COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year

Abstract

COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.

Figure

Clinical and pathophysiological staging in COVID-19 (A) A good immune response will adequately control viral replication, resulting in mild symptoms in around 80% of infections. (B) Poorly controlled viral replication leads to apoptosis of pneumocytes and endothelial cells, which will activate platelets, induce coagulation factors such as TF, and release VWF multimers, and will lead to increased chemotaxis, cytokine and chemokine production, NET formation, and activation of the plasma kinin-kallikrein and complement system. Hypoxia contributes to the hypercoagulable state by increased expression of TF and PAI-1, decreased TF pathway inhibitor and protein S, and an increased inflammatory response and platelet activation. Further destruction of pneumocytes, pulmonary microangiopathy, and microthrombi cause more severe symptoms and need for additional oxygen supply. (C) The so-called cytokine storm fuels proinflammatory and procoagulatory processes further, resulting in systemic endotheliitis and capillary leakage, cellular dysfunction, organ dysfunction, and overt activation of the coagulation cascade, and leads to the need for organ support and a high prevalence of microthrombi and macrothrombi. (D) The timeframe of resolution of local inflammation and coagulation after discharge are still unknown. IL=interleukin. NETs=neutrophil extracellular traps. PAI-1=plasminogen activator inhibitor-1. PEEP=positive end-exploratory pressure. TF=tissue factor. TGF-β=transforming growth factor beta. ULN=upper limit of normal. VWF=von Willebrand factor.