LAUSR

Coagulation activation is a prominent feature ofSARS-CoV-2infection (COVID-19). Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We thus sought to assess activation of the contact system and intrinsic pathway in subjects with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathwayswere measured in samples from inpatients with COVID-19 andhealthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by ELISA, while extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa generation (MVTF). Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and thirty age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 were demonstrated by increased plasma levels offactor XIIa:C1 esterase inhibitor (FXIIa:C1), kallikrein:C1, FXIa:C1, FXIa:α1antitrypsin, and FIXa:antithrombin (FIXa:AT). MVTF levels were also increased in COVID-19 subjects. Since FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both the contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specificallythe total length of hospitalization, length of ICU stay, and extent of lung CT changes.We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.