Discovery Of Novel Pathogenic Mechanisms in Thrombotic Diseases: Antiphospholipid Syndrome and COVID-19

Thrombosis is the first cause of death worldwide and constitutes a complication in multiple diseases, such as infection, cancer, and autoimmunity. Identification of new molecular mechanism that leads to thrombosis is important to design new safer and more effective therapies. This thesis focuses on two pathologies with a thrombotic profile: the autoimmune disease antiphospholipid syndrome (APS), and the infectious disease COVID-19. We discovered that β2GpI interacts with Fb αC-domains through domain I - the major epitope recognized by anti-β2GpI antibodies found in APS patients - and that this interaction leads to thinner and shorter fibrin fibers, leading to clots that are more easily cleared by the fibrinolytic system. These results suggest that β2GpI could prevent the formation of fibrin clot with a prothrombotic phenotype, and that anti-β2GpI antibodies found in APS could impair this anticoagulant activity. We demonstrated by that the main protease of SARS-CoV-2 (Mpro) can trigger plasma coagulation in vitro by activating FVII and FXII and we observed that Mpro has a secondary substrate specificity for Arginine residues in P1. These results have two important implications. The first is that targeting Mpro for the treatment of COVID-19 not only is beneficial for blocking the infection, but also might prevent thrombotic complications. The second is that the target prediction studies need to consider that Mpro has an additional substrate specificity for Arginine, that could extend the number of possible Mpro cleavages.