In vivo and ex vivo impact of

Abstract: Venous thromboembolism (VTE) is multifactorial, and established hereditary risk factors explain only part of heritable risk. The protein C (PC) pathway is central to anticoagulant control, and common variants in thrombomodulin and endothelial PC receptor genes ( THBD , PROCR ) have been proposed as modulators. In 73 participants, we used standardized in vivo coagulation activation with recombinant activated factor VII (15 μg/kg) and measured thrombin markers and activated PC (APC) over 8 hours. Endothelial colony-forming cell–based ex vivo experiments were performed in 43 participants. In vivo, the ratio of APC area under the curve (AUC) to thrombin-antithrombin complex (TAT) AUC, which reflects the endogenous anticoagulant response relative to thrombin generation, provided the best model fit (adjusted R 2 = 0.345). The APC response was lower in individuals with previous VTE (median, 0.13 vs 0.26) and PROCR 655A>G carriers (0.11 vs 0.26), but higher in factor V Leiden (FVL) carriers (0.32 vs 0.14) and THBD 1418C>T carriers (0.38 vs 0.13). The THBD 1418C>T effect was driven by reduced TAT AUC (30.6 vs 82.7 pmol × h/L), whereas the PROCR 655A>G effect reflected a lower APC AUC (8.6 vs 10.7 pmol × h/L). Ex vivo, the APC AUC/thrombin AUC ratio was lower with previous VTE and PROCR 655A>G, higher with FVL, and not associated with THBD 1418C>T. No in vivo or ex vivo association was observed for PROCR 4678C>G. This study provides in vivo evidence that common THBD and PROCR variants modulate PC pathway function, establishing the APC response as a sensitive end point for subtle genetic effects beyond FVL.