PlA2 Polymorphism of &bgr;3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

Background—Mechanisms by which the PlA2 (Leu33Pro) polymorphism of &bgr;3 integrins could lead to an increased risk for coronary events are unclear. This study was designed to examine the effect of this polymorphism on blood coagulation. Methods and Results—In normal subjects (12 with PlA1A1, 9 with PlA1A2, and 3 with PlA2A2), we evaluated the activation of prothrombin, factor V, and factor XIII and fibrinogen removal by quantitative immunoblotting; thrombin-antithrombin III complex generation using ELISA; and levels of fibrinopeptide A and B by high-performance liquid chromatography in blood collected every 30 seconds at sites of standardized microvascular injury before and after 7 days of aspirin ingestion (75 mg/d). Compared with the PlA1A1 subjects, the PlA2 carriers exhibited higher maximum rates of thrombin B-chain generation (by 31.6%;P =0.005), thrombin-antithrombin III complex generation (by 30.7%;P =0.003), fibrinogen consumption (by 31.3%;P =0.002), prothrombin consumption (by 26.1%;P =0.011), and activation of factor V (by 14.1%;P =0.033) and factor XIII (by 27.0%;P =0.012). In the PlA1A1 homozygotes, aspirin ingestion resulted in reductions in the velocity of thrombin B-chain formation (by 32.1%;P =0.007), prothrombin consumption (by 30.4%;P =0.018), factor Va generation (by 28.9%;P =0.014), fibrinogen removal (by 41.2%;P =0.001), and factor XIII activation (by 22.6%;P =0.026). In the PlA2 carriers, aspirin did not alter the velocity of all these processes. After aspirin ingestion, fibrinopeptide A and B concentrations in the last 30-second interval were significantly reduced, but only in the PlA1A1 subjects. Conclusions—The presence of the PlA2 allele is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin, which might favor coronary thrombosis in the PlA2 carriers.