The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia

Abstract

In coronavirus disease 2019 (COVID-19), multiple thromboinflammatory events contribute to the pathophysiology, including coagulation system activation, suppressed fibrinolysis, vascular endothelial cell injury, and prothrombotic alterations in immune cells such as macrophages and neutrophils. Although thrombocytopenia is not an initial presentation as an infectious coagulopathy, recent studies have demonstrated the vital role of platelets in COVID-19-associated coagulopathy SARS-CoV-2 and its spike protein have been known to directly or indirectly promote release of prothrombotic and inflammatory mediators that lead to COVID-19-associated coagulopathy. Although clinical features of vaccine-induced immune thrombotic thrombocytopenia include uncommon locations of thrombosis, including cerebral venous sinus, we speculate coronavirus spike-protein-initiated prothrombotic pathways are involved in the pathogenesis of vaccine-induced immune thrombotic thrombocytopenia, as current evidence suggests that the spike protein is the promotor and other cofactors such as perturbed immune response and inflammatory reaction enhance the production of anti-platelet factor 4 antibody.

Keywords: COVID-19; Coagulopathy; Platelet; Thrombocytopenia; Thrombosis.

Fig. 1

Platelet activation in COVID-19. Both inflammation and coagulation are important promotors of clot formation in coronavirus disease 2019 (COVID-19). Other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding to angiotensin-converting enzyme 2 (ACE2), damage-associated molecular patterns (DAMPs) formed as the consequence of inflammation and thrombin generated in the course of coagulation stimulate platelets to release platelet factor 4, P-selectin, and von Willebrand Factor from α-granule, and adenosine diphosphate (ADP) release from dense granule, and the tissue factor-expressing microvesicle release from platelets. Platelet factor 4 can stimulate neutrophil extracellular traps (NETs) ejection and propagate the inflammation. These responses altogether facilitate platelet aggregation and clot formation. TLRs: Toll-like receptors, PAR1: protease activated receptor 1, GP: glycoprotein, PF4: platelet factor 4, VWF: von Willebrand factor

Fig. 2

Platelet activation in vaccine-induced thrombotic thrombocytopenia (VITT). The spike protein produced after vaccination stimulates dendritic cells/macrophages to initiate the production of anti-spike protein antibody as well as elicit inflammatory reactions. The spike protein also stimulates platelets and vascular endothelial cells directly via angiotensin-converting enzyme 2 (ACE2) binding or indirectly through inflammation and coagulation. Platelet factor 4 released from α-granule of the platelets binds to polyanions, i.e., free-DNA in the virus-vectored vaccine, free-DNA released from neutrophil extracellular traps (NETs), and heparan sulfate released from glycocalyx. Platelet factor 4/polyanion binding expresses immunogenicity and stimulates the anti-platelet factor 4 antibody production. Platelet factor 4/polyanion-antibody binding promotes platelet aggregation and further NETs release from the leukocytes. PF4: platelet factor 4.