title: PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy.
abstract: Genetic variations of the protease-activated receptor-1 (PAR-1) have been associated with platelet receptor density and linked to thrombin receptor-activating peptide (TRAP)-induced phenotypes of platelet aggregation and P-selectin expression. We investigated whether the PAR-1 intervening sequence-14 A>T dimorphism influences platelet procoagulant activity. We also determined whether the P2Y12 antagonist clopidogrel could offset any observed functional polymorphism of the PAR-1 receptor by inhibiting P2Y12-mediated amplification of TRAP-induced responses. We studied 54 patients listed for elective percutaneous coronary intervention assessing TRAP-induced platelet aggregation and markers of procoagulant activity. Platelet responses were measured at baseline, 4 h post clopidogrel 300 mg, and 10 and 28 days following clopidogrel 75 mg daily. Each patient was genotyped for the PAR-1 intervening sequence-14 A/T dimorphism. Increased platelet aggregation and procoagulant responses were observed with PAR-1 A allele homozygotes. Clopidogrel significantly inhibited these platelet responses regardless of PAR-1 genotype, but did not offset the hyper-reactivity associated with the A/A homozygotes. We conclude that a common sequence variation within the PAR-1 gene influences TRAP-induced platelet procoagulant activity as well as aggregation. Higher platelet reactivity associated with PAR-1 IVSn-14 A allele homozygotes persists despite clopidogrel therapy. These individuals may be at higher risk of thromboembolic events and may require additional anti-platelet medication.
authors.affiliation: Cardiovascular Research Unit, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, UK.
authors.forename: S M G
authors.initials: SM
authors.lastname: Smith
authors.forename: H M
authors.initials: HM
authors.lastname: Judge
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.forename: M
authors.initials: M
authors.lastname: Armstrong
authors.forename: A
authors.initials: A
authors.lastname: Dupont
authors.forename: P
authors.initials: P
authors.lastname: Gaussem
authors.forename: R F
authors.initials: RF
authors.lastname: Storey
mesh_terms: D000483:Alleles; D001779:Blood Coagulation Factors / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008875:Middle Aged; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D058919:Purinergic P2 Receptor Antagonists; D044463:Receptor, PAR-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D001779:Blood Coagulation Factors; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D044463:Receptor, PAR-1; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin; C049426:platelet procoagulant factor; D000077144:Clopidogrel; D013988:Ticlopidine