title: Factor XIII Val34Leu polymorphism and gamma-chain cross-linking at the site of microvascular injury in healthy and coumadin-treated subjects.
abstract: 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.
authors.affiliation: Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Undas
authors.forename: B
authors.initials: B
authors.lastname: Brzezinska-Kolarz
authors.forename: K
authors.initials: K
authors.lastname: Brummel-Ziedins
authors.forename: J
authors.initials: J
authors.lastname: Musial
authors.forename: A
authors.initials: A
authors.lastname: Szczeklik
authors.forename: K G
authors.initials: KG
authors.lastname: Mann
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D005176:Factor XIII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000293:injuries*; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000378:metabolism; D014859:Warfarin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D021122:Protein Subunits; D014859:Warfarin; D005337:Fibrin; D005176:Factor XIII