title: Anti-thrombotic action of clopidogrel and P1(A1/A2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin.
abstract: Individual variability in response to clopidogrel is known but its mechanism is poorly understood. We examined the relationship between glycoprotein IIIa polymorphism P1(A1/A2) and anti-thrombotic actions of clopidogrel. Clopidogrel (75 mg/d; 2 weeks) was administered to 48 normolipemic patients with coronary artery disease. Bleeding time, thrombin generation at the site of microvascular injury, platelet function under high shear, using PFA-100 with ADP cartridge, and platelet surface activation markers (P-selectin and fibrinogen binding sites on GPIIb/IIIa complex detected by PAC-1 antibody), were studied both before and after clopidogrel treatment. Both unstimulated and low-dose (0.02 microM and 1 microM) in vitro ADP-stimulated platelets were examined. GP IIIa polymorphism was assessed by polymerase chain reaction and restriction fragment length polymorphism analysis. We identified 32 P1(A1/A1) homozygotes, 15 P1(A1/A2 heterozygotes and one P1(A2/A2) homozygote. Clopidogrel significantly prolonged bleeding time in all subjects, but this effect was greater in P1(A2 carriers (p < 0.01). Furthermore, clopidogrel only depressed thrombin generation at the site of microvascular injury (p < 0.01) in P1(A2) patients and prolonged closure time measured in vitro by PFA-100 (p < 0.05). At baseline spontaneous expression of PAC-1 and P-selectin was higher in P1(A2) subjects as compared to P1(A1) homozygotes (p < 0.05 for both antigens). Clopidogrel lowered the expression of both markers affecting more P1(A2) carriers, so that the difference in binding PAC-1 antibody between platelets from P1(A1) and P1(A2) carriers disappeared, while the difference in P-selectin expression slightly diminished. Anti-thrombotic effects of clopidogrel are more pronounced in CAD patients carrying the P1(A2) allele than in P1(A1) homozygotes.
authors.affiliation: Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Dropinski
authors.forename: Jacek
authors.initials: J
authors.lastname: Musial
authors.forename: Bogdan
authors.initials: B
authors.lastname: Jakiela
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wegrzyn
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.forename: Andrew
authors.initials: A
authors.lastname: Szczeklik
mesh_terms: D001241:Aspirin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D005838:Genotype; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011110:Polymorphism, Genetic; D011516:Prothrombin; D013927:Thrombosis / Q000517:prevention & control; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D039661:Integrin beta3; D019007:P-Selectin; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin