Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

Abstract

Background-The mechanism underlying decreased risk for myocardial infarction in carriers of the Leu34 polymorphism of the factor (F) XIII A-subunit is unclear. Given that acetylation of fibrinogen by aspirin can alter its clotting properties and the presence of fibrin stimulates thrombin-mediated activation of FXIII, we have tested the hypothesis that treatment with aspirin differentially modulates the influence of the FXIII Val34Leu polymorphism on its activation in vivo. Methods and Results-The rates of the disappearance of FXIIIA chain and the appearance of its activated form (FXIIIAa) in sequential 30-second blood samples collected at the site of microvascular injury were compared in 14 healthy carriers of the Leu34 allele and 23 Val34 homozygotes both before and after a 7-day aspirin ingestion (75 mg/d), with the use of quantitative Western blotting. The presence of the Leu34 allele was associated with a significant increase in the maximum rate of FXIII activation by thrombin. Although the Leu34-positive and -negative subjects were similar with respect to aspirin-related impairment of thrombin generation, aspirin led to a more pronounced inhibition of the activation of FXIII in the Leu34 carriers as compared with the Val34 homozygotes. Conclusions-Inhibition of FXIII activation by aspirin is enhanced in the Leu34 carriers in vivo, suggesting that these subjects might benefit more than the Leu34-negative subjects from the reduction in risk for myocardial infarction with low-dose aspirin. Key Words: genetics Ⅲ aspirin Ⅲ coagulation R ecent work has highlighted importance of a common G3 T mutation in the codon 34 of the factor (F) XIII A subunit gene (Val34Leu) as the only hemostatic candidate gene polymorphism, which seems to be associated with a protective effect against myocardial infarction (MI), although this issue still generates controversy. 1,2 Plasma FXIII, composed of noncovalently associated 2A and 2B polypeptide subunits, in its activated form (FXIIIAa) stabilizes the hemostatic plug by cross-linking fibrin ␣-and ␥-chains. 2 Because a valine-to-leucine replacement takes place 3 amino acids away from the thrombin cleavage site at Arg37-Gly38, it has been postulated that this mutation might modulate FXIII activity. Indeed, in vitro studies demonstrated that the Leu34 allele is associated with more rapid FXIII activation 3 and altered clot structure with enhanced fibrin cross-linking. 4 It remains unclear why the Leu34 carriers have lower risk for MI despite faster FXIII activation.Given that acetylation of fibrinogen (Fbg) by aspirin alters its clotting properties assessed in a purified system 5 and that Fbg and/or fibrin stimulate thrombin-mediated FXIII activation, 2 we hypothesized that treatment with aspirin might modulate the influence of the FXIII Val34Leu polymorphism on its activation, and as a consequence, alter the impact of the Leu34 allele on risk of MI. Here we report that aspirin slows FXIII activation in the Leu34 carriers to a greater extent than in the Leu34-negative subjects, prov...

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity

“…16 However, the frequency of alleles was markedly low in our Japanese subjects; therefore, COX-2 may not be involved in aspirin resistance, as demonstrated for COX-1. In Caucasians, the frequency of minor alleles in FXIII SNP (100G4T), which may contribute to activation of FXIII, 19 was 22.1%; however, in this study, there was no minor allele.…”

“…Concerning platelet membrane glycoproteins, it has been reported that genetic polymorphisms of GPIa, 10 GPIba, 11 GPIIIa 12,13 and GPVI 14 influence the efficacy of aspirin or platelet responsiveness. Furthermore, Halushka et al 15 reported the association of platelet aggregation with genetic mutation of COX-1, Papafili et al 16 the association with genetic mutation of COX-2, Higuchi et al 17 the association with genetic mutation of TXA 2 receptors (TP), Stafforini et al 18 the association with genetic mutation of platelet activating factor acetylhydrolase (PAFAH) and Undas et al 19 the association with genetic mutation of coagulation factor XIII (FXIII).…”

Aspirin resistance and diabetes mellitus

“…Acetylation of fibrinogen is a likely mechanism for the observed in vitro and in vivo changes in clot structure after aspirin treatment [21]. Other mechanisms include modulation of thrombin generation and inhibition of coagulation factor XIII activation [22,23].…”

Mass Spectrometric Phenotyping of Val34Leu Polymorphism of Blood Coagulation Factor XIII by Differential Peptide Display

“…Active FXIIIA generates intermolecular amide bonds between lysine and glutamine residues, leading to covalent cross-linking of fibrin strands and conversion of soluble fibrin molecules into a stable insoluble clot. The involvement of FXIII in cardioand cerebrovascular diseases has been investigated recently, and the presence of a Val34Leu mutation is known to correlate with a lower incidence of myocardial infarction and ischemic stroke but an increased risk for hemorrhagic stroke (1)(2)(3)(4)(5). This mutation is localized in the direct vicinity of the cleavage site and is thought to influence the activation process of this protein (1 ).…”