus in COVID-19 patients. In these patients with ileus, 4 (3.8%) developed severe intestinal ischemia and require emergency surgery. Both studies found microthrombi in these resected intestinal samples, which were the main cause of intestinal ischemia and increased mortality.

Additional intestinal ischemia and necrosis follows the formation of mesenteric thrombosis. However, there is currently relatively little data of mesenteric thrombus in COVID-19. Therefore, we have summarized the characteristics of 40 patients in 39 case reports published on PubMed (Supplementary Table 1). The median age of these patients was 50 (20–82) years, 26 (65%) were male, 38 (95%) developed bowel ischemia or necrosis, 30 (75%) needed bowel resection, 7 (17.5%) required no surgery, at least 3 (7.5%) developed sepsis, and 13 (32.5%) died. Other abdominal thrombotic events (such as celiac aortic thrombosis) leading to mesenteric ischemia can also result in severe intestinal necrosis and require intestinal resection (Zamboni et al., 2021).

Mild intestinal ischemia can lead to reduced diet and malabsorption. Severe intestinal ischemia or necrosis leads to the dissemination of gut bacteria, endotoxins, and microbial metabolites into the blood (Figure 2 bottom), aggravating hyperinflammation and the hypercoagulability state. Such patients need emergency excision of the necrotic bowel, which significantly increases mortality.FIGURE 2

Figure 2. Intestinal thrombosis leads to intestinal mucosal necrosis and dissemination of gut bacteria, endotoxins, and microbial metabolites in blood. (Top) Mesenteric vascular endotheliitis (initiated by viremia and accelerated by cytokines), hyperactivated platelets and high levels of phosphatidylserine (PS) promote a high rate of mesenteric thrombus in COVID-19 patients (mesenteric vein is shown in Supplementary Figure 1). (Bottom) Intestinal microthrombi and hypoxemia rapidly lead to intestinal mucosal ischemia and necrosis. The damaged gut–blood barrier leads to dissemination of gut bacteria, endotoxins, and microbial metabolites in blood.

Long-Term Gastrointestinal Sequelae

Long-term GI complications are common in recovering COVID-19 patients. In one systematic review of post-acute COVID-19 manifestations, diarrhea was among the top 10 most common complaints, with a prevalence of 6%. Other long-term GI symptoms include nausea, vomiting, abdominal pain, loss of appetite, and weight loss (Aiyegbusi et al., 2021Huang et al., 2021). The exact mechanisms of the GI sequelae remain unclear. Recently, persistent endotheliopathy, higher levels of thrombin (Fogarty et al., 2021), and residual SARS-CoV-2 viral antigens in the GI tract (Cheung et al., 2022) were described in convalescent COVID-19 patients. These data suggest that prolonged intestinal infection, persistent endothelial injury (abnormal intestinal–blood barrier), and microthrombi could be causes of the persistent GI symptoms.

The Mechanisms of Intestinal Thrombosis

Damaged Endothelial Cells

Resected bowel samples from COVID-19 patients routinely exhibit thrombi and endotheliitis, indicating the important role of EC injury in mesenteric thrombosis (Bhayana et al., 2020Chiu et al., 2020Kaafarani et al., 2020). SARS-CoV-2 infection (Varga et al., 2020) and elevated inflammatory cytokines (He et al., 2016) damage mesenteric vascular ECs. In response, EC cell margins retract, extending phosphatidylserine (PS) positive filopods and releasing endothelial microparticles (MPs; Figure 3BHe et al., 2016). The PS+ filopods and MPs can be co-stained by Xa and Va and support fibrin formation (Figures 3BD). The exposed PS then activates tissue factor on ECs, triggering the extrinsic coagulation pathway (Versteeg et al., 2013). Next, higher levels of FVIII and vWF released from damaged EC contribute to the hypercoagulable state and platelet aggregation, respectively (Goshua et al., 2020). Thrombomodulin is then released from ECs in its soluble form, which has an attenuated capacity to activate Protein C due to a lack of other cofactors on ECs, such as endothelial protein C receptor (Versteeg et al., 2013). Finally, upregulation of endothelial cell adhesion molecules recruits neutrophils and platelets and further contributes to thrombosis (Tong et al., 2020Li L. et al., 2021).FIGURE 3

Figure 3. Phosphatidylserine exposure on activated/apoptotic cells and microparticles (MPs) promotes fibrin formation. (A) Phosphatidylserine is usually confined to the inner leaflet of the cell membrane. This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of non-PS by floppases (left). Upon stimulation, calcium transients will inhibit ATP-dependent transport and stimulate the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure (right). (B–D) Human umbilical vein ECs were treated with healthy human plasma and TNF-ɑ (our previous study; He et al., 2016). (B) ECs retracts the cell margins, extends PS positive filopods and releases endothelial-MPs. (C) The PS+ filopods and MPs can be co-stained by Xa and Va. (D) ECs (green) were incubated with MPs-depleted plasma (MDP) in the presence of calcium for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Considerable fibrin stands among cultured ECs along with filopodia. (E) Confocal images showed PS expression on platelets of patients stained with Alexa 488 lactadherin (our previous study; Ma et al., 2017). MPs from the activated platelet (*) had formed at the margin area located between the distinct outlines. (F) MPs from plasma were co-stained by Xa and Va (or lactadherin and annexin V; our previous study; Gao et al., 2015). (G) MPs that were incubated with recalcified MDP for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Converted fibrin networks were detected around MPs. The inset bars represent 5 μm in (B–D,G) and 2 μm in (E,F).

Hyperactivated Platelets and Phosphatidylserine Storm

Although COVID-19 patients exhibit mild thrombocytopenia, the remaining platelets are hyperactivated (Manne et al., 2020Taus et al., 2020Zaid et al., 2020). Studies have shown that platelets from COVID-19 patients have increased P-selectin and αIIbβ3 expression. P-selectin on activated platelets interacts with integrin αIIb3 on monocytes to form platelet-monocyte complexes, which induce monocyte tissue factor expression (Hottz et al., 2020). The activated platelets can also induce neutrophils to release neutrophil extracellular traps (NETs; Middleton et al., 2020). Furthermore, platelets from COVID-19 patients aggregate and adhere more efficiently to collagen-coated surfaces under flow conditions (Manne et al., 2020Zaid et al., 2020). Meanwhile, activated platelets release α- and dense-granule contents including FV, FXI, fibrinogen and vWF (Zaid et al., 2020). In addition, activated platelets also produce inflammatory cytokines, fueling cytokine storm (Taus et al., 2020Zaid et al., 2020). Most importantly, activated platelets expose higher levels of PS and release higher numbers of PS+ MPs (Figures 3EGZaid et al., 2020Althaus et al., 2021).

Phosphatidylserine is the most abundant negatively charged phospholipid in mammalian cells and is usually confined to the inner leaflet of the cell membrane (Versteeg et al., 2013). This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of other phospholipids by floppases (Figure 3A left). Upon stimulation, transiently increased calcium inhibits ATP-dependent transport and stimulates the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure on the outer membrane (Figure 3A right). During this process, microvesicles derived from the budding of cellular membranes will be released. These MPs are typically <1 μm and express PS (Burnier et al., 2009). The exposure of PS on the surface of cells and MPs provides a catalytic surface for factor Xa and thrombin formation in vivo (Versteeg et al., 2013). We have previously demonstrated that PS mediates 90% of Xa and thrombin formation and significantly increases thrombosis in vivo (Shi and Gilbert, 2003).

Cytokines and virus infection can activate blood cells and ECs, resulting in higher levels of PS+ cells and MPs. As COVID-19 progresses, the developing cytokine storm activates more blood cells, leading to PS storm. Platelets are highly sensitive to circulating cytokines, releasing large amounts of cytokines and PS exposed MPs into the plasma (Taus et al., 2020Althaus et al., 2021) and thus are a major contributor to PS storm. Previous studies found an unusual elevation of FVa in severe COVID-19 patients (248 IU/dl, higher than any previous disease; Stefely et al., 2020von Meijenfeldt et al., 2021). The degree of FVa elevation in these patients may be the result of PS storm.

Collectively, SARS-CoV-2 infection is the initiating factor for injury of the intestinal vascular ECs, which is then aggravated by systemic cytokines, leading to endotheliitis. Subsequently, the hyperactivated platelets in circulation rapidly accumulate around the damaged ECs, inducing tissue factor expression, NET release, and activating the intrinsic/extrinsic coagulation pathways. Simultaneously, the high levels of PS expression in circulating cells and MPs further promote thrombin and fibrin formation (Figure 2 top).

