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

Abstract

Background Mechanisms by which the Pl A2 (Leu33Pro) polymorphism of β 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 Pl A1A1 , 9 with Pl A1A2 , and 3 with Pl A2A2 ), 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 Pl A1A1 subjects, the Pl A2 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 Pl A1A1 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 Pl A2 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 Pl A1A1 subjects. Conclusions The presence of the Pl A2 allele is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin, which might favor coronary thrombosis in the Pl A2 carriers.