Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination.
OBJECTIVE
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.


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 PlA2. 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 PlA1/A1 and 30 PlA1/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 PlA1/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.
Cooke
Glen E
GE
Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210-1252, USA. glen.cooke@osumc.edu
Liu-Stratton
Yiwen
Y
Ferketich
Amy K
AK
Moeschberger
Melvin L
ML
Frid
David J
DJ
Magorien
Raymond D
RD
Bray
Paul F
PF
Binkley
Philip F
PF
Goldschmidt-Clermont
Pascal J
PJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D016824:Antigens, Human Platelet / Q000235:genetics*; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism; D000077144:Clopidogrel; D003094:Collagen / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D003594:Cytoplasmic Granules / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D016824:Antigens, Human Platelet; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; D004837:Epinephrine