Antiphospholipid Antibodies in COVID-19

Individuals with severe coronavirus disease 2019 (COVID-19) are at high risk for thrombosis in macro- and microvascular beds. Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia in which patients form autoantibodies to phospholipids and phospholipid-binding proteins such as prothrombin and beta-2-glycoprotein I (β2GPI). These antiphospholipid antibodies (aPL) then engage clotting factors and cell surfaces, where they activate coagulation cascades, endothelial cells, platelets, and neutrophils- thereby tipping the balance toward thrombosis. A defining feature of APS is its ability to promote thrombosis in vascular beds of all sizes, including both arterial and venous circuits. The catastrophic variant of APS (CAPS) is often fatal and bears many similarities to the coagulopathy seen in patients with COVID-19. Reports of aPL in COVID-19 and their possible relationship to thrombosis have begun to emerge in small case reports and series. While viral infections are known triggers of transient aPL, the extent to which these antibodies may be pathogenic has not been well defined. Our preliminary data testing patients hospitalized with COVID-19 reveal that half of patients have positive testing for at least one type of aPL. The presence of aPL correlates with neutrophil activation and disease severity. Our hypothesis is that aPL are targetable amplifiers of COVID-19 severity. If correct, the hypothesis has significant implications for treating patients with acute disease (anticoagulation, plasmapheresis), as well as disease that has resolved (antibody persistence, convalescent plasma). Aim 1 will expand aPL testing to hundreds of individuals hospitalized with COVID-19 in order to understand clinical correlations and determine long-term outcomes. The hypothesis is that aPL will associate with higher rates of macrovascular thrombosis (stroke, venous thromboembolism) and microvascular thrombosis (respiratory failure, kidney injury) in COVID-19. Aim 2 will characterize COVID-19-derived IgG/IgM fractions and affinity-purified aPL in vitro. The hypothesis is that COVID-19-derived aPL will have in vitro activities similar to aPL isolated from patients with established APS. Aim 3 will determine the extent to which COVID-19-derived aPL are pathogenic in animal models. The hypothesis is that transfer of COVID-19 antibody fractions into mice will potentiate thrombosis, thereby confirming the pathogenic potential of these antibodies in vivo.