In vivo and ex vivo impact of THBD and PROCR polymorphisms on the anticoagulant response of the protein C pathway.
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 protein C 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 protein C (APC) over 8 hours. Endothelial colony-forming cell-based ex vivo experiments were performed in 43 participants. In vivo, the APC area-under-the-curve (AUC)/thrombin-antithrombin complex (TAT) AUC ratio, reflecting 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; P=.009) and PROCR 655A>G carriers (0.11 vs. 0.26; P=.014), but higher in factor V Leiden (FVL) carriers (0.32 vs. 0.14; P=4.3×10-4) and THBD 1418C>T carriers (0.38 vs. 0.13; P=.032). The THBD 1418C>T effect was driven by reduced TAT AUC (30.6 vs. 82.7 pmol×h/L; P=.032), while the PROCR 655A>G effect reflected a lower APC AUC (8.6 vs. 10.7 pmol×h/L; P=0.04998). 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 endpoint for subtle genetic effects beyond FVL.