Early Antithrombotic Treatment

Vaccines and antithrombotic therapy are effective measures to reduce intestinal damage and fight against the COVID-19 pandemic (Baden et al., 2021Chalmers et al., 2021). Vaccines induce adaptive immunity to clear the virus, reducing intestinal infection and intestinal damage. However, the usefulness of vaccines is limited by incomplete vaccine acceptance and viral mutations (Hacisuleyman et al., 2021Wang et al., 2021). Vaccines are also ineffective for already infected patients. Therefore, more attention should be paid to antithrombotic therapy. Studies had shown that thrombotic events mainly occurred within 7 days of COVID-19 diagnosis (both inpatients and outpatients; Mouhat et al., 2020Ho et al., 2021). Meanwhile, two large randomized controlled trials (RCTs) from the same platform showed that therapeutic anticoagulation reduced mortality in moderate cases but not in severe ones, suggesting that delayed anticoagulant therapy may lead to treatment failure (REMAP-CAP Investigators et al., 2021a,b). More importantly, a recent study reported three asymptomatic COVID-19 patients who developed abdominal (or intestinal) thrombosis leading to intestinal necrosis (Zamboni et al., 2021). All these data suggest that antithrombotic therapy should be initiated once COVID-19 is diagnosed (excluding patients with contraindications). Early prophylactic antithrombotic therapy can reduce the activation of vascular ECs and blood cells, preventing intestinal thrombosis, ensuring sufficient intestinal perfusion, maintaining the normal gut–blood barrier, avoiding malabsorption, malnutrition, and intestinal flora entering the bloodstream. Further, attenuated injury and decreased microthrombi in convalescent patients may lower the risk of long-term GI sequelae. Meanwhile, unobstructed systemic circulation can also accelerate the removal of SARS-CoV-2, inflammatory cytokines and damaged blood cells by the mononuclear phagocyte system.

Anticoagulation

Table 1 summarizes the RCTs of anticoagulant therapy in COVID-19 patients. For outpatients, early anticoagulant therapy reduced hospitalization and supplemental oxygen (Gonzalez-Ochoa). While, delayed treatment had no similar effect (ACTIV-4B and Ananworanich). Thus, oral anticoagulant therapy should be initiated in outpatients once COVID-19 is diagnosed. For non-critically ill patients, therapeutic doses of low molecular weight heparin (LMWH) reduced thrombotic events and mortality, and increased organ support-free days (REMAP-CAP, ACTIV-4a, ATTACC; RAPID; HEP-COVID). However, therapeutic doses of rivaroxaban did not improve clinical outcomes and increased bleeding (ACTION). This is potentially because novel oral anticoagulants do not share the anti-inflammatory and antiviral functions of heparin. Intestinal damage might also result in abnormal absorption of oral anticoagulants. Therefore, therapeutic LMWH should be the first choice for non-critically ill patients. For critically ill patients, RCTs showed that moderate and therapeutic doses were not superior to prophylactic ones. Results from several other studies suggest that the overwhelming thrombosis leads to failure of anticoagulant therapy at therapeutic doses (Leentjens et al., 2021Poor, 2021). Faced with this dilemma, an editorial in N Engl J Med argued that profibrinolytic strategies should be considered (Ten Cate, 2021). More studies are needed to explore optimal antithrombotic therapy in critically ill patients.TABLE 1

Table 1. Randomized clinical trials of anticoagulant therapy in COVID-19 patients.

Inhibition of Platelet Activation

As COVID-19 progresses, cytokine storm activates platelets, which not only participate in primary hemostasis, but also are the major components of PS storm. Autopsy results show a high prevalence of platelet-fibrin-rich microthrombi in lung and extrapulmonary organs, including the gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). Early inhibition of platelet activation can reduce platelet activity and prevent PS storm, thus decreasing thrombosis and mortality. Several observational studies have shown that aspirin decreases mechanical ventilation, ICU admission, and mortality (Chow et al., 2020Santoro et al., 2022). The RCTs testing antiplatelet agents were still preliminary. A recent RCT suggested that aspirin was associated with an increase in survival and reduction in thrombotic events (RECOVERY Collaborative Group, 2022). In addition, anti-inflammatory therapy (e.g., dexamethasone, 6 mg once daily; RECOVERY Collaborative Group et al., 2020) inhibits cytokine storm, as well as platelet activation, reducing mortality. Overall, inhibition of platelet activation is also important to reduce mortality through the prevention of thrombosis and organs damage.

Factors Influencing Antithrombotic Treatment

Thrombotic Risk Factors or Co-morbidities

Studies have shown that obesity, hyperglycemia and diabetes are associated with increased thrombotic events (including intestinal thrombosis), COVID-19 severity, and mortality (Drucker, 2021Stefan et al., 2021). Other thrombotic risk factors include previous venous thromboembolism, active cancer, known thrombophilic condition, recent trauma or surgery, age ≥70 years, respiratory/cardiac/renal failure, and inflammatory bowel disease (Susen et al., 2020). These factors or co-morbidities heighten basal inflammatory levels and endothelial damage, leading to premature cytokine and PS storms, ultimately increasing thrombosis and mortality. Thus, more active antithrombotic therapy strategies should be adopted in these patients. For patients with mild COVID-19 with these factors, the French Working Group on Perioperative Hemostasis and the French Study Group on Thrombosis and Hemostasis recommend higher (intermediate) doses of anticoagulant therapy (Susen et al., 2020). For moderately ill patients, therapeutic doses of anticoagulant therapy should be initiated as soon as possible to prevent excessive microthrombus formation. The need for extended thromboprophylaxis in discharged patients remains controversial. However, a recent RCT showed that rivaroxaban (10 mg/day, 35 days) improved clinical outcomes in discharged COVID-19 patients with higher thrombotic risk factors (Ramacciotti et al., 2022), supporting extended thromboprophylaxis in patients with these risk factors or co-morbidities.

Vaccination

Although more than half the world population has received at least one dose of the vaccines, there are relatively little data of antithrombotic therapy in vaccinated patients. Studies of viral dynamics show that the viral loads of vaccinated patients are as high as that of unvaccinated patients, but drop significantly faster (Brown et al., 2021Klompas, 2021). Thus, vaccinated patients have shorter hospital stays, and are less likely to progress to critical illness and death (Tenforde et al., 2021Thompson et al., 2021). Nevertheless, antithrombotic therapy is still beneficial for the vaccinated patients. Firstly, heparin has anti-inflammatory and antiviral functions and can interfere with the binding of SARS-CoV-2 to ACE2 and shorten the duration of virus infection (Kwon et al., 2020Pereyra et al., 2021). Secondly, antithrombotic therapy protects cells from damage, PS exposure, and microthrombi formation, maintains unobstructed blood circulation, and facilitates virus clearance (by vaccine-induced adaptive immunity). Thirdly, thrombosis remains an important factor in disease progression. Antithrombotic therapy further reduces thrombosis and mortality, especially in vaccinated patients with high risk factors or co-morbidities. Lastly, although vaccines reduce the incidence, a subset of vaccinated patients will still develop long-term sequelae or Long Covid (Ledford, 2021Antonelli et al., 2022). Persistent viral infection and microthrombi are the primary causes (Ledford, 2021Xie et al., 2022), and early antithrombotic therapy is still needed to prevent them.

Conclusion and Future Research

During COVID-19 disease progression, SARS-CoV-2 infiltrates the blood stream from the initial respiratory tract infection, causing viremia, hyperactivated platelets and PS storm. The virus settles into the vascular beds of extrapulmonary organs, ultimately causing infection of intestinal epithelial cell. Damaged ECs, combined with hyperactivated platelets and PS storm, promote intestinal thrombosis, resulting in intestinal ischemia or necrosis. The damaged gut–blood barrier leads to malabsorption, malnutrition and intestinal flora entering the bloodstream, which significantly increase disease severity and mortality. Prolonged intestinal infection, persistent endothelial injury and microthrombi contribute to the long-term GI sequelae after discharge. Early prophylactic antithrombotic therapy can prevent microthrombi, ensuring sufficient intestinal perfusion, maintaining the normal intestinal function, and reducing the risk of long-term GI sequelae. More active antithrombotic therapy should be adopted in patients with other thrombotic risk factors or co-morbidities. Even in vaccinated COVID-19 patients, antithrombotic therapy is also important to decrease (intestinal) thrombosis, mortality and the risk of long-term GI sequelae.

With the Omicron pandemic, patients requiring hospitalization and ICU treatment decline rapidly. However, people are increasingly concerned about Long Covid. In terms of long-term GI sequelae, the detailed mechanisms of prolonged intestinal infection and persistent microthrombi remain unclear. And whether anticoagulant therapy can decrease GI symptoms in patients with long-term GI sequelae deserves further study. Finally, the impact of vaccines on long-term GI sequelae remains unclear in previously infected and breakthrough infected patients.

