key: cord-0705009-ec8g19nq
authors: Spyropoulos, Alex C.
title: The management of venous thromboembolism in hospitalized patients with COVID-19
date: 2020-08-25
journal: Blood Adv
DOI: 10.1182/bloodadvances.2020002496
sha: 8d10f9a849976305576e182d21fa38d9ec4e8e58
doc_id: 705009
cord_uid: ec8g19nq

The high incidence of thromboembolic disease, and in particular venous thromboembolism (VTE), has emerged as an important consideration in hospitalized and critically ill patients with coronavirus disease 2019 (COVID-19). The coagulopathy of COVID-19 is postulated to result from interactions of the inflammatory and immune systems with the coagulation system, manifesting as a cytokine storm associated with hyperinflammation and coagulation and platelet activation. Unique characteristics of VTE in hospitalized and critically ill patients with COVID-19 include the high incidence of VTE (and especially pulmonary embolism) when compared with historical controls; the finding of in situ pulmonary embolism associated with microthrombi, which suggests a thrombotic microangiopathic process in addition to classic macrovessel disease; and, most important from a clinical perspective, the unusually high rate of VTE that has been reported despite standard thromboprophylaxis. This raises the possibility that intermediate or weight-based heparin dosing may be more effective than fixed dosing for thromboprophylaxis in high-risk subsets of patients hospitalized with COVID-19. There have been several guidance statements focusing on the management of VTE in hospitalized and critically ill patients with COVID-19, including the most recent statement by the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis, which includes comprehensive guidance on the diagnosis, prevention, and treatment of VTE in this patient population. Ongoing randomized trials that address key clinical questions, especially more intense thromboprophylactic strategies and novel antithrombotic approaches, have the potential to reduce the morbidity and mortality from VTE in hospitalized and critically ill patients with COVID-19.

The high incidence of thromboembolic disease, and in particular venous thromboembolism (VTE), has emerged as an important consideration in hospitalized and critically-ill patients with coronavirus disease 2019 . The coagulopathy of COVID-19 is postulated to result from interactions of the inflammatory and immune systems with the coagulation system, manifesting as a cytokine storm associated with hyperinflammation and coagulation and platelet activation. Unique characteristics of VTE in hospitalized and critically ill COVID-19 patients include the high incidence of VTE (and especially pulmonary embolism) when compared to historical controls, the finding of in situ pulmonary embolism associated with microthrombi that suggest a thrombotic microangiopathc process in addition to classic macrovessel disease, and most importantly from a clinical perspective, the unusually high rate of VTE that has been reported despite standard thromboprophylaxis. This raises the possibility that intermediate or weight-based heparin dosing may be more effective than fixed dosing for thromboprophylaxis in high-risk subsets of hospitalized COVID-19 patients. There have been a number of guidance statements focusing on the management of VTE in hospitalized and critically-ill patients with COVID-19, including the most recent statement by the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis that includes comprehensive guidance on the diagnosis, prevention and treatment of VTE in this patient population. Ongoing randomized trials that address key clinical questions, especially more intense thromboprophylactic strategies, and novel antithrombotic approaches, have potential to reduce the morbidity and mortality from VTE in hospitalized and critically ill COVID-19 patients.

An important consideration that has emerged in the management of hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is the development of thromboembolic disease, and in particular venous thromboembolism (VTE). 1 COVID-19 is associated with a coagulopathy characterized by mild thrombocytopenia (platelet counts 100,000 -150,000 x 10 9 per liter), elevated levels of D-dimer (> 6 times the upper limit of normal [ULN]), high levels of fibrinogen and factor VIII, and slight prolongation of the prothrombin time (~3.0 seconds). 5, 6 It is postulated that either the SARS-CoV2 infection itself or the cytokine storm produced by hyperinflammation and resulting platelet activation induces a prothrombotic state, and these markers of inflammation and coagulopathy have been associated with morbidity and increased mortality in hospitalized COVID-19 patients. [5] [6] [7] This hypercoagulable state may explain the high rate of VTE reported in COVID-19 patients despite anticoagulant thromboprophylaxis, as well as high rates of arterial thromboembolic events such as myocardial infarction, ischemic stroke, and peripheral arterial embolism. 2, 6, 8 

There are key unique characteristics of VTE in hospitalized and especially critically-ill patients with COVID-19 disease. First, the frequent finding of very elevated D-dimers (> 6 times ULN) in hospitalized COVID-19 patients may prompt an aggressive diagnostic and treatment approach without objectively-verified VTE events, despite the controversy that an elevated D-dimer may not be a reliable predictor of VTE in this population but rather a marker of the cytokine storm seen in patients with severe disease associated with a poor outcome. 9 Second, the rates of VTE described by multiple cohort studies are anywhere from two to ten-fold higher in those with COVID-19 than in those without the disease using similar cohorts, including critically-ill patients with acute respiratory distress syndrome. 10, 11 This is particularly impressive for the high rates of PE seen in critically-ill COVID-19 patients, where there may be less bias from systematic screening and ascertainment of more clinically important events compared with results found by screening ultrasonography for lower extremity DVT. Third, an in situ mechanism for PE in critically-ill COVID-19 patients (in addition to classical thromboembolic mechanisms) has been proposed based on autopsy reports which found an unusually high degree of microthrombi in the lung arteries, suggesting a thrombotic microangiopathic process. [12] [13] [14] Fourth, although COVID-19 specific data is lacking, high quality data has shown that the risk of hospital-associated VTE extends for up to 6 weeks post-hospital discharge in high VTE risk medically ill patients, including those with pneumonia, sepsis, and any condition requiring management in an ICU setting. 15 In selected populations at high VTE risk and low bleed risk, based on key risk factors (including elevated D-dimers) or risk models for thrombosis and bleeding, extendedduration thromboprophylaxis for approximately 4 weeks with a direct oral anticoagulant (DOAC) (e.g. rivaroxaban, betrixaban) provides a net clinic benefit by reducing VTE risk without incurring a significant increase in the risk of major bleeding. 16 c) The duration of treatment should be at least 3 months.

COVID-19 is emerging as a highly contagious disease that has coagulopathic manifestations in hospitalized and critically ill patients that appear to have unique characteristics mediated by immune-dependent, cytokine-dependent, and coagulationdependent processes, leading to a heightened thrombotic state. There is an urgent need for high quality data, especially from large outcome studies and prospective registries that include both the hospital and immediate post-hospital discharge period using a coordinated effort by hospitals, healthcare funding agencies, professional societies, and organizations dedicated to thrombotic disorders. There are ongoing randomized trials that address key clinical questions, especially whether more intense thromboprophylactic strategies improve morbidity and mortality in hospitalized COVID-19 patients and the effect of anticoagulation on outcomes in critically ill COVID-19 patients. Lastly, there is a need for novel antithrombotic approaches, including the role of immunomodulatory agents, contact pathway inhibitors, hemostatic modulators, and dual pathway inhibition with anticoagulant/antiplatelet therapy, in the management of COVID-19 associated coagulopathy. 5 The insights from these studies will be essential in understanding the pathogenesis of immonothrombosis and the management of VTE in hospitalized and critically ill patients with COVID-19 disease.

Alex C. Spyropouloscontributed to the concept, analysis/interpretation of data, critical writing and revising intellectual content

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