Coagulopathy of Coronavirus Disease 2019

Abstract

Objectives: Recent studies have reported a high prevalence of thrombotic events in coronavirus disease 2019. However, the significance of thromboembolic complications has not been widely appreciated. The purpose of this review is to provide current knowledge of this serious problem.

Design: Narrative review.

Data sources: Online search of published medical literature through PubMed using the term "COVID-19," "SARS," "acute respiratory distress syndrome," "coronavirus," "coagulopathy," "thrombus," and "anticoagulants."

Study selection and data extraction: Articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease 2019, and anticoagulant therapy. Reference lists were reviewed to identify additional relevant articles.

Data synthesis: Coronavirus disease 2019 is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration. Monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions. In the initial phase of the infection, D-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal. Increased D-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism. In all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended. The etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system. Although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities.

Conclusions: Severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. D-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations.

Figure 1.

Various types of thrombus formation in coronavirus disease 2019 (COVID-19). Venous thrombosis and pulmonary thromboembolism are common complications in COVID-19. Increased fibrinogen and factor VIII, activated coagulation, direct viral endothelial infection and endothelial injury, and increased platelet-vessel wall interaction activation play roles in the development of thrombotic complications. In addition, there may be pulmonary microvascular coagulation in COVID-19. The prevalence of arterial thrombosis is also high and involvement of antiphospholipid antibodies has been suggested.

Figure 2.

Lung injury in coronavirus disease 2019 (COVID-19). COVID-19 infection causes acute lung injury induced by activation of residential macrophages, lymphocyte apoptosis, and neutrophils. The macrophages produce cytokines and chemokines including monocyte chemotactic protein 1 (MCP-1), interferon-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1, and releases these mediators into the alveolar space. Increased tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) stimulates the lymphocyte apoptosis. COVID-19 also induces vascular endothelial damage through activating the complement system that leads to increased permeability and inflammatory thrombus formation. The fibrinolytic system is activated releasing fibrin degradation fragments (d-dimers) in the circulation. When the changes in the blood vessel are dominant and the damage in the alveolar space is relatively mild, that situation is considered as type-L, and when the damage advances to the alveolar space, it turns to type-H. MAC = membrane attack complex, NETs = neutrophil extracellular traps, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Figure 3.

Thrombus formation in coronavirus disease 2019 (COVID-19). There are four major factors that accelerate thrombosis formation. First, severe acute respiratory syndrome coronavirus 2 infection-induced cytokine storm activates coagulation. Proinflammatory cytokines such as interleukin (IL)-1β and IL-6 stimulate the expression of tissue factor on immune cells and initiates extrinsic coagulation cascade activation. Second, the fibrinolytic system is suppressed by the decreased activity of urokinase-type plasminogen activator and increased release of plasminogen activator inhibitor-1. Third, platelets are activated by various proinflammatory cytokines and the damaged endothelium readily bind platelets. Fourth, endothelial damage induced by inflammation further accelerates the thrombotic reaction.