References

Aiyegbusi, O. L., Hughes, S. E., Turner, G., Rivera, S. C., McMullan, C., Chandan, J. S., et al. (2021). Symptoms, complications and management of long COVID: a review. J. R. Soc. Med. 114, 428–442. doi: 10.1177/01410768211032850

PubMed Abstract | CrossRef Full Text | Google Scholar

Althaus, K., Marini, I., Zlamal, J., Pelzl, L., Singh, A., Häberle, H., et al. (2021). Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood 137, 1061–1071. doi: 10.1182/blood.2020008762

PubMed Abstract | CrossRef Full Text | Google Scholar

Ananworanich, J., Mogg, R., Dunne, M. W., Bassyouni, M., David, C. V., Gonzalez, E., et al. (2021). Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19. Clin. Infect. Dis. doi: 10.1093/cid/ciab813 [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

Antonelli, M., Penfold, R. S., Merino, J., Sudre, C. H., Molteni, E., Berry, S., et al. (2022). Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID symptom study app: a prospective, community-based, nested, case-control study. Lancet Infect. Dis. 22, 43–55. doi: 10.1016/S1473-3099(21)00460-6

CrossRef Full Text | Google Scholar

Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., et al. (2021). Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416. doi: 10.1056/NEJMoa2035389

CrossRef Full Text | Google Scholar

Bhayana, R., Som, A., Li, M. D., Carey, D. E., Anderson, M. A., Blake, M. A., et al. (2020). Abdominal imaging findings in COVID-19: preliminary observations. Radiology 297, E207–E215. doi: 10.1148/radiol.2020201908

PubMed Abstract | CrossRef Full Text | Google Scholar

Bradley, B. T., Maioli, H., Johnston, R., Chaudhry, I., Fink, S. L., Xu, H., et al. (2020). Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington state: a case series. Lancet 396, 320–332. doi: 10.1016/S0140-6736(20)31305-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Brown, C. M., Vostok, J., Johnson, H., Burns, M., Gharpure, R., Sami, S., et al. (2021). Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings – Barnstable County, Massachusetts, July 2021. MMWR Morb. Mortal. Wkly Rep. 70, 1059–1062. doi: 10.15585/mmwr.mm7031e2

PubMed Abstract | CrossRef Full Text | Google Scholar

Burnier, L., Fontana, P., Kwak, B. R., and Angelillo-Scherrer, A. (2009). Cell-derived microparticles in haemostasis and vascular medicine. Thromb. Haemost. 101, 439–451. doi: 10.1160/TH08-08-0521

CrossRef Full Text | Google Scholar

Bushman, F. D., McCormick, K., and Sherrill-Mix, S. (2019). Virus structures constrain transmission modes. Nat. Microbiol. 4, 1778–1780. doi: 10.1038/s41564-019-0523-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Caccialanza, R., Formisano, E., Klersy, C., Ferretti, V., Ferrari, A., Demontis, S., et al. (2021). Nutritional parameters associated with prognosis in non-critically ill hospitalized COVID-19 patients: the NUTRI-COVID19 study. Clin. Nutr. doi: 10.1016/j.clnu.2021.06.020 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Chalmers, J. D., Crichton, M. L., Goeminne, P. C., Cao, B., Humbert, M., Shteinberg, M., et al. (2021). Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline. Eur. Respir. J. 57:2100048. doi: 10.1183/13993003.00048-2021

PubMed Abstract | CrossRef Full Text | Google Scholar

Chan, K. H., Sridhar, S., Zhang, R. R., Chu, H., Fung, A. Y., Chan, G., et al. (2020). Factors affecting stability and infectivity of SARS-CoV-2. J. Hosp. Infect. 106, 226–231. doi: 10.1016/j.jhin.2020.07.009

CrossRef Full Text | Google Scholar

Chang, L., Zhao, L., Gong, H., Wang, L., and Wang, L. (2020). Severe acute respiratory syndrome coronavirus 2 RNA detected in blood donations. Emerg. Infect. Dis. 26, 1631–1633. doi: 10.3201/eid2607.200839

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheung, C. C. L., Goh, D., Lim, X., Tien, T. Z., Lim, J. C. T., Lee, J. N., et al. (2022). Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut 71, 226–229. doi: 10.1136/gutjnl-2021-324280

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheung, K. S., Hung, I. F. N., Chan, P. P. Y., Lung, K. C., Tso, E., Liu, R., et al. (2020). Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in faecal samples from a Hong Kong cohort: systematic review and meta-analysis. Gastroenterology 159, 81–95. doi: 10.1053/j.gastro.2020.03.065

CrossRef Full Text | Google Scholar

Chiu, C. Y., Sarwal, A., Mon, A. M., Tan, Y. E., and Shah, V. (2020). Gastrointestinal: COVID-19 related ischemic bowel disease. J. Gastroenterol. Hepatol. 36:850. doi: 10.1111/jgh.15254

PubMed Abstract | CrossRef Full Text | Google Scholar

Chow, J. H., Khanna, A. K., Kethireddy, S., Yamane, D., Levine, A., Jackson, A. M., et al. (2020). Aspirin use is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized patients with COVID-19. Anesth. Analg. 132, 930–941. doi: 10.1213/ANE.0000000000005292

CrossRef Full Text | Google Scholar

Connors, J. M., Brooks, M. M., Sciurba, F. C., Krishnan, J. A., Bledsoe, J. R., Kindzelski, A., et al. (2021). Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA 326, 1703–1712. doi: 10.1001/jama.2021.17272

PubMed Abstract | CrossRef Full Text | Google Scholar

D’Amico, F., Baumgart, D. C., Danese, S., and Peyrin-Biroulet, L. (2020). Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention, and management. Clin. Gastroenterol. Hepatol. 18, 1663–1672. doi: 10.1016/j.cgh.2020.04.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Das Adhikari, U., Eng, G., Farcasanu, M., Avena, L. E., Choudhary, M. C., Triant, V. A., et al. (2021). Faecal SARS-CoV-2 RNA is associated with decreased COVID-19 survival. Clin. Infect. Dis. doi: 10.1093/cid/ciab623 Epub ahead of print

PubMed Abstract | CrossRef Full Text | Google Scholar

Deng, W., Bao, L., Gao, H., Xiang, Z., Qu, Y., Song, Z., et al. (2020). Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in rhesus macaques. Nat. Commun. 11:4400. doi: 10.1038/s41467-020-18149-6

CrossRef Full Text | Google Scholar

Di Filippo, L., De Lorenzo, R., D’Amico, M., Sofia, V., Roveri, L., Mele, R., et al. (2021). COVID-19 is associated with clinically significant weight loss and risk of malnutrition, independent of hospitalisation: a post-hoc analysis of a prospective cohort study. Clin. Nutr. 40, 2420–2426. doi: 10.1016/j.clnu.2020.10.043

PubMed Abstract | CrossRef Full Text | Google Scholar

Drucker, D. J. (2021). Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning. Cell Metab. 33, 479–498. doi: 10.1016/j.cmet.2021.01.016

CrossRef Full Text | Google Scholar

El Moheb, M., Naar, L., Christensen, M. A., Kapoen, C., Maurer, L. R., Farhat, M., et al. (2020). Gastrointestinal complications in critically ill patients with and without COVID-19. JAMA 324, 1899–1901. doi: 10.1001/jama.2020.19400

PubMed Abstract | CrossRef Full Text | Google Scholar

Fogarty, H., Townsend, L., Morrin, H., Ahmad, A., Comerford, C., Karampini, E., et al. (2021). Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J. Thromb. Haemost. 19, 2546–2555. doi: 10.1111/jth.15490

CrossRef Full Text | Google Scholar

Gao, C., Xie, R., Yu, C., Ma, R., Dong, W., Meng, H., et al. (2015). Thrombotic role of blood and endothelial cells in uremia through phosphatidylserine exposure and microparticle release. PLoS One 10:e0142835. doi: 10.1371/journal.pone.0142835

PubMed Abstract | CrossRef Full Text | Google Scholar

Gonzalez-Ochoa, A. J., Raffetto, J. D., Hernández, A. G., Zavala, N., Gutiérrez, O., Vargas, A., et al. (2021). Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. Thromb. Haemost. 121, 944–954. doi: 10.1055/a-1414-5216

