key: cord-0906110-fr9okcn7
authors: Thomas, M. R.; Scully, M
title: Clinical features of thrombosis and bleeding in COVID-19
date: 2022-04-26
journal: Blood
DOI: 10.1182/blood.2021012247
sha: f11c1c432e145083f5a5b2bdbcea5912e5494751
doc_id: 906110
cord_uid: fr9okcn7

Infection with the SARS-CoV-2 virus, resulting in COVID-19 disease has presented a unique scenario associated with high thrombotic rates. The risk of venous thrombosis is some 3-6 fold higher than for patients admitted to hospital for other indications and for patients who have thrombosis, mortality appears increased. Thrombosis may be a presenting feature of COVID-19. Pulmonary thrombi are the most frequent events, some related to deep vein thrombosis, but also in situ micro- and macrovascular thrombosis. Other venous thromboses include catheter and circuit-associated in patients requiring haemofiltration and ECMO. Arterial thrombosis is less commonly documented, with 3% of ICU patients having major arterial strokes and up to 9% myocardial infarction, which is likely multifactorial. Risk factors for thrombosis above those already documented in hospital settings include duration of COVID-19 symptoms before admission to hospital. Laboratory parameters associated with higher thrombotic risk include higher D-dimer, low fibrinogen and low lymphocyte count, with higher FVIII and von Willebrand factor levels indicative of more severe COVID-19 infection. All patients should receive thromboprophylaxis when admitted with COVID-19 infection, but the dose and length of treatment still remain debated. Treatment for thrombosis remains as per standard VTE guidelines, but adjustments may be required depending on other factors relevant to the patient admission.

COVID-19 disease is the result of infection with the SARS-CoV-2 virus 1 . Many individuals have mild disease or may be asymptomatic but approximately 20% of cases required hospital admission with moderate or severe disease. Definitions have been published with severe COVID-19 infection identified as SpO 2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50% 2 .

COVID-19 infection is a thrombo-inflammatory disorder and the primary prothrombotic features are termed 'COVID-19-associated coagulopathy'. 3 Evidence suggests this is linked to the inflammatory response against SARS-CoV-2, with complex interactions between the virus, immune, inflammatory systems and coagulation pathways at local and systemic levels, and the inflammatory response and endothelial injury involved in development of micro-and macrovascular thrombosis. COVID-19 has been associated with increased rates of both venous thromboembolism (VTE), including pulmonary embolism (PE), deep vein thrombosis (DVT), and arterial thrombosis, including acute ischaemic stroke and peripheral arterial thrombosis. Concurrent venous and arterial thrombosis have been reported. 4 In severe COVID-19 disease, there is an increased risk of bleeding. 5

Initial studies from Wuhan reported abnormalities in clotting parameters in COVID-19

including elevated D-dimer levels, and it was rapidly recognised these abnormal parameters were associated with prognosis. Early studies showed an association between D-dimer and survival 6 and elevated D-dimer continues to be a consistent marker of poor outcome. 7 COVID-associated coagulopathy (CAC) 3 has been described as a unique syndrome distinct from bacterial sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC), with increased fibrinogen 3 and D-dimer levels in CAC, but initially only minimal changes in platelet count and prothrombin time. 3 Comparably, the levels of natural anticoagulants (Protein C and antithrombin) are in the normal range and levels of protein S are reduced . 8 Other features include marked elevation of Factor VIII and von Willebrand factor (VWF).

VWF antigen/ADAMTS-13 activity ratio has been associated with the degree of severity of COVID-19 infection. 9 Platelet count is generally well preserved in COVID-19 disease but, in a large retrospective study, 20% patients had platelets<150 x10 9 /L. 10 Mortality rates were higher with severe thrombocytopenia with relative risk of death 3.42 (95%CI 2. 36-4.96) , for platelet count 100-150 x10 9 /L; 9.99 (95% CI 7.16-13.94) for platelets 50-100 x10 9 /L and 13.68 (95% CI 9.89-18.92) for platelets<50 x10 9 /L. 10 The incidence of DIC is low in COVID-19, reported at <1% even in severe cases, 4, 11 and often a pre-terminal event. 12 A higher rate of 8.7 % (16/183) cases meeting ISTH criteria for diagnosis of DIC, is still below that seen in sepsis where DIC occurs in about 30% cases. 12 The progressive consumptive coagulopathy seen in the later phases of some COVID-19 cases may be due to superimposed bacterial infection. 3 Thus, clinically relevant thrombocytopenia, reduced fibrinogen and DIC are rare in COVID- 19 patients but have been associated with significant bleeding manifestations. 13 Autopsy studies Pulmonary microthrombi are commonly found at post mortem examination of patients with COVID-19, in addition to the major pulmonary thrombosis reported as a common fatal complication in autopsy series. 14 One study compared lung autopsies from patients with COVID-19 and H1N1 influenza and alveolar capillary microthrombi were nine times more common in patients with COVID-19, consistent with the clinical increase in thrombosis compared to many other viral pneumonias. 15 Microthrombi have been identified at autopsy in some extrapulmonary organs but less consistently across studies and at significantly lower rates. 16, 17 

Incidence of VTE in COVID-19 patients Patients admitted to hospital with COVID-19 infection are at high risk for venous thrombosis, but accurate assessment of the true incidence has been challenging. Reported rates vary, not only with study quality, but stage of disease and where the patient is treated (ward vs intensive care unit ICU). These factors, in turn, may also affect the intensity of anticoagulation used as 4 thromboprophylaxis, which may impact the likelihood of developing thrombosis.

Prophylactic anticoagulation is not routinely used as standard of care in hospitalised patients in some countries e.g. China, thus the high incidence of DVT in early Chinese studies could be due to prolonged hospital stays and immobility without thromboprophylaxis. 18 Other factors affecting thrombosis rates include proactive screening for DVT using Doppler US, or PE with CT pulmonary angiography.

Interpretation is further complicated because (i) criteria for hospitalisation with COVID-19 and thresholds for ICU admission differ between institutions, (ii) difference in co-morbidities may also influence thrombosis rates and (iii) treatments have improved over time. 19 Meta-analyses have estimated overall VTE rates of 12-31% in COVID-19 inpatients, with lower VTE rates in more recent metanalyses [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] (Table 1) In the systematic review and meta-analysis of 49 studies and >18 000 patients by Jimenez et al, pooled incidence for VTE in COVID-19 patients was 17.0%. 28 Incidence of DVT was 12.1% and PE was 7.1%. In subgroup meta-analyses, VTE incidence was higher when identified by screening (33.1%) than by clinical diagnosis (9.8%), in ICU patients (27.9%) vs ward cases (7.1%), in prospective studies (25.5%) compared to retrospective studies (12.4%) and when catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs were included. 28 VTE rates in COVID-19 compared to other diseases Critically ill patients exhibit a VTE rate of 5-10% despite thromboprophylaxis. 31 VTE rates in patients with COVID-19 appear greater still, with 3-6 times the expected rates of thrombosis in COVID-19

populations vs retrospective comparator non-COVID-19 ICU populations. 4,32 COVID-19 has an increased PE rate compared to SARS and MERS or H1N1 influenza. 33 However, the high VTE rates seen in critically ill COVID-19 patients may simply be consistent with a particularly sick ICU subpopulation e.g. in non-COVID-19 patients with severe sepsis and septic shock, VTE incidence was 37% with systematic screening, despite patients receiving thromboprophylaxis. 34

Thrombosis may be the presenting feature of COVID-19 35, 36 and a significant proportion of events are diagnosed soon after hospital admission. In one Italian study, almost 50% of patients were diagnosed with thrombosis within 24 hours of hospital admission. 37 UK national data on COVID-19 vaccination, SARS-CoV-2 positive test data and hospital admissions to the NHS describes thrombosis risk and timing of thrombotic events 38 (Figure 1 ) and showed 5 highest incidence rate ratios of VTE on days 1-7 (13.78 [12.66 to 14.99] ) and days 8-14 (13.86 [12.76 to 15 .05]) after positive SARS-CoV-2 test result. 38 A VTE incidence of 2.6% in the first 90 days post discharge in patients without thromboprophylaxis has been documented. 39 However, in a prospective multicentre study of >1 800 discharged patients, six week VTE rate was 4.8/1000 discharges, similar to baseline rates in the previous year of 3.1/1000 discharges. 40 In a prospective observational single centre study of 485 consecutive patients with systematic screening for VTE, VTE incidence was low at 6 weeks after COVID-19 hospitalisation, with one DVT (0.7%) and one symptomatic PE (0.7%) detected. Post discharge thromboprophylaxis was prescribed in 28%. 41

Classical DVT embolising to PE may be relatively less common in COVID-19 disease 42 and a high incidence of pulmonary thrombosis without DVT has been described, with DVT present in only 42% COVID-19 patients with PE in one meta-analysis, 27 lower than the usual prevalence of 60%. 43 One reason could be that the thrombus has completely embolised, but another explanation is that it supports the increased incidence of in situ thrombosis and microvascular thrombosis identified at post mortem examination in COVID-19

patients. 33, 44 The contribution of in situ thrombosis and thrombosis in smaller vessels is further reinforced by the high incidence of peripheral rather than central pulmonary emboli. 45 Dual energy CT imaging has been used to study lung perfusion in COVID- 19 and scan appearances also appear more in keeping with pulmonary thrombosis in situ than embolism. 46 The mechanism of in situ thrombosis likely still reflects Virchow's triad with endothelial inflammation, systemic and local prothrombotic changes and altered local pulmonary blood flow in response to lung parenchymal processes. 42 Further confirmation of this theory was based on histological analysis. 15

CVST. 47, 48 A multi-national retrospective study reported on all cases of CVST with COVID-19 infection to June 2020 and compared the 13 patients to historic CVST patients from the same centres. Patients with COVID-19 tended to be older and have fewer standard CVST risk factors and poorer outcomes. 49 A recent multicentre cohort study of 13 500 consecutive patients with COVID-19 over a three month period reported an image-proven CVST incidence of 8.8 per 10,000 cases, much higher than the expected rate of 5 per million/year. 50 A retrospective cohort study 6 based on electronic health records of >500,000 patients with COVID-19 found the incidence of CVST in the two weeks after a COVID-19 diagnosis was 42.8 / million people. 38 Mortality rate in one study was 25%, despite the standard management of anticoagulation, endovascular thrombectomy and surgical haematoma evacuation. 50 Variable increases in inflammatory and hypercoagulabilty markers were found, but it is unclear whether monitoring these has any value for predicting risk or severity of sinus thrombosis. 51 Other venous thrombotic complications well described in COVID-19 include central venous catheter-associated thrombosis and thrombosis in venous-venous ECMO circuits. 13, 36 Very high rates of thrombosis in extracorporeal circuits (up to 8%) have been reported. 4 In an international cohort study from the Extracorporeal Life Support Organization (ELSO) of ECMO support in COVID-19, circuit changes were required in 148 (15%) of 983 patients, 52 and haemodialysis circuits have been observed to clot at unusually high frequency (28/29 patients on renal replacement therapy in one cohort). 4

Thrombotic complications in COVID-19 have been associated with increased mortality in several studies. 53 36 In a meta-analysis of 42 studies including >8 000 COVID-19 patients, a thrombotic complication was associated with 74% increase in odds of overall mortality (23% vs 13%). 54 It is unknown if thrombosis is a direct cause of the worse outcomes or a marker of disease severity. A further metaanalysis showed no mortality difference between hospitalised COVID-19 patients with and without VTE, although patients with VTE were more likely to be admitted to ICU and mechanically ventilated. 55 The long-term impact of COVID-19-related VTE is unclear. The usual incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after acute PE is 2-3% 56 , but persistent respiratory symptoms will be initially difficult to disentangle from morbidity of post ICU and long COVID.

Early investigators identified standard VTE risk factors such as age, obesity, smoking, immobilisation, previous VTE and co-morbidities, 57 as well ICU-associated risk factors 58 contribute to venous thrombosis risk in COVID-19. Laboratory parameters associated with higher risk for VTE include higher D-dimer, lower lymphocyte count or higher neutrophil:lymphocyte ratio and prolongation of clotting 7 times, with D-dimer being the strongest predictor. 53, 59 Ethnicity (Black race) has also been identified as a thrombotic risk factor in one study. 60 Li et al developed the 'Wuhan score' for thrombosis prediction with risk factors comprising age, cancer, longer duration of symptoms prior to admission, lower fibrinogen, higher D-dimer and D-dimer increment. D-dimer increment ≥1.5 fold had the most significant association with VTE in hospitalized COVID-19 patients in their cohort. 61 64 with CTPA as first line of imaging due to high degree of accuracy and ability to identify coexisting lung pathologies. Particular challenges include unstable patients who cannot be transferred or patients with acute kidney injury where contrast may be an issue.

Compression US can assess for DVT although absence of DVT does not imply the absence of pulmonary thrombosis, particularly because of the potential for in situ pulmonary thrombosis in COVID-19. 65 Echocardiography may suggest PE with clot in the right side of the heart or new right heart strain, but has a more limited diagnostic role. 65

Current guidelines recommend management as per non-COVID VTE, with anticoagulation being the cornerstone of therapy, as there is a paucity of COVID-19 specific evidence in this area. 64 Risk stratification remains central to identify patients at increased risk of early death who may benefit from reperfusion therapy, mechanical circulatory support or both. 65 The inclusion of troponin in the definition of intermediate risk PE (RV strain on echo or imaging, raised troponin and elevated PESI score) is confounded by the fact that troponin levels are frequently increased in COVID-19. 65, 66 Parenteral anticoagulation is preferred in critically ill patients with evolving practice worldwide towards LMWH becoming the standard of care for prevention and treatment of thromboembolism compared to UFH, due to better bioavailability, fixed dosing and decreased risk of heparin-induced thrombocytopenia (HIT). 67 Duration of anticoagulation on discharge follows the standard guidance for anticoagulation for non-COVID VTE. 64

We have less data to inform us about rates of arterial thromboembolism in COVID-19 but increased arterial events in COVID-19 patients have been reported as affecting up to 3% patients in ICU cases (95%CI 2-5%). 36 Acute ischaemic stroke Acute cerebrovascular events such as stroke may occur in relation to COVID-19 infection, 68, 69 with an incidence up to 3% 36,37 and a propensity towards occlusion of large vessels, multi-territory vessels and uncommon vessels, e.g. pericallosal artery. 70 In two retrospective studies, stroke symptoms developed later during the hospital episode, a median of 10 days after symptom onset, 71, 72 however diagnosing stroke in sedated ventilated patients may be challenging. In a proportion of COVID-19 patients presenting with stroke, diagnosis of the viral infection was made after admission 51 and guidelines therefore recommend appropriate personal protective equipment for acute stroke teams.

Stroke patients with COVID-19 infection have a higher severity score (NIHSS-National Institutes of Health Stroke scale) at admission, 73,74 and a more severe disease course. 71, 72 More recently, a case series reported large vessel stroke as a presenting feature of COVID-19 in the young (<50 years). 75 The role of mechanical thrombectomy (MT) in acute ischaemic stroke patients with COVID-19 is yet to be determined. 76 Evidence from current studies indicates a negative impact of COVID-19 on outcomes in stroke patients who receive MT, irrespective of timely, successful angiographic recanalization. 76 Cardiac thrombosis In >3000 hospitalised patients with COVID-19, myocardial infarction was the commonest arterial thrombotic complication occurring in 8.9%. 16 Some cardiac complications in COVID-19 may be related directly due to thrombosis 9 but elevated myocardial injury markers may be seen in COVID-19 patients without macrovascular occlusion. 6 Alternative mechanisms include direct viral myocyte invasion, myocarditis, endothelial damage, type 2 MI and stress cardiomyopathy and hence cardiac involvement is likely to be multifactorial. 77, 78 Limb ischaemia, mesenteric ischaemia, and large vessel arteriosclerosis obliterans have been described 4,79-81 COVID-19 'toes' may represent acro-ischaemia ?digital microvascular thromboembolism 82 , microvascular inflammation 83 or be related to therapy, for example, vasopressors.

Given the increased risk of both macro-and microvascular thrombosis in COVID-19 patients, anticoagulation therapy has been explored from the early stages of the pandemic. Early data on patients admitted on long term anticoagulation suggested reduced thrombosis rate but no effect on mortality, 36 but results from differing cohorts were inconsistent. However, utilising propensity score-matched cohorts, no significant difference was found in mortality, time to ventilation or length of stay. 84, 85 There have been >75 clinical trials registered investigating different primary thromboprophylactic strategies in COVID-19, 86 the majority studying heparin. Table   2 summarises the design and outcomes of the major recent RCT and international multiplatform studies.

Patients with severe COVID-19 do not appear to benefit from therapeutic anticoagulation according to the results of the INSPIRATION RCT; the multiplatform (ACTIV-4a, ATTAC and REMAP-CAP) studies, and the subgroup analysis of HEP-COVID RCT which looked at the approximately one-third of patients that were on ICU. [87] [88] [89] In hospitalised patients with moderate COVID-19, the data is mixed. In the ACTION RCT, therapeutic rivaroxaban did not improve survival or duration of hospitalisation compared to standard heparin thromboprophylaxis. 90 In the RAPID RCT, there was no significant difference between therapeutic or prophylactic dose heparin in the composite outcome of ICU admission, need for ventilation or death. However, therapeutic dose anticoagulation was associated with a decrease in the secondary outcome of death at 28 days. 91 In contrast, in the non-critically ill patients in the multiplatform study, therapeutic anticoagulation was associated with 4.6% increased probability of survival to hospital discharge without requirement for organ support, although no effect on in-hospital mortality (7.3% vs. 8.2%). 92 In the HEP-COVID RCT, therapeutic dose anticoagulation in non-ICU patients (two-thirds of patient cohort) significantly reduced the composite outcome of VTE, arterial thromboembolism and mortality. 89 The two findings from the international multiplatform trial appear to be contradictory, with benefits seen of primary thromboprophylaxis with treatment-dose anticoagulation in people in with moderate COVID-19 disease, but not in those with severe disease. This may be due to several different factors. The first could be due to the pathophysiology of COVID-19 at different stages of the disease -in critically ill patients the thrombotic and inflammatory changes may be too far progressed to be affected by higher doses of anticoagulation. 93 However, other explanations may be due to the inherent study design and other confounding factors. Critically, a platform study does not equal an randomised controlled trial, as if patients did not undergo randomisation concurrently it cannot be guaranteed that the trial groups have (on average) equivalent patient populations. 94 More importantly, 'standard' heparin dosing was not standardised in these trials. 93 In the non-critically ill study, 26.5% of the control group received intermediate dose and 20 .4% of the therapeutic-dose group did not receive therapeutic anticoagulation. 93 Finally, different populations were investigated in the two studies with most patients recruited in the UK for the critically ill study but US/Brazil for moderately ill meaning a differing ethnic mix, as well as other variables are likely. 93 Given the ACTION study included mainly stable non-ICU patients (90%), 90 it is important to consider why therapeutic anticoagulation with rivaroxaban did not improve outcomes in the ward setting, in contrast to the results with therapeutic LMWH from the international multiplatform trial and HEP-COVID. 89, 92 The investigators postulate that it may be because rivaroxaban does not share the other anti-inflammatory properties of heparin, may not affect microvascular thrombosis, or simply because oral anticoagulants may not be well absorbed in hospitalised 11 patients with erratic eating habits (rivaroxaban is dependent on food for absorption). 90 There are differences across the studies as a whole that need to be considered, such as definitions of critically ill patients, different composite primary outcomes and cut-offs for an elevated D-dimer level. 95 In the anticoagulation trials in patients with COVID-19, many screened patients were not deemed eligible or did not consent to participate. The findings might therefore not be generalisable to all moderately ill patients with COVID-19 admitted to hospital wards. 90 Safety data appear much more consistent, with bleeding risk increasing with increased intensity anticoagulation in most studies. In the BEMICOP study there were no major bleeding events, most likely due to the short duration of the treatment period. 96 Several meta-analysis of anticoagulation in patients with COVID-19 have already been published. [97] [98] [99] Limitations are present too in the meta-analyses, such as combining different anticoagulants, combining ICU and non-ICU patients and combining different doses of anticoagulants. A meta-analysis by Reis et al 2021 which included 8 RCTs and 5580 patients concluded that moderately affected COVID-19 patients may benefit from therapeutic-dose anticoagulation, but the risk for bleeding is increased. Intermediate-dose anticoagulation may have little or no effect on thrombotic events or death, but may increase major bleeding in moderate to severe COVID-19 patients. However, it acknowledged that the certainty of evidence is still low. 97 When considering thromboprophylaxis in the COVID-19 outpatient setting, it seems likely that there would be a net benefit to patients at low bleeding risk if risk of symptomatic VTE is >1.8% at 35-42 days post discharge, extrapolating from the RCT assessing extended thromboprophylaxis in general medical patients. 64 However, overall VTE rates post discharge appear to be lower than this, as described above. It may be that selectively using thromboprophylaxis in high-risk patients is the best strategy, but the question remains how to risk stratify.

