Mechanism of the development of thrombotic thrombocytopenia in COVID-19 infected patients and after vaccination

Background: Abnormal coagulation profiles were frequently observed in severe Covid-19 infected patients while Covid-19 vaccine-induced unusual thrombotic events and thrombocytopenia. A high incidence of developing platelet-activating antibodies has been detected in these patients. However, the mechanism of what triggers the bodies to produce these antibodies and what else contributes to the development of this abnormal coagulation have not yet been revealed. Aims: We provide a mechanism to describe the development of thrombotic thrombocytopenia in Covid-19 infected patients and after vaccination Methods: We used Dynamic light scattering (DLS), Quartz crystal microbalance (QCM), and Single-molecule force spectroscopy (SMFS) to prove that Covid-19-Spike glycoprotein (SP) cluster platelet factor 4 (PF4). The response of platelets to the resulting PF4/SP complexes was investigated in platelet aggregation tests and visualized by confocal laser scanning microscopy. Based on binding features of PF4 to Covid-19-SP and current reports, we proposed a novel mechanism describing factors that trigger the bodies to produce platelet-activating PF4-antibodies and cause abnormal coagulation. Results: We found that Covid-19-Spike glycoprotein (SP) cluster platelet factor 4 (PF4) and switched the surface zeta potential of PF4 from positive to negative values. The binding of Covid-19-SP to PF4 is as strong and stable as binding to PF4/Heparin complexes. Importantly, the resulting PF4/SP complexes induced platelet aggregation at a critical concentration ratio. We notice many similar binding features of PF4/Covid-19-SP complexes as compared with auto heparin-induced thrombocytopenia antibodies. Our findings allow us to i) propose a mechanism that describes the development of platelet-activating PF4-antibodies in Covid-19 infected and vaccinated patients and ii) explain the abnormal clotting disorder in patients. Conclusions: We concluded that not only platelet-activating antibodies but also PF4/Covid-19-SP complexes activate platelets. PF4 binds stably to the virus explain also the fact that causes a higher frequency of blood clots observed after AstraZeneca vaccination as compared with that of Pfizer-BioNTech Covid-19 vaccine.