CrossRef Full Text | Google Scholar

Goshua, G., Pine, A. B., Meizlish, M. L., Chang, C. H., Zhang, H., Bahel, P., et al. (2020). Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-Centre, cross-sectional study. Lancet Haematol. 7, e575–e582. doi: 10.1016/S2352-3026(20)30216-7

CrossRef Full Text | Google Scholar

Guo, M., Tao, W., Flavell, R. A., and Zhu, S. (2021). Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat. Rev. Gastroenterol. Hepatol. 18, 269–283. doi: 10.1038/s41575-021-00416-6

CrossRef Full Text | Google Scholar

Hacisuleyman, E., Hale, C., Saito, Y., Blachere, N. E., Bergh, M., Conlon, E. G., et al. (2021). Vaccine breakthrough infections with SARS-CoV-2 variants. N. Engl. J. Med. 384, 2212–2218. doi: 10.1056/NEJMoa2105000

CrossRef Full Text | Google Scholar

Hasanoglu, I., Korukluoglu, G., Asilturk, D., Cosgun, Y., Kalem, A. K., Altas, A. B., et al. (2021). Higher viral loads in asymptomatic COVID-19 patients might be the invisible part of the iceberg. Infection 49, 117–126. doi: 10.1007/s15010-020-01548-8

PubMed Abstract | CrossRef Full Text | Google Scholar

He, Z., Si, Y., Jiang, T., Ma, R., Zhang, Y., Cao, M., et al. (2016). Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease. Thromb. Haemost. 115, 738–751. doi: 10.1160/TH15-09-0710

CrossRef Full Text | Google Scholar

Ho, F. K., Man, K. K. C., Toshner, M., Church, C., Celis-Morales, C., Wong, I. C. K., et al. (2021). Thromboembolic risk in hospitalized and nonhospitalized COVID-19 patients: a self-controlled case series analysis of a nationwide cohort. Mayo Clin. Proc. 96, 2587–2597. doi: 10.1016/j.mayocp.2021.07.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Hottz, E. D., Azevedo-Quintanilha, I. G., Palhinha, L., Teixeira, L., Barreto, E. A., Pão, C. R. R., et al. (2020). Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients. Blood 136, 1330–1341. doi: 10.1182/blood.2020007252

PubMed Abstract | CrossRef Full Text | Google Scholar

Hu, F., Chen, F., Ou, Z., Fan, Q., Tan, X., Wang, Y., et al. (2020). A compromised specific Humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cell. Mol. Immunol. 17, 1119–1125. doi: 10.1038/s41423-020-00550-2

CrossRef Full Text | Google Scholar

Huang, N., Pérez, P., Kato, T., Mikami, Y., Okuda, K., Gilmore, R. C., et al. (2021). SARS-CoV-2 infection of the oral cavity and saliva. Nat. Med. 27, 892–903. doi: 10.1038/s41591-021-01296-8

PubMed Abstract | CrossRef Full Text | Google Scholar

INSPIRATION Investigators Sadeghipour, P., Talasaz, A. H., Rashidi, F., Sharif-Kashani, B., Beigmohammadi, M. T., et al. (2021). Effect of intermediate-dose vs. standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 325, 1620–1630. doi: 10.1001/jama.2021.4152

PubMed Abstract | CrossRef Full Text | Google Scholar

Jacobs, J. L., and Mellors, J. W. (2020). Detection of SARS-CoV-2 RNA in blood of patients with COVID-19: what does it mean? Clin. Infect. Dis. doi: 10.1093/cid/ciaa1316 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Kaafarani, H. M. A., El Moheb, M., Hwabejire, J. O., Naar, L., Christensen, M. A., Breen, K., et al. (2020). Gastrointestinal complications in critically ill patients with COVID-19. Ann. Surg. 272, e61–e62. doi: 10.1097/SLA.0000000000004004

CrossRef Full Text | Google Scholar

Klompas, M. (2021). Understanding breakthrough infections following mRNA SARS-CoV-2 vaccination. JAMA 326, 2018–2020. doi: 10.1001/jama.2021.19063

PubMed Abstract | CrossRef Full Text | Google Scholar

Kwon, P. S., Oh, H., Kwon, S. J., Jin, W., Zhang, F., Fraser, K., et al. (2020). Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell Discov. 6:50. doi: 10.1038/s41421-020-00192-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220. doi: 10.1038/s41586-020-2180-5

CrossRef Full Text | Google Scholar

Ledford, H. (2021). Do vaccines protect against long COVID? What the data say. Nature 599, 546–548. doi: 10.1038/d41586-021-03495-2

CrossRef Full Text | Google Scholar

Leentjens, J., van Haaps, T. F., Wessels, P. F., Schutgens, R. E. G., and Middeldorp, S. (2021). COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year. Lancet Haematol. 8, e524–e533. doi: 10.1016/S2352-3026(21)00105-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lemos, A. C. B., do Espírito Santo, D. A., Salvetti, M. C., Gilio, R. N., Agra, L. B., Pazin-Filho, A., et al. (2020). Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb. Res. 196, 359–366. doi: 10.1016/j.thromres.2020.09.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, L., Huang, M., Shen, J., Wang, Y., Wang, R., Yuan, C., et al. (2021). Serum levels of soluble platelet endothelial cell adhesion molecule 1 in COVID-19 patients are associated with disease severity. J. Infect. Dis. 223, 178–179. doi: 10.1093/infdis/jiaa642

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Schneider, A. M., Mehta, A., Sade-Feldman, M., Kays, K. R., Gentili, M., et al. (2021). SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes. J. Clin. Invest. 131:e148635. doi: 10.1172/JCI148635

CrossRef Full Text | Google Scholar

Livanos, A. E., Jha, D., Cossarini, F., Gonzalez-Reiche, A. S., Tokuyama, M., Aydillo, T., et al. (2021). Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms. Gastroenterology 16, 2435.e34–2450.e34. doi: 10.1053/j.gastro.2021.02.056

CrossRef Full Text | Google Scholar

Lopes, R. D., de Barros, E., Silva, P. G. M., Furtado, R. H. M., Macedo, A. V. S., Bronhara, B., et al. (2021). Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet 397, 2253–2263. doi: 10.1016/S0140-6736(21)01203-4

CrossRef Full Text | Google Scholar

Luo, Y., Xue, Y., Mao, L., Yuan, X., Lin, Q., Tang, G., et al. (2020). Prealbumin as a predictor of prognosis in patients with coronavirus disease 2019. Front. Med. 7:374. doi: 10.3389/fmed.2020.00374

PubMed Abstract | CrossRef Full Text | Google Scholar

Lv, L., Jiang, H., Chen, Y., Gu, S., Xia, J., Zhang, H., et al. (2021). The faecal metabolome in COVID-19 patients is altered and associated with clinical features and gut microbes. Anal. Chim. Acta 1152:338267. doi: 10.1016/j.aca.2021.338267

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, R., Xie, R., Yu, C., Si, Y., Wu, X., Zhao, L., et al. (2017). Phosphatidylserine-mediated platelet clearance by endothelium decreases platelet aggregates and procoagulant activity in sepsis. Sci. Rep. 7:4978. doi: 10.1038/s41598-018-24187-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Manne, B. K., Denorme, F., Middleton, E. A., Portier, I., Rowley, J. W., Stubben, C., et al. (2020). Platelet gene expression and function in patients with COVID-19. Blood 136, 1317–1329. doi: 10.1182/blood.2020007214

PubMed Abstract | CrossRef Full Text | Google Scholar

Mao, R., Qiu, Y., He, J. S., Tan, J. Y., Li, X. H., Liang, J., et al. (2020). Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 5, 667–678. doi: 10.1016/S2468-1253(20)30126-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Marcos-Jubilar, M., Carmona-Torre, F., Vidal Laso, R., Ruiz-Artacho, P., Filella, D., Carbonell, C., et al. (2022). Therapeutic versus prophylactic bemiparin in hospitalized patients with non-severe COVID-19 pneumonia (BEMICOP): an open-label, multicenter, randomized trial. Thromb. Haemost. 122, 295–299. doi: 10.1055/a-1667-7534

PubMed Abstract | CrossRef Full Text | Google Scholar

McFadyen, D. J., Stevens, H., and Karlheinz, P. (2020). The emerging threat of (micro)thrombosis in COVID-19 and its therapeutic implications. Circ. Res. 127, 571–587. doi: 10.1161/CIRCRESAHA.120.317447

CrossRef Full Text | Google Scholar

Middleton, E. A., He, X. Y., Denorme, F., Campbell, R. A., Ng, D., Salvatore, S. P., et al. (2020). Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 136, 1169–1179. doi: 10.1182/blood.2020007008

