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CLINICAL RESEARCH

Effect of Platelet Antigen Polymorphism on Platelet Inhibition by Aspirin, Clopidogrel, or Their Combination

Glen E. Cooke, MD, FACC^_*,_*, Yiwen Liu-Stratton, PhD^_*, Amy K. Ferketich, PhD, Melvin L. Moeschberger, PhD, David J. Frid, MD, FACC^_*, Raymond D. Magorien, MD, FACC^_*, Paul F. Bray, MD, Philip F. Binkley, MD, MPH, FACC^_* and Pascal J. Goldschmidt-Clermont, MD, FACC

^_* Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, Ohio
Division of Epidemiology and Biometrics of the School of Public Health, The Ohio State University, Columbus, Ohio
Thrombosis Research Section, Department of Medicine, College of Medicine, Baylor University, Houston, Texas
Department of Medicine, Duke University Medical Center, Durham, North Carolina

Manuscript received February 24, 2005; revised manuscript received September 15, 2005, accepted September 19, 2005.

^_* Reprint requests and correspondence: Dr. Glen E. Cooke, 235 Davis HLRI, The Ohio State University, 473 West 12th Avenue, Columbus, Ohio 43210-1252. (Email: glen.cooke{at}osumc.edu).

OBJECTIVES: We studied the modifier effect of platelet antigen polymorphism (Pl^A2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease.

BACKGROUND: Clopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism Pl^A2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective.

METHODS: Thirty Pl^A1/A1 and 30 Pl^A1/A2 patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied.

RESULTS: Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from Pl^A1/A2 donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of Pl^A1/A1 and Pl^A1/A2 platelets.

CONCLUSIONS: The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. Pl^A2 functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.

Abbreviations and Acronyms   ADP = adenosine diphosphate   ANOVA = analysis of variance   ASA = acetylsalicylic acid   CHD = coronary heart disease   GP = glycoprotein   PlA = platelet antigen polymorphism   PRP = platelet-rich plasma

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