The factor XIII-A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

Abstract

Background: Factor XIII (FXIII) promotes fibrin crosslinking and red blood cell (RBC) retention in clots. The FXIII-A polymorphism, Val34Leu, is associated with protection against venous thrombosis. This effect is hypothesized to result from fibrinogen concentration-dependent changes in fibrin structure. Effects of the FXIII-A Val34Leu polymorphism in whole blood clots have not been investigated. Aim: Characterize effects of FXIII-A Val34Leu polymorphism and fibrinogen on whole blood clots. Methods: We isolated platelet-poor plasmas from human donors (FXIIIVal/Val, FXIIIVal/Leu, FXIIILeu/Leu), reconstituted plasmas with platelets and RBCs, and triggered clotting. We assessed contributions of gender, age, clotting times, thrombin generation, FXIII activity, FXIII-A Val34Leu polymorphism, and fibrinogen to clot mass. We also reconstituted FXIII-depleted plasma with platelets, RBCs, and purified FXIIIVal/Val or FXIIILeu/Leu, varied fibrinogen, and characterized effects on clot mass. Results: Clot mass was associated with age, fibrinogen, prothrombin time, and thrombin generation. Clots reconstituted with plasmas from individuals with FXIII-AVal/Val and FXIII-AVal/Leu did not differ in mass from clots with FXIII-ALeu/Leu. However, clots containing a 34Val allele demonstrated a fibrinogen concentration-dependent increase in mass, whereas clots with homozygous 34Leu did not. In plasmas with high fibrinogen, mass was higher for clots with 34Val alleles compared with clots with homozygous 34Leu. In clots reconstituted with purified FXIII, increasing fibrinogen enhanced clot mass in the presence of 34Val, but decreased mass in the presence of 34Leu. Conclusions: FXIII 34Leu mitigates the effect of elevated fibrinogen on whole blood clot mass. The Val34Leu polymorphism may protect against venous thrombosis by reducing clot mass.