Pl
            <sup>A2</sup>
            Polymorphism of β
            <sub>3</sub>
            Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

Undas, Anetta; Brummel, Kathleen E.; Musiał, Jacek; Mann, Kenneth G.; Szczeklik, A

doi:10.1161/hc4701.099787

Cited by 143 publications

(107 citation statements)

References 40 publications

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“…Recently, we have shown a different thrombin-lowering effect of aspirin in relation to the Pl A2 polymorphism of ␤ 3 integrins. 13 Taken together, these results suggest that genotyping for both common polymorphisms may help us identify patients who are more likely to benefit from the prophylactic use of aspirin.…”

Section: Discussionmentioning

confidence: 87%

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

et al. 2003

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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...

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Section: Discussionmentioning

confidence: 87%

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

et al. 2003

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“…Clearly, PIA2-carriers generate more thrombin after microvascular trauma which underlines the functional meaning of this particular platelet SNP also suggesting some pharmagenomic importance [25,26]. A more complex interpretation can be derived from the data from another study showing that ligation of the PIA2-genotype integrin could affect outside-in signalling efficacy with the consequence of more intense platelet-platelet interaction, but also increased adherence to immobilized adhesion molecules.…”

Section: Discussionmentioning

confidence: 92%

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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Aims/hypothesis. The gene encoding the β 3 -subunit (GPIIIa) of the platelet α 2 β 3 -integrin (fibrinogen receptor) shows a polymorphism PlA1/A2 with the A2 allele putatively associated with an increased risk of acute ischaemic events. This study investigated whether Type 2 diabetes as a particular macrovascular risk factor associates with the thrombogenic PIA2 genotype. Methods. The PlA genotype was determined in 112 consecutive Type 2 diabetic patients additionally classified according to the presence of macrovascular disease. Forty-four non-diabetic patients with angiografically documented cardiovascular disease (CAD/ AMI) and a further 59 non-diabetic subjects with no angiografical signs of CAD were investigated as genomic background control (n=103). PIA-genotyping was carried out by standard restriction fragment length analysis (RFLA) of PCR amplified lymphocyte template DNA. Results. The overall allelic PlA2-prevalence accounted to 34.8% (39/112) in diabetic patients as compared to 14.6% (15/103) in non-diabetic patients [OR 3.1 (1.6-6.1), p<0.01].This odds ratio increased to 7.0 (2.5-19.7), (p<0.01) in subjects free of criteria of macrovascular disease. In non-diabetic control subjects without CAD there was an allelic PIA2 frequency of 10.2% (6/59) as compared to 20.5% (9/44) in patients with CAD and a history of AMI being less than either diabetes subgroup. The PIA2 prevalence in the subgroup of diabetes patients with macrovascular complications did not differ from the respective value in patients without macrovascular disease. [29.0% (20/69) vs. 44.2% (19/43)]. Conclusion/interpretation. This study confirms a trendwise association of PlA2 with severe coronary artery disease, but rather suggests an even stronger, highly significant association with the metabolic condition of Type 2 diabetes mellitus. This justifies the speculation that pathways dependent on the platelet α 2 β 3 integrin physiology could be implicated in the pathogenesis of Type 2 diabetes which lends further support to the "common soil" hypothesis of diabetes and vascular disease. [Diabetologia (2003) Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; GPIIIa, β 3 subunit of the platelet surface α 2 β 3 -integrin (GPIIb-IIIa, fibrinogen-receptor); PIA, platelet antigen; RGD, aminoacidsequence Arg-Gly-Asp; SNP, single nucleotide polymorphism. Diabetologia (2003) 46:984-989

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“…Poor response to aspirin has been associated with inadequate dose, poor absorption, and noncompliance, [18][19][20] though other intrinsic mechanisms may also exist. 21,22 Regarding clopidogrel, poor response may be related to noncompliance, inadequate dosing or absorption, 23 body mass index, 24 genetic polymorphisms of cytochrome P450 3A4 and the P2Y12 receptor, 25,26 and increased platelet activity related to an acute thrombotic event. 27 We observed a significant association between older age and percentage platelet inhibition.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Risk Factors for Aspirin and Clopidogrel Resistance in Cerebrovascular Stenting

Prabhakaran¹,

Wells²,

Lee³

et al. 2008

American Journal of Neuroradiology

135

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Pl ^A2 Polymorphism of β ₃ Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

Cited by 143 publications

References 40 publications

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

Prevalence and Risk Factors for Aspirin and Clopidogrel Resistance in Cerebrovascular Stenting

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Pl A2 Polymorphism of β 3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

Cited by 143 publications

References 40 publications

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

Aspirin Alters the Cardioprotective Effects of the Factor XIII Val34Leu Polymorphism

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

Prevalence and Risk Factors for Aspirin and Clopidogrel Resistance in Cerebrovascular Stenting

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Pl ^A2 Polymorphism of β ₃ Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury