key: cord-0698008-tjie7pqv
authors: Massaro, Gianluca; Lecis, Dalgisio; Martuscelli, Eugenio; Chiricolo, Gaetano; Sangiorgi, Giuseppe Massimo
title: Clinical Features and Management of COVID-19 Associated Hypercoagulability
date: 2021-10-30
journal: Card Electrophysiol Clin
DOI: 10.1016/j.ccep.2021.10.005
sha: 238114f90cb1f9bb4e2fdeec454c051691ecd6e9
doc_id: 698008
cord_uid: tjie7pqv

Covid-19 is an acute respiratory disease of viral origin caused by Sars-Cov2. This disease is associated with a hypercoagulable state resulting in arterial and venous thrombotic events. The latter are more frequent, especially in patients who develop a severe form of the disease and are associated with an increased mortality rate. It is therefore essential to identify patients at higher risk in order to initiate antithrombotic therapy. Hospitalized patients treated with treatment-dose of anticoagulants had better outcomes than those treated with prophylactic-dose. However, several trials are ongoing to better define the therapeutic and prevention strategies for this insidious complication.

Coronavirus disease-2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 carries several important cardiovascular implications 1,2 . Since this pandemic disease broke out, it has been observed an increasing occurrence of thromboembolic events in patients without a history of cardiovascular disease 3 . The progressive acquisition of knowledge on the pathogenetic effects of Sars-Cov2 infection has found a prominent role of the venous and arterial vascular system in the disease. Accumulated evidence has shown that coagulopathy is frequently observed in COVID-19 patients, especially in those with critical illness 4 .

Han et al. reported increased D-dimer values and fibrin/fibrinogen degradation products and reduced prothrombin time (PT)-activity in patients with COVID-19 5 . The increase in D-dimer is particularly marked in severe patients and can be used in patient triaging and disease monitoring. Sars-Cov2 infection in severe forms triggers a vicious cycle that includes hypercoagulability, endothelial cell activation, and massive release of inflammatory mediators 6 ( Figure 1 ). All this leads to an increased incidence of pulmonary and systemic thrombotic phenomena. A large series of autopsies documented an incidence of venous thromboembolism of 42.5% and pulmonary embolism of 21% 7 . Among the most feared systemic complications of Sars-Cov2 infection is disseminated intravascular coagulation (DIC), primarily characterized by thrombotic phenomena, with a lower incidence of bleeding and thrombocytopenia than other viral infections. Autopsies also revealed thrombotic microangiopathy observed in the lungs, termed 'pulmonary intravascular coagulopathy' (PIC) 7 . In severe COVID-19 the "cytokine storm" is associated with abnormal coagulation parameters. Interestingly, it has been noticed that in COVID-19 patients, higher IL-6 blood levels are directly related to fibrinogen levels predisposing to a hypercoagulable state and thromboembolic events 8 . COVID-19 associated hypercoagulability can essentially be grouped into two main clinical manifestations: venous thrombotic events and arterial thrombotic events (ATE) (Figure 2 ).

A major cause of morbidity and mortality in COVID-19 patients is thromboinflammation (the coordinated activation of thrombosis and inflammation). Laboratory tests revealed in a great percentage of patients hospitalized with COVID-19 the evidence of a coagulopathy resembling disseminated intravascular coagulation (DIC) with marked elevated levels of D-Dimers in the plasma, a mild prolongation of the prothrombin time (PT), and borderline thrombocytopenia 9 . The postmortem examinations of COVID-19 patients showed extensive endothelial injury and diffuse microthrombosis [10] [11] [12] . However, the etiology of COVID-19-associated coagulopathy is still J o u r n a l P r e -p r o o f controversial and is likely to be heterogeneous, involving many different cell types. Indeed, observational studies and case series showed that not all the COVID-19 patients admitted to the ICU fulfilled the ISTH criteria for DIC (elevation of D-Dimer levels, moderate-to-severe thrombocytopenia, prolongation of PT time and decreased fibrinogen levels). Goshua G. et al. observed that in a cohort of critically ill patients with COVID-19 the platelet counts were typically normal or mildly elevated and fibrinogen levels were markedly increased: findings that are inconsistent with coagulopathy of consumption such as DIC 13 . The global interpretation from these diverse reports is that although COVID-19-associated coagulopathy has some shared pathophysiological features with DIC, the coagulopathy observed in patients with COVID-19 can be considered as a distinct entity. In COVID-19, the variable state of hypercoagulability depends both on the type of cell involvement (e.g. endothelial cells, platelets, and leukocytes) and the time of sample collection during the disease process. In patients with severe COVID-19 elevated levels of inflammatory markers (such as C-reactive protein, ferritin, erythrocyte sedimentation rate, and cytokines, including IL-1β, IL-6, and TNF) lead to a hyperinflammatory response known as "cytokine storm", which is associated with poor outcomes. Jose R. et al. showed the correlation between elevated circulating levels of inflammatory cytokines and abnormal coagulation parameters 14 . The IL-6 levels have been shown to correlate directly with fibrinogen levels in patients with COVID- 19 8 as well as the levels of prothrombotic acute phase reactants (fibrinogen, vWF, and factor VIII) are increased in patients with COVID-19 compared with healthy individuals 15, 16 . In a recent review, Sean X. Gu et al. identified platelets and endothelial cells as the two main cell types whose dysfunction contributes to the inflammation and coagulopathy associated with COVID-19, leading to thrombosis and eventually death 17 . In the context of cardiovascular risk factors (diabetes mellitus, obesity, aging, smoking), the mechanism of thrombocytopathy and endotheliopathy has been well represented. These findings are in line with the evidence that COVID-19 patients with cardiovascular risk factors have a high incidence of vascular complications (such as venous thromboembolism, arterial thrombosis, and thrombotic microangiopathy), which contribute to the high mortality [18] [19] [20] .

Contrary to what was thought in the past regarding their limited functions, platelets interact with many other cell types, including circulating blood cells and endothelial cells, either directly or through the release of signaling molecules, thus functioning as a blood component that bridges the immune system (through interactions with various leukocytes) and thrombosis (via platelet activation and release of hemostatic and inflammatory mediators) 21 22 . Activated platelets express on their surface some molecules involved in the stimulation of the immune system (such as P-selectin and CD40L).

Moreover, activated platelets can release αgranules, complement C3, and various cytokines (CCL2, IL-1β, IL-7, IL-8) thus triggering the immune system activation camp 23, 24 . Another cause of platelets hyperactivation is hypoxia 25 , a condition widely documented in COVID-19 patients who develop mild to severe hypoxia with peripheral blood oxygen desaturation. Additionally, platelets dysfunction could be associated with a direct viral infection. ACE2, the cell-entry receptor for SARS-CoV-2, is expressed in the respiratory epithelium and endothelial cells 26 , but SARS-CoV-2 RNA traces were detected in platelet 22 . Other potential methods of SARS-CoV-2 entry into platelets independent of ACE2 are emerging 27 . At last, a potential mechanism for platelet hyperactivation and thrombocytopenia consists in the formation of immune-complexes similar to that seen in heparin- 30 . It has been well documented that age is the major risk factor for COVID-19 related death. Aging is strictly associated with endothelial dysfunction due to oxidative and nitrosative stress. In aged endothelial cells, the accumulation of reactive oxygen species (ROS) can decrease the availability of nitric oxide (NO), a potent vasodilator with antiplatelet properties and cardioprotective effects 31 . One of the most important functions of the vascular endothelium is to maintain a balance between pro-inflammatory and anti-inflammatory factors. In the elderly the simultaneous invasion of the endothelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-converting enzyme 2 (ACE2) receptor can exacerbate endothelial dysfunction and damage, further promoting vascular inflammation and thrombosis.

A high incidence of thrombotic events, particularly deep vein thrombosis (DVT) and pulmonary embolism (PE), has been documented in COVID-19 patients. As described in many studies, elevated J o u r n a l P r e -p r o o f D-Dimer level is a common finding in COVID-19 patients. Anyway, high D-Dimer levels meet low specificity in the absence of overt venous thromboembolism (VTE) clinical manifestations. Then, it is essential to recognize some "red flags" that can increase VTE suspicion in COVID-19 patients. The occurrence of typical DVT symptoms (asymmetric limb pain or edema), the increasing supplemental oxygen requirement, and hemodynamic instability in the setting of imaging findings inconsistent with worsening COVID-19 pneumonia or the onset of acute unexplained right ventricular dysfunction can be considered clinical manifestations of VTE 32 . Several scoring risk systems have been developed to help the clinician in the identification of VTE (Table 1 ). The most used are the Padua prediction score (including factors such as previous VTE, active cancer, reduced mobility, known thrombophilic condition, recent trauma or surgery, age ≥ 70 years, respiratory/cardiac failure, acute myocardial infarction/stroke, acute infection, obesity, and ongoing hormonal treatment; < 4: low risk of VTE; ≥ 4: high risk of VTE), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score (seven risk factors: active cancer, previous VTE, thrombophilia, lower limb paralysis, immobilization < 7 days, intensive care unit/coronary care unit stay, age > 60 years; more than one positive factor increases the risk of symptomatic VTE to 7.2%) and the Wells' score (clinical signs/symptoms of DVT, PE most likely diagnosis, tachycardia (>100 bpm), immobilization/surgery in previous four weeks, prior DVT/PE, hemoptysis, active malignancy) 33 . These tools are helpful to identify patients estimated at higher risk for VTE and start prevention with a standard dose of subcutaneous unfractionated heparin (UFH) or low-molecular-weight heparin LMWH the published guidelines.

The most consistent hemostatic abnormalities with COVID-19 include, as mentioned before, increased D-dimer levels 34 . A prospective study comparing coagulation parameter disorders among patients with COVID-19 and healthy controls suggested that the D-dimer levels (10.36 vs 0.26 ng/L; p < 0.001), fibrin/fibrinogen degradation products (33.83 vs 1.55 mg/L; p < 0.001), and fibrinogen (5.02 vs 2.90 g/L; p < 0.001) in all SARS-CoV-2 cases were substantially higher than those in healthy controls. Moreover, these biomarkers, especially d-dimer and fibrinogen degradation products, were higher in patients with severe SARS-CoV-2 infection than those with mild disease 5 . Another common finding is mild thrombocytopenia. A meta-analysis showed that patients with severe disease were found to have a significantly lower platelet count (mean difference: − 31 × 109/L, 95% confidence interval − 35 to − 29 × 109/L), and thrombocytopenia was associated with a five-fold higher odds of having the severe disease (odds ratio: 5.13; 95% confidence interval 1. 81-14.58) 35 .

Other hemostatic abnormalities variably associated with COVID-19 severity are the prolongation of the prothrombin time (PT), international normalized ratio (INR) 13,14, and thrombin time (TT) 38 . A J o u r n a l P r e -p r o o f trend toward shortened activated partial thromboplastin time (aPTT) is variably associated with the disease severity 37,39 . Tang et al. 40 assessed 183 patients with COVID-19, 21 (11.5%) of whom died.

The patients who died showed increased levels of D-dimer and fibrin degradation products (w3.5and w1.9-fold, respectively) and PT prolongation (by 14%) (p < 0.001) when compared with survivors. Among the patients who died, 71% fulfilled the International Society on Thrombosis and Haemostasis (ISTH) criteria 41 for Disseminated Intravascular Coagulation (DIC), compared with only 0.6% among survivors. Taken all together, these hemostatic abnormalities indicate some forms of coagulopathy that may predispose to thrombotic events. However, the underlying mechanism leading to the clinical manifestations of VTE is still unknown.

Nevertheless, it is uncertain whether these hemostatic changes are a specific effect of SARS-CoV-2 infection or are a consequence of the cytokine storm that precipitates the onset of Systemic inflammatory response syndrome (SIRS) as documented in other severe viral diseases 42, 43 . A recent study reported three cases with severe COVID-19 and cerebral infarction, with one associated with bilateral limb ischemia, in the setting of elevated antiphospholipid antibodies 44 . The presence of antiphospholipid antibodies (e.g., anticardiolipin IgA, anti-β2-glycoprotein I IgA, and IgG) has been described in the serum of COVID-19 patients. This finding may contribute to an increased risk of both venous and arterial thrombosis 45, 46 . However, some studies have highlighted that in setting a high degree of inflammation, like in SIRS, and an increased level of inflammatory markers, those antibodies can be falsely positive 47 . Whether antiphospholipid antibodies play a significant role in the pathophysiology of thrombosis associated with COVID-19 requires further investigation.

To yield a definitive diagnosis of VTE, imaging studies can be helpful. The American Heart Association guidelines on managing massive and submassive pulmonary embolism recommend performing 

The relationship between viral respiratory infections and arterial thrombosis, especially acute coronary syndrome (ACS), is clearly described 53 Cases of ACS have been previously described with influenza or other viral illness. They have been attributed to a combination of SIRS as well as localized vascular or plaque inflammation 54 . During the COVID-19 pandemics, small series of patients with coronary, cerebrovascular, and peripheral arterial thrombotic events have also been reported, but their true incidence and consequences are not well described. In a series of 18 patients with COVID-19 and ST-segment elevation, in more than 50% of them, the origin was considered to be non-coronary 55 . Acute limb ischemia has been reported in two young COVID-19 patients with occlusion of major arteries of the upper and lower limbs 56 . In the systematic review and meta-summary of YK Tan et al., it has been reported that the incidence of acute ischemic stroke in COVID-19 patients ranges from 0.9% to 2.7%. From this meta-summary, it has been observed that acute ischemic stroke severity in COVID-19 patients is typically at least moderate (NIHSS score 19 ± 8), with a high prevalence (40.9%) of large vessel occlusion. Notably, a significant number of cases tested positive for antiphospholipid antibodies. While it is reported that antiphospholipid antibodies are commonly found in COVID-19 infections, the true prevalence of antiphospholipid-antibody positivity in the general population is not known. It has also been detected in healthy individuals. Hence, the significance of antiphospholipid antibodies in the pathogenesis of acute ischemic stroke in COVID-19 patients remains uncertain. It may be worthwhile for future studies to repeat and trend these serological markers after the acute thrombotic setting.

At last, the mortality rate of COVID-19 patients experiencing acute ischemic stroke has been reported high (38.0%) 57 . Recently Cantador et al. observed the 1% incidence of systemic arterial thrombotic events in a large cohort of 1419 COVID-19 patients, with a death rate of 28.6%. In this study, the incidence of thrombotic events, at least for cerebrovascular, seems to be higher than expected with very serious consequences 58 (36) . Hence, it is reasonable to hypothesize that initial measurement of cardiac damage biomarkers immediately after hospitalization for SARS-CoV-2 infection, and longitudinal monitoring during the hospital stay may help identify a subset of patients with possible cardiac injury and thereby predict the progression of COVID-19 towards a worse clinical picture 59 . However, not all such events are due to thrombotic ACS. These data, taken all together, suggest that, although COVID-19 may favor the J o u r n a l P r e -p r o o f occurrence of thrombotic events, the destabilization and thrombosis of atherosclerotic plaques do not seem to be a frequent mechanism that warrants the need for specific systematic preventive measures. Nevertheless, a high level of suspicion and clinical surveillance should undoubtedly be maintained.

Coagulopathy associated with Sars-Cov2 infection has peculiar characteristics compared with that associated with conventional sepsis, as evidenced by the difference in coagulation parameters described above. This is confirmed by the evidence of reduced mortality in patients with COVID19 and elevated D-dimer undergoing anticoagulation than non-COVID19 patients 60 .

COVID19 disease is associated with a higher incidence of thrombotic than hemorrhagic complications, which is the rationale for pharmacological schemes targeting the coagulation pathway.

In the early stages of the pandemic, the absence of randomized clinical trials (RCT) forced physicians to take an empirical approach to the use of anticoagulant regimens. Early evidence of different clinical pictures and numerous variables characterizing COVID disease19 led to the realization that the "one-size-fits-all" strategy was not feasible.

To date, more than 75 RCT testing anticoagulant regimens in different clinical settings have been designed 61 .

The choice of drug and dosage in RCTs depends on the expected rate of thrombotic events in the study population: the use of prophylactic or intermediate doses has been preferred in trials of patients with mild COVID 19, whereas patients with critical illness or requiring intensive care have been treated with higherdose regimens.

Given the higher incidence of thrombosis in venous versus arterial districts 49, 62 , clinical trials have tested more pharmacological regimens to prevent and treat VTE. The use of such strategies in different types of patients will be discussed below.

The main approaches used in RCTs for the prevention and treatment of thrombotic complications of COVID19 include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, direct oral anticoagulants (DOACs), antiplatelet drugs, direct parenteral thrombin inhibitors (DTIs), fibrinolytic agents, and drugs less commonly used in clinical practice such as dociparstat, dipyridamole, and nafamostat. The most significant evidence is with heparins and antiplatelet drugs.

Data on head-to-head comparisons between different drugs are lacking, so the choice is often driven by practical considerations.

Their wide use, mainly in the hospital setting, has made heparins the most studied anticoagulant drugs to treat COVID-19 coagulopathy. In addition to its anticoagulant effect, heparin also has anti-inflammatory properties and protective effects on the endothelium 63 .

In prophylactic anticoagulation, once-daily LMWH is preferred over twice-daily subcutaneous UFH administration to reduce healthcare worker exposure. Therapeutic anticoagulation with UHF has the advantage that it can be temporarily discontinued and shows utility, especially in patients who are candidates for invasive procedures. However, frequent blood draws to check that APTT is in the therapeutic range favor LMWH for the reasons already stated. 

Patients with mild COVID-19 generally do not require hospitalization and should maintain home isolation.

There are several ongoing clinical trials on the use of LMWH 61 Numerous clinical trials are ongoing to evaluate the use of different anticoagulant regimens in patients with severe disease. The design of the trials involves the use of more intense anticoagulation. In some studies, the administration of fibrinolytic agents is tested in patients with very severe forms, despite the rather limited sample size.

A complication observed in patients with severe forms of COVID19 is disseminated intravascular coagulation (DIC). Traditionally, DIC is characterized by thrombotic and hemorrhagic complications, whereas in the specific setting of Sars-Cov2 disease, the former is more frequent than the latter. In patients with COVID-19

and DIC, prophylactic anticoagulation should be administered in the absence of overt bleeding. There is a tendency to recommend a less intense anticoagulation regimen in these patients; however, the individual risk of VTE and significant bleeding must be weighed.

Some trials in acutely ill medical patients have shown that the extension of anticoagulation therapy after discharge is associated with reducing thromboembolic events at the cost of increased bleeding 69 . Given the particular tendency to hypercoagulability of patients with COVID19, some trials evaluate the use of different pharmacological regimens, including DOACs 7071 .

Arterial complications of Sars-Co2 infection have received less attention due to their lower incidence compared to their venous counterparts 6249 . A report from the New York City area shows that 57% of arterial thromboses in patients with COVID19 (upper-and lower limb ischemia, bowel ischemia, and cerebral ischemia) were treated with systemic anticoagulant therapy alone, 6% with administration of systemic tissueplasminogen activator, 27% with revascularization and 10% with amputation 72 .

Patients with acute coronary thrombosis and concomitant Sars-Cov2 infection have a higher thrombotic burden and a worse prognosis 73 . Hospital admissions for STEMI were reduced during the pandemic, with a more extended treatment delay and hospitalization 74 . The treatment of patients with STEMI and established or suspected COVID-19 raised essential questions. The proposal to increase thrombolysis to protect healthcare workers 75 was not adopted by the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Primary PCI was confirmed as the gold-standard therapy for STEMI, while thrombolysis can be helpful when the catheterization laboratory is not available or timely primary PCI cannot be achieved 76 .

For patients with COVID19 and ischemic stroke, the use of thrombolysis and thrombectomy should be continued. There are some difficulties in managing neurological rehabilitation, mostly related to organizational issues and risk of infection 77 .

Acute limb Thrombosis Associated with COVID-19 is characterized by greater clot burden and increased rate of amputation and death 78 . As for myocardial infarction and ischemic stroke, treatment involves prompt intervention, characterized first by therapeutic anticoagulation, preferably with UFH, and then by an assessment based on the stability and viability of the limb on the most appropriate approach.

A turning point in the fight against COVID-19 has been the development of vaccines, whose efficacy, especially against severe forms of the disease, and safety profile has led to a rapid "conditional marketing authorization" by the main regulatory agencies 79 .

Abnormal activation of the coagulation system has been implicated in the pathogenesis of some severe adverse reactions related to the administration of anti-COVID19 vaccines. After the marketing authorization, there have been increasing reports, albeit rare, of thrombotic complications at unusual sites, associated with thrombocytopenia, arising mainly following the administration of viral vector vaccines (Vaxzevria by AstraZeneca AB and COVID-19 Vaccine Janssen by Janssen-Cilag International NV). The incidence of this complication, named Vaccine-associated Immune Thrombosis and Thrombocytopenia (VITT) syndrome, remains largely unknown and appears to be between 1 in 125,000 and 1 in 1000000 80 .

In April 2021, the New England Journal of Medicine reports a total of 39 cases of thrombosis, observed after administration of the Vaxzevria vaccine, in different descriptive studies [81] [82] [83] . Clinical manifestations appear between 5 and 24 days after the first administration of the AstraZeneca serum. The affected population is predominantly female with an age of less than 50 years. In some cases (25.9%), affected women were using oral contraceptives. In most cases, thrombosis involved cerebral veins, although cases of involvement of the splanchnic venous district and pulmonary embolism have been described. Of note, severe thrombocytopenia (platelet count <25000/mm3) was present in 52.6% of the cases evaluated. The concomitance of thrombocytopenia and thrombosis suggested an autoimmune mechanism in the pathogenesis of the syndrome.

A German group led by Andreas Greinacher shed light on the pathogenesis of VITT, highlighting its similarities to the condition known as Heparin-induced thrombocytopenia (HIT) 84 . HIT is due to the formation of autoantibodies directed against a complex epitope formed by platelet-derived factor 4 (PF4) and heparin or another polyanionic molecule. These autoantibodies can bind the FcγIIa receptor (FcRγIIa) present at the platelet surface causing intense intravascular platelet activation and aggregation 85 . They have also been found in VITT, even in the absence of previous heparin exposure 81 . The cause of the formation of these antibodies in patients with VITT is unclear.

Cases of platelet count reduction associated with bleeding in the absence of thrombotic phenomena have been is a causal link between this condition and the vaccine, an autoimmune-type mechanism has been hypothesized here too 86 .

Coagulopathy is common in acute sepsis. However, hypercoagulability associated with Sars-Cov2 infection has peculiar features.

COVID19 is associated with a high rate of thrombotic complications, mainly in the venous district. The  The diagnosis of thrombotic complications such as DVT or PE cannot be derived solely from laboratory parameters but needs to be correlated with symptoms and must be supported by imaging methods such as CT angiography or ultrasound. Some scoring systems can be useful (Table 1)  Current recommendations do not indicate antithrombotic prophylaxis in all COVID-19 patients. However, in subjects at high risk of VTE (immobility, procoagulative status, previous VTE), antithrombotic prophylaxis should be considered. 

COVID-19 and Cardiovascular Disease

Potential Effects of Coronaviruses on the Cardiovascular System: A Review. 2020; JAMA Cardiol

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic

Coagulopathy in COVID-19

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

Scientific Reviewer Committee. Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19

Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive

The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome

Clinical Characteristics of Coronavirus Disease 2019 in China

Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study

COVID-19 cytokine storm: the interplay between inflammation and coagulation

Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis

Severe COVID-19 infection associated with endothelial activation

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in

Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19)

Platelets and Immunity: Going Viral

Platelet gene expression and function in patients with COVID-19

Platelet Granule Exocytosis: A Comparison with Chromaffin Cells. Front Endocrinol

The Non-Hemostatic Aspects of Transfused Platelets

Altered expression of platelet proteins and calpain activity mediate hypoxiainduced prothrombotic phenotype

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

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Circulating markers of angiogenesis and endotheliopathy in COVID-19

Evidence of systemic endothelial injury and microthrombosis in hospitalized COVID-19 patients at different stages of the disease

Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part II: The Aging Heart in Health: Links to Heart Disease

Lip GYH. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up

Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic

D-dimer is Associated with Severity of Coronavirus Disease 2019: A Pooled Analysis

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis

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

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

Shortened activated partial thromboplastin time: causes and management

Abnormal coagulation parameters are associated with poor prognosis J o u r n a l P r e -p r o o f in patients with novel coronavirus pneumonia

Guidelines for the diagnosis and management of disseminated intravascular coagulation

Zika and Chikungunya Virus and Risk for Venous Thromboembolism

Haemostatic Changes in Five Patients Infected with Ebola Virus

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Role of Infectious Diseases in the Antiphospholipid Syndrome (Including Its Catastrophic Variant)

Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis

Antiphospholipid antibodies and multiple organ failure in critically ill cancer patients

Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the

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

Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected with Pulmonary CT Angiography

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

Hospitalist-Operated Compression Ultrasonography: a Point-of-Care Ultrasound Study (HOCUS-POCUS)

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection

Role of acute infection in triggering acute coronary syndromes

Elevation in Patients with Covid-19 -A Case Series

Acute limb ischaemia in two young, nonatherosclerotic patients with COVID-19

COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature

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

Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis

Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2

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

Arterial Thrombotic Events in Adult Inpatients With COVID-19

More than an anticoagulant: Do heparins have direct antiinflammatory effects?

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Coagulation and anticoagulation in COVID-19

Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19

Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID)

Broadening the Categories of Patients Eligible for Extended Venous Thromboembolism Treatment

Acute Arterial Thromboembolism in Patients with COVID-19 in the

High Thrombus Burden in Patients With COVID

Presenting With ST-Segment Elevation Myocardial Infarction

How to balance acute myocardial infarction and COVID-19: the protocols from Sichuan Provincial People's Hospital

EAPCI Position Statement on Invasive Management of Acute Coronary Syndromes during the COVID-19 pandemic

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review

Lower-extremity Arterial Thrombosis Associated with COVID

Is Characterized by Greater Thrombus Burden and Increased Rate of Amputation and Death

COVID-19 vaccine-associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination

Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca COVID-19 Vaccination: Guidance Statement from the GTH

Heparin induced thrombocytopenia

Thrombocytopenia following Pfizer and Moderna SARS-COV -2 vaccination

Coronavirus Disease 2019-Associated Thrombosis and Coagulopathy: Review of the Pathophysiological Characteristics and Implications for Antithrombotic Management

Items Score Active Cancer (metastases and/or chemoradiotherapy in the previous 6 months) 3 Previous VTE (with the exclusion of superficial vein thrombosis) 3Bedrest for ≥ 3 days 3