| Summary: | Factor (F) XII and FXI play a central role in venous thrombus formation in preclinical disease models and contributes to venous thromboembolism (VTE) in humans. Agents targeting FXIa have been developed and effectively prevent VTE in humans. C1 esterase inhibitor (C1INH) is a serine protease inhibitor that inhibits several proteases, including FXII and FXI. In this study, we investigated the anticoagulant activity of C1INH in humans and mice. First, plasma C1INH levels were determined in a population-based nested case-control study consisting of 405 VTE patients and 829 age- and sex-matched controls derived from the Tromsø Study. Participants with plasma C1INH levels in the highest quartile had a significantly lower risk of VTE (odds ratio [OR] of 0.68, confidence interval 0.49-0.96, P<0.05), unprovoked VTE (OR 0.59, confidence interval 0.39-0.89) and pulmonary embolism (OR 0.57, confidence interval 0.34-0.92) compared to participants with C1INH levels in the lowest quartile after adjustment for age and sex. Secondly, plasma-based thrombin generation studies were conducted to assess the anticoagulant function of C1INH. Supplementation of normal human pooled plasma with exogenous human purified C1INH (0.2 and 0.4mg/ml) significantly inhibited thrombin generation initiated with silica (P<0.05) and significantly prolonged the activated partial thromboplastin assay clotting time (P<0.001). Thirdly, administration of a clinically approved human purified C1INH product to mice significantly reduced thrombus weight (P<0.05) in the murine inferior vena cava stenosis model of venous thrombosis. Studies with C1 inhibitor deficient mice and substrate selective C1INH variants are currently ongoing. Our results indicate that C1INH serves as an endogenous anticoagulant with higher plasma levels of C1INH associated with a decreased future risk of VTE. Further, exogenous C1INH effectively inhibits thrombin generation in vitro and venous thrombus formation in a mouse model. Our findings suggest that C1INH may prevent ...
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