key: cord-0766038-j3v3i8vm
authors: Marietta, Marco; Coluccio, Valeria; Luppi, Mario
title: COVID-19, coagulopathy and venous thromboembolism: more questions than answers
date: 2020-07-11
journal: Intern Emerg Med
DOI: 10.1007/s11739-020-02432-x
sha: 7ca975b66b9adddfe485f6d95a1eb38af0ded8b6
doc_id: 766038
cord_uid: j3v3i8vm

The acute respiratory illnesses caused by severe acquired respiratory syndrome corona Virus-2 (SARS-CoV-2) is a global health emergency, involving more than 8.6 million people worldwide with more than 450,000 deaths. Among the clinical manifestations of COVID-19, the disease that results from SARS-CoV-2 infection in humans, a prominent feature is a pro-thrombotic derangement of the hemostatic system, possibly representing a peculiar clinicopathologic manifestation of viral sepsis. The severity of the derangement of coagulation parameters in COVID-19 patients has been associated with a poor prognosis, and the use of low molecular weight heparin (LMWH) at doses registered for prevention of venous thromboembolism (VTE) has been endorsed by the World Health Organization and by Several Scientific societies. However, some relevant issues on the relationships between COVID-19, coagulopathy and VTE have yet to be fully elucidated. This review is particularly focused on four clinical questions: What is the incidence of VTE in COVID-19 patients? How do we frame the COVID-19 associated coagulopathy? Which role, if any, do antiphospolipid antibodies have? How do we tackle COVID-19 coagulopathy? In the complex scenario of an overwhelming pandemic, most everyday clinical decisions have to be taken without delay, although not yet supported by a sound scientific evidence. This review discusses the most recent findings of basic and clinical research about the COVID-associated coagulopathy, to foster a more thorough knowledge of the mechanisms underlying this compelling disease.

In December 2019, a cluster of acute respiratory illnesses caused by severe acquired respiratory syndrome corona virus-2 (SARS-CoV-2) virus occurred in Wuhan, Hubei Province, China. The disease has rapidly spread from Wuhan to many other countries, soon becoming a global health emergency. Indeed, at the time of this writing, more than 8.6 million cases of COVID19 have been reported worldwide with more than 450,000 deaths [1] .

Although most patients have mild manifestations and good prognosis after infection, some of them develop severe symptoms and die from multiple organ complications [2] [3] [4] . The pathogenesis of COVID-19, the disease that results from SARS-CoV-2 infection in humans, remains unclear, but it is very likely that the most severe manifestations of this disease may be linked to host-pathogen interaction immune mechanisms [5, 6] . In critically ill COVID-19 patients, indeed, massive cytokine storms (including IL-6, TNF-α, and other inflammatory biomarkers), as well as increments of circulating neutrophils and monocyte activation, are typically observed together with low T lymphocyte counts and functional exhaustion of effector T cell responses [5, 6] . Such ineffective and detrimental expansions of innate/ humoral responses, alongside T cell suppression, are reminiscent of classical features of sepsis, which is currently defined as a life-threatening organ dysfunction induced by dysregulated host response to infection, being characterized not only by systemic inflammatory response syndrome (SIRS) with related endothelial and organ damage, but also by impairment of adaptive T cell immunity [5, 6] . Moreover, the derangement of the hemostatic system observed in end-stage COVID-19 could well fit with the idea that severe COVID-19 possibly represents a peculiar clinicopathologic form of viral sepsis, displaying a prominent prothrombotic feature instead of the hemorrhagic one observed in other viral diseases, such as Lassa, Marburg and Ebola hemorrhagic fevers [7] .

From a clinical perspective, the extent of the derangement of coagulation parameters in patients affected by severe COVID-19 pneumonia has been found to be associated with a poor prognosis [8, 9] . In these patients, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) at doses registered for prevention of venous thromboembolism (VTE) seemed to be associated with a lower risk of death [10] and is currently recommended by the World Health Organization [11] and by several scientific societies [12] [13] [14] [15] [16] [17] [18] (Table 1) .

However, some relevant issues on the relationships between COVID-19, coagulopathy and VTE have yet to be fully elucidated.

Data on this issue are puzzling, as the reported incidence of VTE in COVID-19 patients ranges from 0% to about 8% in general wards [19] [20] [21] [22] , and from 16 to 35% in the ICU setting, often despite adequate LMWH prophylaxis [21] [22] [23] [24] [25] [26] [27] [28] .

An even higher rate of VTE, up to 58%, has been reported in consecutive autopsies performed in COVID-19 patients in whom VTE was not suspected before death [29] (Table 2) .

Several reasons may account for this discrepancy: just a few studies systematically screened patients for VTE, and imaging in suspected cases is challenging in the setting of a striking pandemic, with overcrowded hospital wards, given the risk of transmitting infection to other patients or health-care workers and the technical problems in performing investigation for pulmonary embolism (PE) in critically ill patients in prone position.

On this ground, it is conceivable that a non-negligible portion of PE episodes remains undiagnosed, because of these technical constraints. However, deep vein thrombosis (DVT) is rarely found in these patients [24] , raising the question whether the occlusions observed in the pulmonary vascular bed of COVID-19 patients result from embolization of a DVT or from a localized thrombotic microangiopathy [19] .

The question is not trivial, as the pathophysiological mechanism triggering the pulmonary vascular disease in COVID-19 could impact on the treatment. Indeed, whereas high doses of UFH or LMWH are the mainstay of treatment in case of established pulmonary embolism from peripheral vein thrombosis, the same treatment would be ineffective, or even dangerous because of the bleeding risk, in the hypothesis that a thrombotic microangiopathy would be mainly responsible for the pulmonary vascular occlusion observed in COVID-19 patients in the absence of a proven DVT [19] .

On these grounds, a better knowledge of the pathogenesis of COVID-19 coagulopathy is urgently needed to provide more precisely targeted treatments to this disease.

How do we frame the COVID-19-associated coagulopathy, that is, DIC, SIC, CAC or PIC?

Despite a rapidly growing amount of literature on this topic [7, [30] [31] [32] [33] [34] [35] , the pathophysiological mechanisms underlying the derangement of the hemostatic system induced by SARS-Cov2 have not been fully elucidated yet. Indeed, no evidence of an intrinsic procoagulant effect exerted by the SARS-CoV-2 virus is so far available. Therefore, the most reasonable hypothesis is that the virus activates the coagulation cascade by eliciting a large-scale inflammatory response, similar to that observed in other forms of sepsis. Several studies have already demonstrated the tight interconnection between thrombosis and inflammation, two processes mutually reinforcing each other [36, 37] . Both coagulation factors and platelets are directly implicated in the modulation of the host immune response, displaying proinflammatory functions independent of their hemostatic effects [38] [39] [40] . Moreover, the cytokines storm stimulates the expression of tissue factor on monocytes/macrophages and vascular endothelial cells, on whose surfaces the coagulation cascade is initiated. The thrombus formation at the microvascular level contributes to tissue ischemia and organ dysfunction [41] .

A remarkable inflammatory response can be observed in COVID-19 patients, attested by a significant increase in fibrinogen, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) and ferritin levels [42, 43] . Moreover, the increase of IL-6 levels has been found to correlate with that of fibrinogen, confirming the link between inflammation and procoagulant changes [44] .

The hypercoagulable state of COVID-19 patients has been assessed mainly by viscoelastic methods [44] [45] [46] or by an increase in D-dimer levels, whose extent correlates with the risk of death [8, 47, 48] . This finding is not surprising, as increased D-dimer levels have already been demonstrated to be associated with a poorer outcome in other cohorts of septic patients [49] .

However, the exact role of D-Dimer test in the context of COVID-19 coagulopathy deserves some further comments. [15] VTE prophylaxis in severe or critically ill pts. Strongly recommended with LMWH in pts. at low or moderate risk of bleeding and with no contraindication VTE prophylaxis in mild and moderate pts.

Recommended with LMWH in pts. assessed to have a high or moderate risk of VTE (PADUA or IMPROVE RAM), in the absence of contraindication VTE prophylaxis after hospital discharge Consider prolonged outpatient VTE prophylaxis with LMWH in pts with persistent risk factors for VTE VTE treatment

Curative anticoagulant parenteral treatment with LMWH recommended in pts. suspected for VTE, in absence of contraindication ASH [16] VTE prophylaxis in all hospitalized pts. Recommended with LMWH or fondaparinux unless the risk of bleeding is judged to exceed the risk of thrombosis VTE prophylaxis after hospital discharge Consider extended thromboprophylaxis after discharge using a regulatory-approved regimen (DOAC up to 40 days) Anticoagulation Forum [17] VTE prophylaxis in non-critically ill hospitalized pts.

Recommended with LMWH standard doses, regardless of VTE risk assessment score VTE prophylaxis in ICU pts. Recommended with increased doses of heparin (e.g., enoxaparin 40 mg SC BID, enoxaparin 0.5 mg/kg SC BID, UFH 7500 IU SC TID or low-intensity IV VTE prophylaxis after discharge Not routinely recommended; consider on a case-by-case basis CHEST Guidelines [18] VTE prophylaxis in acutely ill hospitalized pts.

Recommended with LMWH or fondaparinux at standard doses over intermediate or full treatment dosing or over DOAC VTE prophylaxis in critically ill hospitalized pts.

Recommended with LMWH of UFH over fondaparinux or DOAC Suggested current standard dose over intermediate or full treatment dosing VTE prophylaxis after hospital discharge Recommended inpatients prophylaxis only over inpatient plus extended prophylaxis after hospital discharge WHO World Health Organization, VTE venous thromboembolism, OD once daily, SC subcutaneously, BID twice daily, TID three times daily, IV intravenously, ISTH International Society on Thrombosis and Hemostasis, pts patients, SISET Italian Society on Thrombosis and Hemostasis, LMWH low molecular weight heparin, UFH unfractionated heparin, CrCl Creatinine clearance, PT prothrombin time, APTT activated partial thromboplastin time, CrCL creatinine clearance, ICU intensive care unit, ASH American Society of Hematology, DOAC direct oral anticoagulants Cattaneo [19] 64 GW pts on LMWH prophylaxis yes 0% DVT Zhang [20] 143 GW pts. (37% on LMWH prophylaxis) yes 16% proximal DVT, 30% distal DVT (one ward) 8.8% DVT (all the hospital) Lodigiani [21] 314 GW pts (75% on LMWH prophylaxis) 48 ICU pts (100% on LMWH prophylaxis) yes GW: PE 2.5%, 1% DVT (including UEDVT), 1.9% stroke ICU: PE 4.2%, 4.1% isolated DVT (including UEDVT), 6.3% stroke Middeldorp [22] 123 GW pts (standard LMWH prophylaxis) 75 ICU pts (doubled LMWH prophylaxis)

Yes (28% GW) GW: PE 6.6%, 13% DVT (including UEDVT) ICU: PE 15%, 32% DVT (including UEDVT) Thomas [23] 63 ICU pts (standard LMWH prophylaxis) no 8% PE, 1.5% DVT (including UEDVT) Klok [24] 184 ICU pts on LMWH prophylaxis no 35% PE, 1.6% DVT (including UEDVT) 3.8% ATE Poissy [25] 107 ICU pts (100% on VTE prophylaxis) no 20.6% PE Cui [26] 81 ICU pts NOT on LMWH prophylaxis yes 25% DVT Llitjos [27] 26 ICU pts (31% LMWH prophylactic, 69% therapeutic) yes 23% PE VTE significantly higher in pts. on prophylactic vs therapeutic anticoagulation (100% vs. 56%) Helms [28] 150 A recent review of nearly 20 papers reporting original data on D-dimer levels in COVID-19 showed some relevant bias, as most publications neither identified whether D-dimer values were reported as D-dimer units (DDU) or fibrinogen equivalent units (FEU) (~ 2 × differences), nor report on normal cutoff values [50] . These methodological flaws greatly reduce the usefulness of this parameter on a clinical decision setting.

Moreover, the reliability of D-dimer test as prognostic factor in septic patients has already been questioned by Semeraro and colleagues in a paper published before the onset of COVID-19 pandemic [51] . The The authors found that the D-dimer levels poorly correlate with the risk of death in a population of septic patients admitted to ICU. On the other hand, they showed that D-dimer corrected for thrombin and plasmin generation (DD corr ) more properly reflects the tilting of coagulation-fibrinolysis balance, displaying a high prognostic value in septic patients [51] . Notably, the authors found the highest mortality in patients with low DD corr levels, which reflect the fibrinolytic shutdown associated with late and more severe phases of sepsis. The mechanisms behind fibrinolysis suppression are multiple and include PAI-1 elevation, TAFI activation, and release of nuclear products such as histones and DNA.

This finding warrants particular attention in the context of COVID-19 coagulopathy, as it has been reported that fibrinolysis shutdown, assessed by elevated D-dimer levels and complete failure of clot lysis at 30 min on thromboelastography, predicts thromboembolic events and need for hemodialysis in critically ill COVID-19 patients [52] . Of note, in this population of 44 COVID-19 admitted to ICU, the median ISTH disseminated intravascular coagulation (DIC) score was 0 (0-2), with no patients having a score higher than 4 [52] .

Consistent with this finding, other reports showed that COVID-19 patients do not typically develop overt systemic DIC, unless in the late stages of the disease, as demonstrated by the consistent observation that platelet count and fibrinogen concentration are not significantly reduced in these subjects, despite a marked increase in D-dimer concentrations [7, 8] .

Moreover, only 21.6% of subjects in a cohort of critically ill COVID-19 patients have been found to meet the criteria for an infection-induced organ dysfunction and coagulopathy according to the sepsis-induced coagulopathy (SIC) score of the International Society on Thrombosis and Haemostasis [7, 53] .

These findings suggest that the linear progression from SIC to DIC usually seen in septic patients does not necessarily occur in the process of SARS-Cov2 infection, which seems to be rather associated with a peculiar form of coagulopathy, termed by some authors as "COVID-19-associated coagulopathy" (CAC) [54] . CAC displays clinical and laboratory features distinct from either DIC or SIC, such as the lack of consumption of platelets and coagulation factors, first of all fibrinogen, the very low incidence of bleeding, and the main involvement of the pulmonary microcirculation, determining a localized microangiopathy, named by other authors as pulmonary intravascular coagulopathy (PIC) [55] . (Table 4 ).

This peculiar involvement of pulmonary microvascular bed during the course of SARS-CoV2 infection fits well with the reported high rate of acute respiratory distress syndrome (ARDS) in COVID-19 patients (about 40% of cases) [9] . Of note, ARDS itself has been identified as a hemostatic disease occurring as a result of endotheliopathy in critically ill patients. Generalized endotheliopathy in turn activates in a vicious circle the inflammatory and microthrombotic pathway, which promotes consumptive thrombocytopenia, TTP-like syndrome, and hypoxic multi-organ failure [56] .

How do we gather these puzzling data on a unified clinicopathological picture, helpful to improve the management of CAC?

1. Although the mechanism underlying CAC has not been fully elucidated, it is conceivable that the major role in its development is played by the activation of the thromboinflammation pathway induced by a "cytokines storm" elicited by SARS-CoV2 infection. 2. As in other forms of sepsis, endothelial dysfunction leading to widespread microthrombosis, mainly localized in the pulmonary vascular bed, is observed in COVID-19 patients. In this regard, it has been demonstrated that SARS-CoV-2 uses angiotensin-converting enzyme (ACE) 2 receptor to facilitate viral entry into target cells [56, 57] . Thye ACE2 system is a critical protective pathway against heart failure, myocardial infarction and hypertension, and against lung disease and diabetes mellitus [58] . In experimental models of lung disease, catalytically active ACE2 alleviates pulmonary injury and vascular damage and prevents pulmonary hypertension, decreases lung fibrosis and arterial remodeling, and improves right ventricular performance [58] . ACE2 is highly expressed on alveolar epithelial type II cells (AECII), which can serve as a reservoir for viral invasion, and also in endothelial cells. SARS-CoV-2 infection can induce endothelial cell injury in several organs, because of direct viral involvement, of the host inflammatory response and of the induction of apoptosis and pyroptosis [59, 60] . COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and the clinical sequelae in patients affected by this disease [61] . 3. Thrombotic microangiopathy, induced by an enhanced platelet-vessel wall interaction, mainly induced by the release of (ultralarge) von Willebrand factor (VWF) mul-timers as a result of inflammation-induced endothelial cell perturbations, is thought to be a major component of the SIC [62] . The level of (ultralarge) VWF multimers in patients with sepsis has been shown to be inversely correlated with the plasma level of ADAMTS-13, and several studies have confirmed the association between low ADAMTS-13 levels and sepsis severity. Of note, very recently Bazzan and colleagues reported significantly reduced ADAMTS-13 levels in a cohort of COVID-19 patients [63] . Moreover, they found that ADAMTS-13 levels lower than 30% were significantly associated with a higher mortality, suggesting that low ADAMTS-13 associated with high plasma VWF levels can have a role in the strong prothrombotic tendency observed in COVID-19 patients [63] .

Taken together, these findings suggest that the pathogenesis of CAC, although multifactorial, is mainly localized at a microvascular level, with a late involvement of venous and arterial vessels. Such a pathophysiological picture raises some questions about the effectiveness of fully antithrombotic doses of anticoagulants to effectively tackle this disease, as later discussed.

Among the coagulation abnormalities found in COVID-19 patients, some reports of positivity for antiphospholipid antibodies (APL) are of particular interest [64] [65] [66] (Table 3) .

However, these findings are worth discussing. The tests for assessing APL are slippery ones, because their results are affected by several pre-, post-and analytical factors, including methodical problems due to the heterogeneity of the autoimmune antibodies, inadequate standardization of assays, differences in local working conditions, difficulties in correct interpretation of the results, lack of large prospective evaluation studies, lack of a link between antibody potency and clinical effect [67] .

Notably, only the paper from Harzallah and colleagues reported the results of lupus anticoagulant (LA), anticardiolipin (aCL) and anti-beta2 glycoprotein I (aGPI) IgG and IgM tests [65] , whereas current guidelines recommend performing all three tests to diagnose antiphospholipid syndrome (APS) [68] .

The same guideline recommends confirming the positivity of APL on two or more occasions, at least 12 weeks apart [68] , but the results of this further control, if performed, are not reported by the authors [64] [65] [66] .

Moreover, the significance of positivity for aCL and aGPI IgA, reported by Zhang and colleagues, is controversial, and the implementation of these assays is not currently recommended [64] .

We should recall that APL positivity has been frequently observed during viral infections, but the association with thrombotic phenomenon on this setting is unclear, depending on the aCL and aGPI titers, especially in hepatitis B and C virus infections [69] . Of note, Bowles and colleagues did not report the results of aCL and aGPI tests [66] , whereas Zhang and Harzallah did not report the titers of these assays [64, 65] .

Moreover, a recently published paper from Galeano-Valle and colleagues found only 2 (8.3%) cases with ACA IgM and aGPI I IgM weakly positive in a cohort of 24 COVID-19 patients with proven VTE [70] .

In conclusion, we believe that there is no convincing evidence that aPL plays a relevant role in the hypercoagulable tendency of COVID-19 patients.

Therefore, we suggest that physicians should be very careful before adopting a more aggressive antithrombotic approach in COVID-19 patients only based on aPL positivity, given the many technical aspects that reduce the usefulness of these tests in such a specific setting.

First reports from the front of Wuhan showed that the use of LMWH or UFH at prophylactic doses reduced 28-day mortality in COVID-19 patients with severe pneumonia and either an SIC score ≥ 4 (mortality rate 40.0% vs 64.2%, p = 0.029), or D-dimer levels > 6-fold the upper limit of normal (mortality rate 32.8% vs 52.4%, p = 0.017) [10] . This finding prompted clinicians to look at the "good old heparin", UFH or LMWH, as the panacea for the treatment of COVID-19, because of its already well-known anticoagulant and anti-inflammatory properties [71, 72] .

Indeed, LMWH has been shown to protect glycocalyx from shedding and to display immunomodulatory properties [73] . Moreover, in vitro and in vivo experimental studies have shown that human coronaviruses utilize heparin sulfate proteoglycans for attachment to target cells [74] , suggesting a potential role for heparin in the therapeutic armamentarium against COVID- 19. Fondaparinux has been also proposed as a treatment for COVID-19 [75] , because of its anti-inflammatory and antiviral properties [76, 77] . Fondaparinux can be an attractive drug in this setting, as it is not associated with heparininduced thrombocytopenia, a fearful side effect of heparin treatment reported in a non-negligible part of COVID-19 patients, which is associated with a worse prognosis [78] .

It is conceivable that doses of LMWH higher than those in use for the prevention of VTE in acutely ill medical patients are able to display a more intense anti-inflammatory activity, lowering cytokines storm and improving the clinical course of the disease.

However, no good evidence is available on the efficacy and safety of high dose of LMWH in COVID-19 patients, and many issues remain to be addressed, regarding the proper timing and the proper dosages and administration schemes of anticoagulant drugs.

The issue of the safety of heparin deserves close attention, as Tang and colleagues found a non-significant trend toward a negative effect of the treatment with LMWH in patients with the less severe degree of coagulopathy, as assessed by an SIC score < 4 or D-dimer levels < 6-fold the upper limit of normal [10] .

As recently pointed out by Landi and De Servi, one-sizefits-all strategy cannot be applied to COVID-19 patients, and an individualized approach carefully balancing thrombotic and hemorrhagic risk should guide the complex management of these patients [79] .

As shown in Table 1 , a puzzling discrepancy exists on the doses of heparin suggested in different clinical settings, and no evidence-based recommendations can be issued.

This lack of knowledge prompted several researchers to design clinical trials, most of which randomized, comparing efficacy and safety of different doses of UFH or LMWH (mainly prophylactic vs therapeutic) in COVID-19 patients (Table 5) .

From a public health's perspective, these trials failed to recruit because of a massive drop of subjects infected by SARS-Cov2.

However, in the worst case scenario of a further outbreak of the pandemic, these already existing protocols could allow to rapidly obtain a stronger evidence about the best 

The COVID-19 pandemic has disrupted many aspects of human life, forcing us to admit that medical knowledge is finite, and that the usual pathway to improve it can be too slow in the devasting scenario of an awfully fast spreading disease.

The CAC reliably illustrates this epistemological problem. The difficult journey toward a better understanding of the coagulation derangement observed in COVID-19 patients has just started, and many questions on this issue still remain unanswered.

It is therefore conceivable that physicians involved in the first-line management of COVID-19 patients are tempted to adopt conceptual shortcuts to rapidly deal with the everyday clinical problems, without waiting for an evidence which is feared to arrive too late for the patients' needs.

On this ground, the scientific community should spare no effort to ensure a faster, but always methodologically sound, process to improve medical knowledge, starting as usual from pathophysiology and cautiously moving toward a stronger evidence provided by properly designed randomized controlled trials.

Perhaps it can be a "long and winding road", but certainly it is worth traveling.

Conflict of interest The Authors declare no potential conflicts of interest.

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent For this type of study, formal consent is not required.

Coronavirus disease (COVID-19) Situation Report-152

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

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

Clinical characteristics of 138 hospitalized patients With 2019 novel coronavirus-infected pneumonia in Wuhan, China

COVID-19: immunopathology and its implications for therapy

Fighting COVID-19 exhausts T cells

Coagulopathy in COVID-19

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

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

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

Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected

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

COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET)

Working party on hemostasis of the Swiss Society of Hematology. Suggestions for thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19

Prevention treatment of VTE associated with COVID-19 Infection Consensus Statement Group. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines

COVID-19 Resources. COVID-19 and VTE/Anticoagulation: frequently asked questions

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST guideline and expert panel report

Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified?

Deep vein thrombosis in hospitalized patients with coronavirus Disease 2019 (COVID-19) in Wuhan, China: prevalence, risk factors, and outcome

Humanitas COVID-19 Task Force (2020) Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Incidence of venous thromboembolism in hospitalized patients with COVID-19

Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom

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

Lille ICU Haemostasis COVID-19 group (2020) Pulmonary Embolism in COVID-19 patients: awareness of an increased prevalence

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients

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

Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study

Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge

COVID-19 update: Covid-19-associated coagulopathy

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up

Understanding the COVID-19 coagulopathy spectrum

COVID-19 and coagulative axis: review of emerging aspects in a novel disease

Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms

Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis

Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions

The coagulation and immune systems are directly linked through the activation of interleukin-1α by thrombin

Coagulation factors VII, IX and X are effective antibacterial proteins against drug-resistant Gramnegative bacteria

Platelets in sepsis: an update on experimental models and clinical data

Tissue factor: an essential mediator of hemostasis and trigger of thrombosis

Clinical and immunologic features in severe and moderate Coronavirus Disease

COVID-19 gone bad: a new character in the spectrum of the hyperferritinemic syndrome?

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

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

COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure

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

D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis

D-dimer is a significant prognostic factor in patients with suspected infection and sepsis

Reporting of D-dimer data in COVID-19: some confusion and potential for misinformation

D-dimer corrected for thrombin and plasmin generation is a strong predictor of mortality in patients with sepsis

Fibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection

Scientific and standardization committee on DIC, and the scientific and standardization committee on perioperative and critical care of the international society on thrombosis and haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation

Levy JH COVID-19 and its implications for thrombosis and anticoagulation

COVID-19 coagulopathy in caucasian patients

Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2

Hyperinflammation and derangement of renin-angiotensinaldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor-and angiotensin II receptor blocker-based cardiovascular therapies

Moch endothelial cell infection and endotheliitis in COVID-19

The role of ADAMTS-13 in the coagulopathy of sepsis

Low ADAMTS 13 plasma levels are predictors of mortality in COVID-19 patients

Coagulopathy and antiphospholipid antibodies in patients with Covid-19

Lupus anticoagulant is frequent in patients with Covid-19

Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19

Antiphospholipid antibody testing and standardization

Subcommittee on lupus anticoagulant/antiphospholipid antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH

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

Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism

The role of heparin in sepsis: much more than just an anticoagulant

The versatile heparin in COVID-19

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS-induced sepsis

Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells

Pulmonary thrombosis in 2019-nCoV pneumonia?

Fondaparinux pentasaccharide reduces sepsis coagulopathy and promotes survival in the baboon model of Escherichia coli sepsis

The 2.8 Å Electron Microscopy Structure of Adeno-Associated Virus-DJ Bound by a Heparinoid Pentasaccharide

Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment

The burden of thrombotic complications in critically ill patients with COVID-19: charting the uncharted

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