Fundamentals in Covid-19-Associated Thrombosis: Molecular and Cellular Aspects

Abstract

The novel coronavirus disease (COVID-19) is associated with a high incidence of coagulopathy and venous thromboembolism that may contribute to the worsening of the clinical outcome in affected patients. Marked increased D-dimer levels are the most common laboratory finding and have been repeatedly reported in critically ill COVID-19 patients. The infection caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is followed by a massive release of pro-inflammatory cytokines, which mediate the activation of endothelial cells, platelets, monocytes, and neutrophils in the vasculature. In this context, COVID-19-associated thrombosis is a complex process that seems to engage vascular cells along with soluble plasma factors, including the coagulation cascade, and complement system that contribute to the establishment of the prothrombotic state. In this review, we summarize the main findings concerning the cellular mechanisms proposed for the establishment of COVID-19-associated thrombosis.

Keywords: COVID-19; blood coagulation; endothelium; monocytes; neutrophil extracellular trap; platelets; thrombosis.

Figure 1

SARS-CoV-2 targets multiple vascular cells. (A) SARS-CoV-2 infection promotes hyperactivation of platelets. The consequences of platelet activation include reorganization of the platelet membrane, which enables fibrinogen binding and allows platelet aggregation, and the translocation of P-selectin to the platelet surface, enabling the formation of platelet-monocyte and platelet-neutrophil aggregates. (B) The crosstalk between platelets and monocytes can upregulate TF expression and release by monocytes, giving these cells a procoagulant phenotype. The infection of human monocytes with SARS-CoV-2 may activate the NLRP3 inflammasome, leading to an increase in procaspase-1 cleavage and IL-1β production and, therefore, resulting in a hypercoagulable state. (C) The interactions between neutrophils and platelets at sites of inflammation facilitate NET formation. It has also been proved that SARS-CoV-2 can induce NET formation in healthy neutrophils in vitro. NETs can propagate thrombus formation due to their thrombogenic properties, including the ability to initiate the intrinsic pathway of coagulation, to degrade natural coagulation inhibitors, and exert antifibrinolytic effects. (D) COVID-19 may trigger endothelial cell dysfunction either due to SARS-CoV-2 infection of endothelial cells or by pro-inflammatory cytokines that are produced in response to viral infection. The activation of endothelial cells results in the loss of the antithrombotic phenotype of the endothelium, occasioning the activation of the coagulation cascade, platelets and complement system in the vasculature. Created with BioRender.com.

Figure 2

SARS-CoV-2 promotes thrombus formation by engaging multiple vascular cells. The SARS-CoV-2 infection triggers the innate immune response, resulting in the activation of monocytes, which in turn elicit a pro-inflammatory cytokine storm. This results in neutrophil recruitment, endothelial cell, and platelet activation. Endothelial cell activation is followed by the release of von Willebrand factor (VWF) and adhesion molecules, leading to platelet recruitment and activation. Platelet activation results in the exposure of new receptors, including glycoprotein αIIbβ3, which enables fibrinogen binding and allows platelet aggregation, and the translocation of P-selectin to the platelet surface, enabling the formation of platelet-monocyte and platelet-neutrophil aggregates. The interaction between platelets and monocytes and pro-inflammatory cytokines upregulate tissue factor (TF) expression and release it into microvesicles. TF then binds to coagulation factor VII (FVII), activating coagulation. SARS-CoV-2 infection may activate the NLRP3 inflammasome, leading to an increase in IL-1β production and, therefore, resulting in a hypercoagulable state. SARS-CoV-2 mediated cytokine storm promotes sustained neutrophil recruitment and activation, culminating in neutrophil extracellular trap (NET) formation, which fosters thrombus formation. Created with BioRender.com.