Endothelial cell-activating antibodies in COVID-19

Patients with coronavirus disease 19 ( COVID-19 ) are at high risk for fibrin-based occlusion of vascular beds of all sizes. Although endothelial cell activation has regularly been described as part of the COVID-19 thrombo-inflammatory storm, the upstream mediators of this activation have yet to be fully elucidated. Here, we began by pursuing the hypothesis that circulating factors such as neutrophil extracellular trap (NET) remnants, D-dimer, or C-reactive protein might predict the COVID-19 serum samples (n=118) that most robustly activated cultured endothelial cells. Indeed, we found modest correlations between serum NET remnants (cell-free DNA, myeloperoxidase-DNA complexes, citrullinated histone H3) and upregulation of surface E-selectin, VCAM-1, and ICAM-1 on endothelial cells. However, a more robust predictor of the ability of COVID-19 serum to activate endothelial cells was the presence of circulating antiphospholipid antibodies, specifically anticardiolipin IgG and IgM and anti-phosphatidlyserine/prothrombin (anti-PS/PT) IgG and IgM. Depletion of total IgG from anticardiolipin-high and anti-PS/PT-high samples markedly restrained upregulation of E-selectin, VCAM-1, and ICAM-1. At the same time, supplementation of control serum with patient IgG was sufficient to trigger endothelial cell activation. These data are the first to reveal that patient antibodies are a driver of endothelial cell activation and add important context regarding thrombo-inflammatory effects of COVID-19 autoantibodies in severe COVID-19.