CrossRef Full Text | Google Scholar

Moore, J. B., and June, C. H. (2020). Cytokine release syndrome in severe COVID-19. Science 368, 473–474. doi: 10.1126/science.abb8925

CrossRef Full Text | Google Scholar

Mouhat, B., Besutti, M., Bouiller, K., Grillet, F., Monnin, C., Ecarnot, F., et al. (2020). Elevated D-dimers and lack of anticoagulation predict PE in severe COVID-19 patients. Eur. Respir. J. 56:2001811. doi: 10.1183/13993003.01811-2020

PubMed Abstract | CrossRef Full Text | Google Scholar

Norsa, L., Bonaffini, P. A., Indriolo, A., Valle, C., Sonzogni, A., and Sironi, S. (2020). Poor outcome of intestinal ischemic manifestations of COVID-19. Gastroenterology 159, 1595.e1–1597.e1. doi: 10.1053/j.gastro.2020.06.041

PubMed Abstract | CrossRef Full Text | Google Scholar

Perepu, U. S., Chambers, I., Wahab, A., Ten Eyck, P., Wu, C., Dayal, S., et al. (2021). Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial. J. Thromb. Haemost. 19, 2225–2234. doi: 10.1111/jth.15450

PubMed Abstract | CrossRef Full Text | Google Scholar

Pereyra, D., Heber, S., Schrottmaier, W. C., Santol, J., Pirabe, A., Schmuckenschlager, A., et al. (2021). Low molecular weight heparin use in COVID-19 is associated with curtailed viral persistence: a retrospective multicenter observational study. Cardiovasc. Res. 117, 2807–2820. doi: 10.1093/cvr/cvab308

PubMed Abstract | CrossRef Full Text | Google Scholar

Polak, S. B., Van Gool, I. C., Cohen, D., von der Thüsen, J. H., and van Paassen, J. (2020). A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod. Pathol. 33, 2128–2138. doi: 10.1038/s41379-020-0603-3

CrossRef Full Text | Google Scholar

Poor, H. D. (2021). Pulmonary thrombosis and thromboembolism in COVID-19. Chest 160, 1471–1480. doi: 10.1016/j.chest.2021.06.016

CrossRef Full Text | Google Scholar

Puelles, V. G., Lütgehetmann, M., Lindenmeyer, M. T., Sperhake, J. P., Wong, M. N., Allweiss, L., et al. (2020). Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592. doi: 10.1056/NEJMc2011400

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramacciotti, E., Barile Agati, L., Calderaro, D., Aguiar, V. C. R., Spyropoulos, A. C., de Oliveira, C. C. C., et al. (2022). Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 399, 50–59. doi: 10.1016/S0140-6736(21)02392-8

PubMed Abstract | CrossRef Full Text | Google Scholar

RECOVERY Collaborative Group (2022). Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 399, 143–151. doi: 10.1016/S0140-6736(21)01825-0

CrossRef Full Text | Google Scholar

RECOVERY Collaborative Group Horby, P., Lim, W. S., Emberson, J. R., Mafham, M., Bell, J. L., et al. (2020). Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 384, 693–704. doi: 10.1056/NEJMoa2021436

PubMed Abstract | CrossRef Full Text | Google Scholar

REMAP-CAP Investigators ACTIV-4a Investigators ATTACC Investigators Goligher, E. C., Bradbury, C. A., McVerry, B. J., et al. (2021a). Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N. Engl. J. Med. 385, 777–789. doi: 10.1056/NEJMoa2103417

PubMed Abstract | CrossRef Full Text | Google Scholar

REMAP-CAP Investigators ACTIV-4a Investigators ATTACC Investigators Lawler, P. R., Goligher, E. C., Berger, J. S., et al. (2021b). Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N. Engl. J. Med. 385, 790–802. doi: 10.1056/NEJMoa2105911

PubMed Abstract | CrossRef Full Text | Google Scholar

Rizvi, A., Patel, Z., Liu, Y., Satapathy, S. K., Sultan, K., and Trindade, A. J. (2021). Gastrointestinal sequelae 3 and 6 months after hospitalization for coronavirus disease 2019. Clin. Gastroenterol. Hepatol. 19, 2438.e1–2440.e1. doi: 10.1016/j.cgh.2021.06.046

CrossRef Full Text | Google Scholar

Santoro, F., Nuñez-Gil, I. J., Vitale, E., Viana-Llamas, M. C., Reche-Martinez, B., Romero-Pareja, R., et al. (2022). Antiplatelet therapy and outcome in COVID-19: the health outcome predictive evaluation registry. Heart 108, 130–136. doi: 10.1136/thoraxjnl-2021-217561

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, J., and Gilbert, G. E. (2003). Lactadherin inhibits enzyme complexes of blood coagulation by completing for phospholipid binding sites. Blood 101, 2628–2636. doi: 10.1182/blood-2002-07-1951

PubMed Abstract | CrossRef Full Text | Google Scholar

Sholzberg, M., Tang, G. H., Rahhal, H., AlHamzah, M., Kreuziger, L. B., Áinle, F. N., et al. (2021). Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 375:n2400. doi: 10.1136/bmj.n2400

CrossRef Full Text | Google Scholar

Spyropoulos, A. C., Goldin, M., Giannis, D., Diab, W., Wang, J., Khanijo, S., et al. (2021). Efficacy and safety of therapeutic-dose heparin vs. standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern. Med. 181, 1612–1620. doi: 10.1001/jamainternmed.2021.6203

PubMed Abstract | CrossRef Full Text | Google Scholar

Stefan, N., Birkenfeld, A. L., and Schulze, M. B. (2021). Global pandemics interconnected – obesity, impaired metabolic health and COVID-19. Nat. Rev. Endocrinol. 17, 135–149. doi: 10.1038/s41574-020-00462-1

CrossRef Full Text | Google Scholar

Stefely, J. A., Christensen, B. B., Gogakos, T., Cone Sullivan, J. K., Montgomery, G. G., Barranco, J. P., et al. (2020). Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am. J. Hematol. 95, 1522–1530. doi: 10.1002/ajh.25979

PubMed Abstract | CrossRef Full Text | Google Scholar

Suh, Y. J., Hong, H., Ohana, M., Bompard, F., Revel, M. P., Valle, C., et al. (2021). Pulmonary embolism and deep vein thrombosis in COVID-19: a systematic review and meta-analysis. Radiology 298, E70–E80. doi: 10.1148/radiol.2020203557

CrossRef Full Text | Google Scholar

Sultan, S., Altayar, O., Siddique, S. M., Davitkov, P., Feuerstein, J. D., Lim, J. K., et al. (2020). AGA institute rapid review of the gastrointestinal and liver manifestations of COVID-19, meta-analysis of international data, and recommendations for the consultative management of patients with COVID-19. Gastroenterology 159, 320.e27–334.e27. doi: 10.1053/j.gastro.2020.05.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Susen, S., Tacquard, C. A., Godon, A., Mansour, A., Garrigue, D., Nguyen, P., et al. (2020). Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. Crit. Care 24:364. doi: 10.1186/s13054-020-03000-7

CrossRef Full Text | Google Scholar

Tan, B. K., Mainbourg, S., Friggeri, A., Bertoletti, L., Douplat, M., Dargaud, Y., et al. (2021). Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax 76, 970–979. doi: 10.1136/thoraxjnl-2020-215383

PubMed Abstract | CrossRef Full Text | Google Scholar

Taus, F., Salvagno, G., Canè, S., Fava, C., Mazzaferri, F., Carrara, E., et al. (2020). Platelets promote thromboinflammation in SARS-CoV-2 pneumonia. Arterioscler. Thromb. Vasc. Biol. 40, 2975–2989. doi: 10.1161/ATVBAHA.120.315175

PubMed Abstract | CrossRef Full Text | Google Scholar

Ten Cate, H. (2021). Surviving Covid-19 with heparin? N. Engl. J. Med. 385, 845–846. doi: 10.1056/NEJMe2111151

PubMed Abstract | CrossRef Full Text | Google Scholar

Tenforde, M. W., Self, W. H., Adams, K., Gaglani, M., Ginde, A. A., McNeal, T., et al. (2021). Association between mRNA vaccination and COVID-19 hospitalization and disease severity. JAMA 326, 2043–2054. doi: 10.1001/jama.2021.19499

CrossRef Full Text | Google Scholar

Thompson, M. G., Burgess, J. L., Naleway, A. L., Tyner, H., Yoon, S. K., Meece, J., et al. (2021). Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N. Engl. J. Med. 385, 320–329. doi: 10.1056/NEJMoa2107058

PubMed Abstract | CrossRef Full Text | Google Scholar

Tong, M., Jiang, Y., Xia, D., Xiong, Y., Zheng, Q., Chen, F., et al. (2020). Elevated expression of serum endothelial cell adhesion molecules in COVID-19 patients. J. Infect. Dis. 222, 894–898. doi: 10.1093/infdis/jiaa349

CrossRef Full Text | Google Scholar

Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., et al. (2020). Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418. doi: 10.1016/S0140-6736(20)30937-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Versteeg, H. H., Heemskerk, J. W., Levi, M., and Reitsma, P. H. (2013). New fundamentals in hemostasis. Physiol. Rev. 93, 327–358. doi: 10.1152/physrev.00016.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

von Meijenfeldt, F. A., Havervall, S., Adelmeijer, J., Lundström, A., Magnusson, M., Mackman, N., et al. (2021). Elevated factor V activity and antigen levels in patients with Covid-19 are related to disease severity and 30-day mortality. Am. J. Hematol. 96, E98–E100. doi: 10.1002/ajh.26085

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, P., Nair, M. S., Liu, L., Iketani, S., Luo, Y., Guo, Y., et al. (2021). Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135. doi: 10.1038/s41586-021-03398-2

CrossRef Full Text | Google Scholar

Wang, W., Xu, Y., Gao, R., Han, K., Wu, G., and Tan, W. (2020). Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 323, 1843–1844. doi: 10.1001/jama.2020.3786

PubMed Abstract | CrossRef Full Text | Google Scholar

Wölfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M. A., et al. (2020). Virological assessment of hospitalized patients with COVID-2019. Nature 581, 465–469. doi: 10.1038/s41586-020-2196-x

CrossRef Full Text | Google Scholar

Xiao, F., Sun, J., Xu, Y., Li, F., Huang, X., Li, H., et al. (2020a). Infectious SARS-CoV-2 in feces of patient with severe COVID-19. Emerg. Infect. Dis. 26, 1920–1922. doi: 10.3201/eid2608.200681

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiao, F., Tang, M., Zheng, X., Liu, Y., Li, X., and Shan, H. (2020b). Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 158, 1831.e3–1833.e3. doi: 10.1053/j.gastro.2020.02.055

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, Y., Xu, E., Bowe, B., and Al-Aly, Z. (2022). Long-term cardiovascular outcomes of COVID-19. Nat. Med. doi: 10.1038/s41591-022-01689-3 [Epub ahead of print].

CrossRef Full Text | Google Scholar

Zaid, Y., Puhm, F., Allaeys, I., Naya, A., Oudghiri, M., Khalki, L., et al. (2020). Platelets can associate with SARS-CoV-2 RNA and are hyperactivated in COVID-19. Circ. Res. 127, 1404–1418. doi: 10.1161/CIRCRESAHA.120.317703

CrossRef Full Text | Google Scholar

Zamboni, P., Bortolotti, D., Occhionorelli, S., Traina, L., Neri, L. M., Rizzo, R., et al. (2021). Bowel ischemia as onset of COVID-19 in otherwise asymptomatic patients with persistently negative swab. J. Intern. Med. 291, 224–231. doi: 10.1111/joim.13385

CrossRef Full Text | Google Scholar

Zang, R., Gomez Castro, M. F., McCune, B. T., Zeng, Q., Rothlauf, P. W., Sonnek, N. M., et al. (2020). TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci. Immunol. 5:eabc3582. doi: 10.1126/sciimmunol.abc3582

CrossRef Full Text | Google Scholar

Zhang, Y., Chen, C., Zhu, S., Shu, C., Wang, D., Song, J., et al. (2020). Isolation of 2019-nCoV from a stool specimen of a laboratory- confirmed case of the coronavirus disease 2019 (COVID-19). China CDC Wkly 2, 123–124. doi: 10.46234/ccdcw2020.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, P., He, Z., Yu, G., Peng, D., Feng, Y., Ling, J., et al. (2021). The modified NUTRIC score can be used for nutritional risk assessment as well as prognosis prediction in critically ill COVID-19 patients. Clin. Nutr. 40, 534–541. doi: 10.1016/j.clnu.2020.05.051

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Shao, B., Dang, Q., Chen, Z., Zhou, Q., Luo, H., et al. (2021). Pathogenesis and mechanism of gastrointestinal infection With COVID-19. Front. Immunol. 12:674074. doi: 10.3389/fimmu.2021.674074

CrossRef Full Text | Google Scholar

Zhao, F., Yang, Y., Wang, Z., Li, L., Liu, L., and Liu, Y. (2020). The time sequences of respiratory and rectal viral shedding in patients with coronavirus disease 2019. Gastroenterology 159, 1158.e2–1160.e2. doi: 10.1053/j.gastro.2020.05.035

CrossRef Full Text | Google Scholar

Zhong, P., Xu, J., Yang, D., Shen, Y., Wang, L., Feng, Y., et al. (2020). COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduct. Target. Ther. 5:256. doi: 10.1038/s41392-020-00373-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, J., Li, C., Liu, X., Chiu, M. C., Zhao, X., Wang, D., et al. (2020). Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 26, 1077–1083. doi: 10.1038/s41591-020-0912-6

Review of Mesenteric Ischemia in COVID-19 Patients

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

Abstract

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

Introduction

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

Case summary

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

figure 1
Fig. 1
figure 2
Fig. 2

Pathophysiology

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

figure 3
Fig. 3

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

Clinical Presentation

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

Investigations

Blood investigations

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

Radiological imaging

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

Computed tomography

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

Management

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

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

Prognosis

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

Conclusion

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

References

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

SARS-CoV-2 and acute diverticulitis: The expanding gastrointestinal manifestations of COVID-19 infection

Authors: Simcha Weissman,Anna Belyayeva,Sachit Sharma,Muhammad Aziz, J Transl Int Med. 2021 Mar; 9(1): 59–60.Published online 2021 Mar 31. doi: 10.2478/jtim-2021-0019PMCID: PMC8016353PMID: 3385080

SARS-CoV-2, the novel coronavirus which emerged in late 2019, has spread rapidly and resulted in a global pandemic. Typical presenting symptoms of SARS-CoV-2 infection, that is, COVID-19, include fever, myalgias, fatigue, dry cough, dyspnea, and anosmia, with pneumonia being the most common disease complication. Although less frequent, gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and diarrhea, have been reported and have in fact implicated the gastrointestinal tract as a primary system involved in the clinical expression of COVID-19. We describe the case of a patient who presented with gastrointestinal symptoms, tested COVID-19 positive, and was subsequently found to have pneumonia as well as acute diverticulitis. This report showcases the need to recognize the expanding gastrointestinal manifestations of the COVID-19 infection and remain astute to its subsequent, often nuanced, clinical implications.

A 61-year old female with a history of lupus nephritis status-post renal transplant, chronic pelvic venous thrombosis status-post vascular stenting, hypertension, and diverticulosis presented to the emergency department (ED) with three days of progressive nausea, vomiting, abdominal pain, and diarrhea. Physical examination revealed tachycardia, tachypnea, bilateral rales, and tenderness in the left lower abdomen. Laboratory tests revealed a leukocyte count of 8.3×103/μL, a neutrophil-to-lymphocyte ratio of 6.65, erythrocyte sedimentation rate of 127 mm/h (normal 0–15 mm/h), and d-dimer of 1,251 (normal < 500 ng/mL). SARS-CoV-2 pharyngeal swab rRT-PCR was positive. Chest radiograph revealed bilateral pulmonary opacities and consolidation. As the patient complained of continued abdominal pain, computed tomography (CT) abdomen and pelvis was ordered and revealed sigmoid colonic diverticular wall thickening and adjacent pericolonic fat stranding, consistent with acute diverticulitis. With bowel rest, intravenous antibiotics, analgesics, and supplemental oxygen, the patient improved and was discharged home after four days.

To our knowledge, while recent case reports have described gastrointestinal symptomatology of COVID-19, this represents the first reported case of COVID-19 associated acute diverticulitis. While the pathophysiologic mechanism is unclear, as with many of the manifestations of COVID-19, we hypothesize that viral entry via colonocyte angiotensin-converting enzyme 2 (ACE-2) receptors or a systemic inflammatory reaction may have been responsible.[1] Viral strain may also impact differential manifestations of COVID-19.[1] Interestingly, on a similar note, the etiopathogenesis of acute diverticulitis also remains uncertain, but the role of viral infection in a subset of cases has been postulated.[23] Notably, as the gastrointestinal symptomatology in this case could have been attributed solely to viral illness, imaging to make a diagnosis of acute diverticulitis may never have been pursued, and in fact was initially deferred. Awareness of this manifestation can help prevent overseeing common and acute gastrointestinal pathology of COVID-19. Moreover, gastrointestinal symptomatology are of unique significance in COVID-19 patients, in contrast to other viral illnesses, owning to the fact that they often appear early and worsen during the disease course.[4]

Thus, while COVID-19-induced diverticulitis remains seemingly rare and largely unexplored, clinicians should maintain a broad differential diagnosis in COVID positive patients presenting with gastrointestinal symptoms.[4] Additionally, on this basis, we believe it is vital to institute SARS-CoV-2 precautions in patients who present with either respiratory or gastrointestinal symptoms amidst the current pandemic. Moreover, as many aspects of this disease continue to be appreciated, clinicians should not shy away from ordering abdominal imaging when other/concomitant pathology is suspected in order to help facilitate earlier and potentially impactful real-time diagnosis and treatment.

