Coagulation disorders and thromboembolic disease in COVID-19: review of current evidence in search of a better approach

Abstract

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an unprecedented global health problem, causing more than 20 million infections and more than 900,000 deaths (September 2020). The SARS-CoV-2 infection, known as COVID-19, has various clinical presentations, from asymptomatic or mild catarrhal processes to severe pneumonia that rapidly progresses to acute respiratory distress syndrome (ARDS) and multiple organ failure. In the last few months, much scientific literature has been devoted to descriptions of different aspects of the coagulation disorders and arterial and venous thrombotic complications associated with COVID-19, particularly venous thromboembolism (VTE). These studies have revealed that SARS-CoV-2 could lead to a prothrombotic state reflecting the high cumulative incidence of associated thrombotic events, particularly in patients admitted to intensive care units (ICUs). As regards the coagulopathy observed in association with SARS-CoV-2 infection, the mechanisms that activate coagulation have been hypothesized as being linked to immune responses, through the release of pro-inflammatory mediators that interact with platelets, stimulate the expression of tissue factor, induce an upregulation of plasminogen activator inhibitor-1, suppress the fibrinolytic system and lead to endothelial dysfunction, triggering thrombogenesis. D-dimer elevation has been recognized as a useful biomarker of poor prognosis, although the best cut-off point for predicting VTE in COVID-19 patients has still not been clarified. This review will try to update all the available scientific information on this important topic with enormous clinical and therapeutic implications.

Keywords: D-dimer; Pulmonary embolism (PE); coronavirus disease 2019 (COVID-19); inflammation; thrombosis.

Figure 1

Pathophysiology of coagulation activation in sepsis. The pathogens and its components stimulate the monocytes via specific receptors situated on the surface of their cells. The activated monocytes produce a hyperimmune response with the release of various cytokines and other inflammatory mediators that activate platelets, neutrophils and endothelial cells. A state of hypercoagulability and endothelial damage that modifies the properties of the endothelium from an anticoagulant to a procoagulant state through the interruption of the glycocalyx and the expression of the von Willebrand factor (VWF). Neutrophils, in their turn, express tissue factor and release granulated proteins and other procoagulant mediators, such as neutrophil extracellular traps (NETs) comprised of procoagulant DNA, histones and other molecular patterns associated with cellular damage. All the above leads to the development of micro- and macrothrombotic phenomena. Adapted from ref (17) [with permission of Sociedad Española de Neumología y Cirugía Torácica (SEPAR) copyright]. G-CSF, granulocyte colony-stimulating factor; TNF, tumor necrosis factor; IFN, interferon; IL, interleukin; NETs, neutrophil extracellular traps.

Figure 2

Rates of VTE in patients with COVID-19 infection according to admission to ICU or not (right) or use of pharmacological thromboprophylaxis or not (left). VTE, venous thromboembolism; COVID-19, coronavirus disease 2019; ICU, intensive care unit.