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

Effect of Platelet Antigen Polymorphism on Platelet Inhibition by Aspirin, Clopidogrel, or Their Combination Glen E. Cooke, Yiwen Liu-Stratton, Amy K. Ferketich, Melvin L. Moeschberger, David J. Frid, Raymond D. Magorien, Paul Bray, Philip F. Binkley, Pascal J. Goldschmidt-Clermont Clopidogrel and acetylsalicylic acid (ASA) improve outcomes in patients with acute coronary syndromes. The relative efficacy of these two inhibitors measured in vitro varies according to the agonist used to stimulate platelets. The combination of ASA and clopidogrel appears superior to either inhibitor used alone. PlA2, a polymorphism of glycoprotein IIb/IIIa, functions as an important modifier of the effect of ASA but not of the effect of clopidogrel. We studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease. 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 PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective. Thirty PlA1/A1and 30 PlA1/A2patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied. 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 PlA1/A2donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of PlA1/A1and PlA1/A2platelets. The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. PlA2functions 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