Prospectively validated risk assessment models to estimate thrombotic and bleeding risk of patients with COVID-19 after hospital discharge are not available. 100 In an open-label, multicentre RCT in Brazil, 320 patients hospitalised with COVID 

Bleeding is a less prominent phenotype in the COVID-19 patient but can cause significant morbidity and a potential cause of death in a subset of patients. 104 However, one needs to unpick the contribution from the COVID-19 disease itself and iatrogenic factors such anticoagulation, procedures, steroids and other ulcerogenic agents.

A multicentre retrospective study of 400 hospitalised patients reported overall bleeding rate of 4.84 (95%CI 2.9-7.3) with major bleeding 2.3% (95%CI 1.0-4.2).

Elevated D-dimer at presentation was predictive not only of thrombosis but of bleeding (adjusted OR for bleeding 3.56 (95% CI 1.1-12.66). 13 Haemorrhage was reported as a cause of death of in 6% COVID-19 patients in one series. 105 In a recent systematic review and meta-analysis of 49 studies and >18 000 patients by Jimenez et al, there was a pooled incidence of 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding. 28 The highest incidence of bleeding was reported for patients receiving intermediate-or full-dose anticoagulation (21.4%), and the lowest in the only prospective study that assessed bleeding events (2.7%). 28

Gastrointestinal (GI) bleeding has been described in 4-13.7% severely affected patients, 40% of whom had stool PCR positive for the SARS-CoV-2 virus. 106, 107 It has been hypothesised that prolonged hypoxia may lead to cell necrosis and mucosal 13 damage leading to GI ulceration. 5 A recent meta-analysis of acute GI bleeding in 127 COVID-19 patients, 59% responded to conservative measures. Mortality rate was low associated with GIB (pooled mortality secondary to GIB 3.5% (95%CI 1.3-9.1%) and low risk of rebleeding (rebleeding risk 11.3% (95% CI 6.8-18.4%). 108 Intracranial haemorrhage Case series have suggested distinct patterns to intracerebral haemorrhage in COVID-19 positive cases compared to non-COVID-19 patients, namely haemorrhage severity, mortality and younger age. 109 This is also described in aneurysmal subarachnoid haemorrhage (high frequency of small aneurysms, dissecting pseudoaneurysms and younger age in COVID-19 positive cases). 110 However, a recent large study from 62 centres in the US did not suggest that rates of intracerebral haemorrhage were higher in patients with COVID-19, occurring in 0.2% (154/85 645) patients with COVID-19 and 0.3% (667/197 073) of patients without the virus. 111 The in-hospital mortality amongst patients with ICH and COVID-19 was significantly higher than those without (40.3% vs 19%, P<0.0001), thought to be mediated by higher frequency of co-morbidities and adverse in-hospital events. 111 Table 1 : Selected systematic reviews and meta-analyses of VTE rates in COVID-19 inpatients A selected summary of studies/metanalysis of the rate of thrombosis in COVID-19 patients in hospital, including ICU rates and proportion of DVT and PEs Table 2 : Design and outcomes of the major randomised controlled trials and international multiplatform studies of thromboprophylaxis in COVID-19 disease.

A summary of the published literature and impact in preventing thrombosis in COIVD-19

Timing of venous and arterial event from presentation of COVID-19 infection to day Incidence rate ratios

The unique characteristics of COVID-19 coagulopathy

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Bleeding and Bleeding Risk in COVID-19

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-ofthe-Art Review

Coagulation profile of COVID-19 patients admitted to the ICU: An exploratory study

The ADAMTS13-von Willebrand factor axis in COVID-19 patients

Thrombocytopenia and its association with mortality in patients with COVID-19

Clinical Characteristics of Coronavirus Disease 2019 in China

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

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

Thrombosis in Hospitalized Patients With COVID-19 in a New York City Health System

Microthrombi in skin biopsy of a patient with COVID-19

Coagulation and anticoagulation in COVID-19

COVID-19 coagulopathy, thrombosis, and bleeding

Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis. Res Pract Thromb Haemost

