Factor XIII Val34Leu polymorphism and gamma-chain cross-linking at the site of microvascular injury in healthy and coumadin-treated subjects.

Fibrin (Fn) cross-linking by activated factor (F) XIII is essential for clot stability. In vitro, a common Leu34 polymorphism of the FXIIIA-subunit increases the rate of thrombin-mediated FXIII activation, but not cross-linking activity upon complete FXIII activation. The effect of FXIII Val34Leu polymorphism on fibrin(ogen) cross-linking in vivo when vascular injury triggers the blood coagulation has not been studied yet. Using quantitative immunoblotting with antibodies raised against FXIIIA-subunits, fibrinogen, and gamma-gamma-dimers, the rates of FXIIIA cleavage and fibrin(ogen) cross-link formation in the fluid phase of 30-s blood samples collected at the site of microvascular injury were compared in the Leu34-positive and -negative healthy individuals and patients on long-term oral anticoagulation. In addition to accelerated FXIII activation, in healthy subjects the presence of FXIII Leu34 allele was associated with increased soluble gamma-gamma-dimer formation by 40% (1355 +/- 17 microg L(-1) for Leu34 carriers vs. 804.3 +/- 17 microg L(-1) for Leu34 non-carriers; P = 0.028) at the site of microvascular injury. This solution phase effect was abolished in coumadin-treated patients (369.4 +/- 75.9 microg L(-1) for Leu34 carriers vs. 290.5 +/- 35.9 microg L(-1) for Leu34 non-carriers; P > 0.05). The present study indicates that the Leu34 allele affects soluble gamma-gamma-dimer formation in untreated individuals, but not in those receiving acenocoumarol. Our data may help elucidate the impact of the FXIII Val34Leu polymorphism on Fn cross-linking in vivo and its modulation by oral anticoagulants.