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(Circulation. 2001;104:2666.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Pl^A2 Polymorphism of ß₃ Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury

Anetta Undas, MD, PhD; Kathleen Brummel, PhD; Jacek Musial, MD, PhD; Kenneth G. Mann, PhD; Andrew Szczeklik, MD, PhD

From the Department of Medicine, Jagellonian University School of Medicine, Krakow, Poland, and the Department of Biochemistry, University of Vermont, Burlington, Vt (K.B., K.G.M.).

Correspondence to Dr Kenneth G. Mann, University of Vermont, Department of Biochemistry, Given Building, Room E407, Burlington, VT 05405. E-mail kmann{at}protein.uvm.edu

Background— Mechanisms by which the Pl^A2 (Leu33Pro) polymorphism of ß₃ 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.

Key Words: glycoproteins • genetics • coagulation • thrombin • aspirin

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