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
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blood clots with low blood platelets. Available: https://www.ema.europa.eu/en/news/
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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.

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

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

Abstract

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

1 INTRODUCTION

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

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

2 METHODS

2.1 Study population and design

2.1.1 COVID-19 cases

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

2.1.2 Contemporaneous control cases

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

2.1.3 Historical control cases

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

2.2 Determination of clinical variables

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

2.3 Determination of laboratory variables

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

2.4 Coagulation factor assay methods

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

2.5 APTT waveform analyses

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

2.6 Statistical methods

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

3 RESULTS

3.1 A cohort of patients with severe COVID-19

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

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

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

TABLE 2. Clinical outcomes and features

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

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

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

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

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

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

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

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

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

3.4 Factor V activity relationships in COVID-19

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

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

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

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

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

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

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

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

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

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

4 DISCUSSION

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

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

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

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

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

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

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

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

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

ACKNOWLEDGEMENTS

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

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

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

ABSTRACT

Introduction

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

Methods

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

Conclusion

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

Introduction

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

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

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

Prevalence

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

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

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

Pathogenesis

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

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

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

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

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

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

Manifestations

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

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

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

Diagnosis

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

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

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

Treatment

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

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

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

Table 1.

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

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

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Table 2.

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

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

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Table 3.

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

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

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How should biomarkers be used to guide management?

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

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

What are the preferred prophylactic anticoagulation regimens?

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

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

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

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

When to increase intensity of anticoagulation

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

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

What is the preferred therapeutic anticoagulation regimens?

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

When are thrombolytics recommended?

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

When to hold anticoagulation?

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

What is the utility of mechanical thromboprophylaxis?

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

What is the appropriate method of monitoring anticoagulation?

Monitoring of patients receiving therapeutic anticoagulation with LMWH

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

Monitoring of patients receiving therapeutic anticoagulation with UFH

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

Heparin resistance

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

What is the recommended approach to control active bleeding?

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

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

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

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

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

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

Conclusion

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

Acknowledgments

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

Declaration of funding

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

Declaration of financial/other relationships

No potential conflict of interest was reported by the author.

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

Authors contributions

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

Take home message

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

COVID-19: Coronavirus disease 2019

WHO: World Health Organization

CAC: COVID-19 associated coagulopathy

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

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

ASH: American Society of Hematology (ASH)

ACCP: American College of Chest Physicians

SCC-ISTH: Scientific and Standardization Committee of ISTH

ACF: Anticoagulation Forum

ACC: American College of Cardiology

vWF: von Willebrand Factor

ICU: Intensive Care Unit

TEG: Thromboelastography

ROTEM: Rotational thromboelastometry

DIC: Disseminated intravascular coagulation

PT: Prothrombin time

PTT: Partial thromboplastin time

AT: Antithrombin

MA: Maximum amplitude

INR: International normalized ratio

VTE: Venous thromboembolism

HIT: Heparin-induced thrombocytopenia

SRA: Serotonin release assay

PE: Pulmonary embolism

CTPA: Computed tomography pulmonary angiogram (CTPA)

LMWH: Low molecular weight heparin

UFH: Unfractionated heparin

RCT: Randomized control trial

DOAC: Direct oral anticoagulants

PPE: Personal protective equipment

CRRT: Continuous renal replacement therapyGo to:

Declaration of interest

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

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