References

1. Patel KP, Patel PA, Vunnam RR, Hewlett AT, Jain R, Jing R. Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19. J Clin Virol. 2020;128:104386. et al. [PMC free article] [PubMed] [Google Scholar]

2. Schieffer KM, Kline BP, Harris LR, Deiling S, Koltun WA, Youchum GS. A Differential Host Response to Viral Infection Defines a Subset of Earlier-Onset Diverticulitis Patients. J Gastrointestin Liver Dis. 2018;27:249–55. [PMC free article] [PubMed] [Google Scholar]

3. Hollink N, Dzabic M, Wolmer N, Bostrom L, Rahbar A. High Prevalence of an Active Human Cytomegalovirus Infection in Patients with Colonic Diverticulitis. J Clin Virol. 2007;40:116–9. [PubMed] [Google Scholar]

4. Galanopoulos M, Gkeros F, Doukatas A, Karianakis G, Pontas C, Tsoukalas N. COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract. World J Gastroenterol. 2020;26:4579–4588. et al. [PMC free article] [PubMed] [Google Scholar]

Covid Raises Blood Clot, DVT Risks for Months After Even Mild Infection

Authors: Michelle Fay Cortez – April 7, 2022 Bloomberg

The risk of developing serious bleeding or potentially deadly blood clots is elevated for months after experiencing even a mild Covid infection, Swedish researchers found. 

While the dangers of post-Covid clotting are well known, it’s less clear how long the risk lasts and what should be done to prevent it. The researchers compared the medical records of 1 million people who tested positive for the virus between February 2020 and May 2021 in Sweden to 4 million of their peers who weren’t infected. 

Bleeding rates were elevated for two months after testing positive for the virus, while there was significant risk of developing blood clots deep in the legs for 70 days after Covid-19. The danger of pulmonary embolism, when a clot travels to the lungs and can kill, was significantly higher for almost four months, according to the report published in the BMJ, a British medical journal. 

“Despite the potential for new variants of concern, most governments are removing restrictions and shifting their focus to determining how best to ‘live with Covid’,” Frederick Ho and Jill Pell from the University of Glasgow’s Institute of Health and Wellbeing, wrote in an editorial. The finding “reminds us of the need to remain vigilant to the complications associated with even mild SARS-CoV-2 infection,” they wrote. 

The results support the use of blood thinners to prevent clotting, especially for high-risk patients, and underscores the need for vaccination, the researchers concluded. The study also found that the risks declined over time, as subsequent outbreaks of Covid caused fewer of the complications than the initial wave of disease. 

The risk of bleeding was almost twice as high for Covid patients in the month after they were infected, while clots called deep vein thrombosis were almost five times higher, the study found. Pulmonary embolism was the greatest risk, with 1,761 events occurring in the 30 days after infection, compared to just 171 among the larger group of people who didn’t contract the virus. 

While the danger was highest for those with other health conditions and the most severe infections, the fact that many more people develop mild cases means they should also remain alert, the experts said. Vaccination may help alleviate the issue of clotting, the experts said. 

“Vaccination could reduce the overall risk both by preventing infection and by reducing its severity when it does occur,” they wrote. 

Bone Marrow Suppression Secondary to the COVID-19 Booster Vaccine: A Case Report

Authors: Toral Shastri 1Navkiran Randhawa 2Ragia Aly 3Masood Ghouse 3

PMID: 35210894 PMCID: PMC8863340DOI: 10.2147/JBM.S350290

Abstract

As of September 2021, SARS-CoV-2 booster shots became widely available in the US to ensure continued protection against the virus. A temporal relationship has been previously reported between the first or second dose of the COVID-19 vaccine and the development of thrombocytopenia. However, adverse events related to the third COVID-19 vaccine are still being reported and studied. We report a 74-year-old male who developed bone marrow suppression and pancytopenia recorded seven days after receiving the Pfizer SARS-CoV-2 vaccine. During his hospital stay, the patient’s hemoglobin, white blood cell, and platelet levels continued to trend downwards. However, all three levels showed improvement one week after discharge without robust intervention. Global vaccination is of utmost importance, as is understanding and documenting post-vaccination reactions including bone marrow suppression. Prompt evaluation and patient education are imperative to improve patient outcomes and combat hesitancy against vaccine administration.

Introduction

Since its emergence in December of 2019, the rapid spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has quickly affected millions of lives across every continent.1 This highly transmittable and pathogenic viral infection has led to massive mitigation efforts and allocation of resources to prevent the spread of transmission and high mortality related to complications.2 The establishment of higher levels of community (herd) immunity and protection against SARS-CoV-2 via the widespread deployment of effective vaccines has become a global effort.3 In December of 2020, the FDA issued an Emergency use Authorization for the Pfizer-BioNTech and Moderna COVID-19 Vaccine as a two-dose series.4 In September 2021, booster vaccines became widely administered in the US due to waning immunity of the COVID-19 vaccines against variants of SARS-CoV-2 along with ensuring continued protection against the virus.5

Serious adverse events such as anaphylaxis, Guillain-Barre Syndrome, myocarditis, pericarditis, thrombocytopenia, and death have been previously reported following the first and/or second dose of vaccine.6 To our knowledge, no cases have been reported regarding bone marrow suppression related to the third COVID-19 vaccine. Adverse events reported between August 12-September 19, 2021 from the COVID-19 booster vaccine supported similar reactions to those after dose two.7 According to the Centers for Disease Control and Prevention (CDC), these initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccination.7 However, adverse events related to the COVID-19 booster are still being reported and studied.6 This report presents a case of bone marrow suppression occurring after the third COVID-19 vaccine without a similar reaction after the first or second dose.Go to:

Case Report

A 74-year-old male with a history of polychondritis and hypothyroidism presented to the hospital after falling out of his chair and inability to ambulate. The patient was found to be mildly confused upon arrival to the emergency room, limiting our ability to obtain a full verbal history. Chart review revealed the patient had received his third Pfizer Covid vaccine shot seven days before admission followed by fatigue, decreased appetite, fever, and chills. The patient had received the second Pfizer Covid-19 shot nine months before the booster. No reactions to the previous two shots were noted.

Upon initial evaluation, vital signs were within normal limits and a physical exam revealed significant tenderness in the upper arm and no gross bleeding (Figure 1). Computed tomography (CT) imaging (Figure 2) was significant for enhancement of the left axillary lymph node. The patient’s initial complete blood count (CBC) was remarkable for a hemoglobin count of 9.9 g/dl and platelet count of 84 x 109/L; both values lower than his prior hemoglobin count of 13.7 g/dl and platelet count of 180 x 109/L from December of 2020. His mean corpuscular volume (MCV) was elevated at 101.3 femtolitres from his prior MCV value of 95.8 femtolitres in December of 2020. His white blood cell (WBC) count was recorded at 7.6 x 109/L.

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Figure 1

The patient’s upper arm showed erythema with no gross bleeding near the injection site

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Figure 2

The patient’s CT imaging of the thoracic region showed enhancement of the left axillary lymph node.

The hemoglobin, WBC, and platelet count further down trended from his baseline (Figures 3​5).5). Anemia labs including ferritin levels (554 ng/mL), vitamin B12 (253 pg/mL), total bilirubin (0.5 mg/dL), and reticulocyte count (0.8%) were nonsignificant during the patient’s hospital stay. The patient’s left shoulder presented with extensive bruising, erythema, papular rash, warmth, and tenderness on palpation during the hospitalization. An improvement in WBC and platelet levels was noted on day 4 of hospitalization.

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Figure 3

The patient’s hemoglobin count throughout his hospital course and 6 days after discharge.

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Figure 4

The patient’s WBC count throughout his hospital course and 6 days after discharge.

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Figure 5

The patient’s platelet count throughout his hospital course and 6 days after discharge.

Before discharge, the patient was fully alert and oriented and reported improvement in his symptoms. Examination of his lateral left arm showed decreased erythema and bruising with slight petechiae. The patient was discharged due to stabilization of labs and encouraged to take oral vitamin B12 supplements. During his outpatient follow-up six days after hospitalization, his hemoglobin increased to 10.5 g/dl, WBC count increased to 4.9 x 109/L, and platelets increased to 101 x 109/L.

Discussion

This paper presents a patient with pancytopenia recorded seven days after receiving the Pfizer booster vaccine. Interestingly, this patient did not report any reactions after the first or second dose of the Pfizer vaccine against SARS-CoV-2. Pancytopenia refers to a decrease in all peripheral bloodlines and is present when all three cell lines are below the normal reference range.8 The patient’s physical exam showed no signs of active bleeding along with his labs indicating no evidence of hemolysis. The patient’s hemoglobin, platelet, and white blood cell count presented below baseline followed by a decrease and slight improvement during his hospital stay. Six days after hospitalization, all three cell lines showed improvement. The temporal association with the booster vaccine and negative infectious disease workup raised suspicion for vaccine-induced bone marrow suppression. In addition, the patient’s reticulocyte count and lactate dehydrogenase value were consistent with hypoproliferation within the bone marrow.

Currently, there is a gap in knowledge of adverse events specific to the third vaccine against SARS-CoV-2 due to the recent initiation of administration and ongoing reporting of events.6 To our knowledge, bone marrow suppression after any dose of vaccine against SARS-CoV-2 has not been previously reported. However, a prior case of pancytopenia after the third vaccination with a recombinant hepatitis B vaccine has previously been reported.9 The patient’s bone marrow biopsy within this case displayed a paucity of late myeloid elements and CD8+ T cells.9 It was believed the patient’s CD8+T cells were causing excessive production of IFN-γ; a stimulant of negative regulators of hematopoiesis such as tumor necrosis factor and lymphotoxin.10 IFN-γ has also previously been reported to create immunological effects comprising an upregulation of histocompatibility gene transcription and alteration in class I and II antigen expression at the cell surface.11 It was predicted these changes resulted in an autoimmune reaction causing suppression of maturation of hematopoietic progenitor cells and pancytopenia.9 Via a similar mechanism, we believe that our patient’s pancytopenia was immune-mediated, potentially triggered by the vaccination.

Vaccines against SARS-CoV-2 (first or second dose) and the induction of Idiopathic Thrombocytopenic Purpura (ITP) have also been recently acknowledged in multiple cases.12 Our patient presented with low platelet levels and associated petechiae and purpura at the site of the vaccination. However, the patient’s presentation of low hemoglobin and white blood cells along with normal reticulocyte levels was more indicative of pancytopenia secondary to bone marrow suppression. In patients presenting with pancytopenia, the history and the physical exam should help assess the severity of the pancytopenia and comorbid illnesses that may complicate the disorder.13 In addition, suspicious medications and exposure to toxic agents should be ruled out.13 Initial screening laboratory evaluation should include the patient’s complete blood count, peripheral blood smear examination, reticulocyte count, complete metabolic panel, prothrombin time/partial thromboplastin time, and blood type and screen. Common interventions to alleviate bone marrow suppression and pancytopenia include treating the underlying cause and utilizing supplements to boost red blood cell production if indicated.

Vaccines against SARS-CoV-2 undergo continuous safety monitoring; adverse events are very rare.14 However, vaccine hesitancy remains a barrier towards full population inoculation against SARS-CoV-2 and is influenced by misinformation regarding vaccine safety.15 One study using an anonymous online questionnaire found a person’s trust in the effectiveness of the vaccine was a major facilitative factor affecting willingness to vaccinate.16 The same study also found that 66.7% of unvaccinated participants thought the vaccine’s safety was not enough, making it the main reason for reluctance or hesitance to be vaccinated.16 Therefore, education of adverse events and available interventions post-vaccination is imperative to prevent the spread of misinformation and combat hesitancy towards vaccination.15

As of September 19, 2021, about 2.2 million people in the United States received a third vaccine against SARS-CoV-2.17 Among those who received the vaccine, 22,000 people reported the effects of the vaccine with no unexpected patterns of adverse reactions.17 Our patient demonstrates abnormal pancytopenia first recorded seven days after receiving the booster vaccine, possibly indicating a rare adverse event from the vaccination given the temporal relationship. While additional studies and observations are indicated to verify bone marrow suppression as an adverse reaction, this case report provides an opportunity for patient education and treatment planning before symptoms arise.

Conclusion

Our case report highlights pancytopenia secondary to bone marrow suppression following Pfizer vaccination against SARS-CoV-2. It is important to consider the possibility of bone marrow suppression following the third vaccine against SARS-CoV-2. Although additional studies are indicated to determine the risk factors and pathogenesis of vaccine-induced bone marrow suppression, prompt evaluation and initiation of interventions can improve patient outcomes

Consent for Publication

Institutional approval was not required to publish the case details. The publication of this study has been consented to by the patient.

Disclosure

The authors report no conflicts of interest in this work.

1. Fernandes A, Chaudhari S, Jamil N, Gopalakrishnan G. COVID-19 vaccine. Endocr Pract. 2021;27(2):170–172. doi:10.1016/j.eprac.2021.01.013 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Network Open. 2021;4(1):e2035057–e2035057. doi:10.1001/jamanetworkopen.2020.35057 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Graham BS. Rapid COVID-19 vaccine development. Science. 2020;368(6494):945–946. doi:10.1126/science.abb8923 [PubMed] [CrossRef] [Google Scholar]

4. Gee J, Marquez P, Su J, et al. First month of COVID-19 vaccine safety monitoring—United States, December 14, 2020–January 13. Morb Mortal Wkly Rep. 2021;70(8):283. doi:10.15585/mmwr.mm7008e3 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Mahase E. Covid-19 booster vaccines: what we know and who’s doing what. BMJ. 2021. doi: 10.1136/bmj.n2082 [PubMed] [CrossRef] [Google Scholar]

6. Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination. Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html. Accessed November 8, 2021. [Google Scholar]

7. Hause AM. Safety monitoring of an additional dose. Centers for Disease Control and Prevention; 2021. Available from: https://www.cdc.gov/mmwr/volumes/70/wr/mm7039e4.htm. Accessed February 11, 2022. [Google Scholar]

8. Valent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology. 2012;2012(1):485–491. doi:10.1182/asheducation.V2012.1.485.3798522 [PubMed] [CrossRef] [Google Scholar]

9. Viallard JF, Boiron JM, Parrens M, et al. Severe pancytopenia triggered by recombinant hepatitis B vaccine. Br J Haematol. 2000;110(1):230–233. doi:

10.1046/j.1365-2141.2000.02171.x [PubMed] [CrossRef] [Google Scholar]10. Collart MA, Belin D, Vassalli JD, De Kossodo S, Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986;164(6):2113–2118. doi:10.1084/jem.164.6.2113 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. Wallach D, Fellous M, Revel M. Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells. Nature. 1982;299(5886):833–836. doi:10.1038/299833a0 [PubMed] [CrossRef] [Google Scholar]

12. Shah SRA, Dolkar S, Mathew J, et al. COVID-19 vaccination associated severe immune thrombocytopenia. Exp Hematol Oncol. 2021;10:42. doi:10.1186/s40164-021-00235-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Elizabeth P, Weinzierl MD, Daniel A, Arber MD. The differential diagnosis and bone marrow evaluation of new-onset pancytopenia. Am J Clin Pathol. 2013;139(1):9–29. doi:10.1309/AJCP50AEEYGREWUZ [PubMed] [CrossRef] [Google Scholar]

14. Centers for Disease Control and Prevention. COVID-19 vaccination; 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/safety-of-vaccines.html. Accessed February 11, 2022.

15. Dror AA, Eisenbach N, Taiber S, et al. Vaccine hesitancy: the next challenge in the fight against COVID-19. Eur J Epidemiol. 2020;35:775–779. doi:10.1007/s10654-020-00671-y [PMC free article] [PubMed] [CrossRef] [Google Scholar]

16. Gan L, Chen Y, Hu P, et al. Willingness to receive SARS-CoV-2 vaccination and associated factors among Chinese adults: a cross sectional survey. Int J Environ Res Public Health. 2021;18(4):1993. doi:10.3390/ijerph18041993 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. STAT. Early data suggest side effects after Covid booster similar to second dose; 2021. Available from: https://www.statnews.com/2021/09/28/side-effect-rates-from-a-third-covid-19-vaccine-dose-similar-to-those-after-second-shot-early-data-indicate/.

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.