Venous Thromboembolism among Hospitalized Patients with COVID-19 Undergoing Thromboprophylaxis: A Systematic Review and Meta-Analysis

Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: a systematic review and meta-analysis

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies

A meta-analysis of the incidence of venous thromboembolic events and impact of anticoagulation on mortality in patients with COVID-19

Incidence of Venous Thromboembolism in Hospitalized Coronavirus Disease 2019 Patients: A Systematic Review and Meta-Analysis

Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis

Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis

Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis

Venous Thromboembolism in Hospitalized Critical and Noncritical COVID-19 Patients: A Systematic Review and Meta-analysis

Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis

Thromboprophylaxis in the intensive care unit: focus on medicalsurgical patients

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation

VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock

Cerebral Venous Sinus Thrombosis as a Presentation of COVID-19

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study

Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up

Postdischarge venous thromboembolism following hospital admission with COVID-19

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Deep venous thrombosis in patients with acute pulmonary embolism: prevalence, risk factors, and clinical significance

Coagulation Abnormalities and Thrombosis in Patients Infected With SARS-CoV-2 and Other Pandemic Viruses

Pulmonary Thromboembolism in COVID-19

Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Cerebral venous thrombosis associated with COVID-19 infection: Causality or coincidence?

Cerebral venous sinus thrombosis associated with SARS-CoV-2; a multinational case series

Cerebral Venous Thrombosis in COVID-19: A New York Metropolitan Cohort Study

SARS-CoV-2 and Acute Cerebrovascular Events: An Overview

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis

Clinical characteristics and outcomes of venous thromboembolism in patients hospitalized for COVID-19: Systematic review and meta-analysis. Thrombosis Update

Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature

Prevention and Treatment of Venous Thromboembolism Associated with Coronavirus Disease 2019 Infection: A Consensus Statement before Guidelines

Venous thromboembolism in the ICU: main characteristics, diagnosis and thromboprophylaxis

Incidence of venous thromboembolism in hospitalized patients with COVID-19

Clinical characteristics and risk factors for symptomatic venous thromboembolism in hospitalized COVID-19 patients: A multicenter retrospective study

The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID-19

Pulmonary embolism

Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease

Pulmonary Thrombosis and Thromboembolism in COVID-19

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Characteristics of ischaemic stroke associated with COVID-19

Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke

Stroke in patients with COVID-19: Clinical and neuroimaging characteristics

Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

SARS-CoV-2 and Stroke in a New York Healthcare System

SARS-CoV-2 and Stroke Characteristics: A Report From the Multinational COVID-19 Stroke Study Group

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

Mechanical Thrombectomy Outcomes in COVID-19

Patients With Acute Ischemic Stroke: A Narrative Review

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

Cardiovascular manifestations and treatment considerations in COVID-19

Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19

Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report

Arterial thromboembolic complications in COVID-19 in low-risk patients despite prophylaxis

Comment on "Characterization of acute acro-ischemic lesions in non-hospitalized patients: A case series of 132 patients during the COVID-19 outbreak

Clustered cases of acral perniosis: Clinical features, histopathology, and relationship to COVID-19

Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

Heparin for Moderately Ill Patients with Covid-19. medRxiv

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Surviving Covid-19 with Heparin?

Platform Trials -Beware the Noncomparable Control Group

Anticoagulant Therapy in Patients Hospitalized With COVID-19

Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial

Safety and Efficacy of Intermediate-and Therapeutic-Dose Anticoagulation for Hospitalised Patients with COVID-19: A Systematic Review and Meta-Analysis

Randomized trials of therapeutic heparin for COVID-19: A meta-analysis

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19

Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an openlabel, multicentre, randomised, controlled trial

American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features

Clinical characteristics of 82 cases of death from COVID-19

Evidence for Gastrointestinal Infection of SARS-CoV-2

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Acute Gastrointestinal Bleeding in COVID-19 Patients: A Systematic Review and Meta-Analysis

Intracranial Hemorrhage in Patients with Coronavirus Disease 2019 (COVID-19): A Case Series

Aneurysmal Subarachnoid Hemorrhage in Patients with Coronavirus Disease 2019 (COVID-19): A Case Series

Intracerebral Hemorrhage and Coronavirus Disease 2019 in a Cohort of 282,718 Hospitalized Patients. Neurocrit Care

Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines

Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial