COVID-19-associated coagulopathy: An exploration of mechanisms

Abstract

An ongoing global pandemic of viral pneumonia (coronavirus disease [COVID-19]), due to the virus SARS-CoV-2, has infected millions of people and remains a threat to many more. Most critically ill patients have respiratory failure and there is an international effort to understand mechanisms and predictors of disease severity. Coagulopathy, characterized by elevations in D-dimer and fibrin(ogen) degradation products (FDPs), is associated with critical illness and mortality in patients with COVID-19. Furthermore, increasing reports of microvascular and macrovascular thrombi suggest that hemostatic imbalances may contribute to the pathophysiology of SARS-CoV-2 infection. We review the laboratory and clinical findings of patients with COVID-19-associated coagulopathy, and prior studies of hemostasis in other viral infections and acute respiratory distress syndrome. We hypothesize that an imbalance between coagulation and inflammation may result in a hypercoagulable state. Although thrombosis initiated by the innate immune system is hypothesized to limit SARS-CoV-2 dissemination, aberrant activation of this system can cause endothelial injury resulting in loss of thromboprotective mechanisms, excess thrombin generation, and dysregulation of fibrinolysis and thrombosis. The role various components including neutrophils, neutrophil extracellular traps, activated platelets, microparticles, clotting factors, inflammatory cytokines, and complement play in this process remains an area of active investigation and ongoing clinical trials target these different pathways in COVID-19.

Keywords: COVID-19; anticoagulation; antiplatelet; inflammation; neutrophils; thrombosis; vascular endothelium; venous thromboembolism (VTE).

Figure 1.

Immune activation and mechanisms of coagulopathy in patients with coronavirus disease 2019 (COVID-19). Multiple processes may contribute to COVID-19-associated coagulopathy including direct infection of type II pneumocytes and endothelial cells, leading to barrier dysfunction and increased permeability; inflammatory responses characterized by activation of T cells, neutrophils, monocytes, macrophages, and platelets resulting in exuberant inflammatory cytokine release (including IL-1, IL-6, IL-10, TNF-α), monocyte-derived TF and PAI-1 expression; and culminating in the development of microvascular and macrovascular thrombi composed of fibrin, NETs, and platelets. IL, interleukin; NETs, neutrophil extracellular traps; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; TNF-α, tumor necrosis factor-alpha.