In vivo and ex vivo impact of THBD and PROCR polymorphisms on the anticoagulant response of the protein C pathway

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 R2 = 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.