title: Inhibition of platelet aggregation by prostaglandin E1 (PGE1) in diabetic patients during therapy with clopidogrel and aspirin.
abstract: Diabetes mellitus (DM) is associated with increased platelet activation and reduced platelet inhibition by clopidogrel. Prostaglandin E1 (PGE1) stimulates adenyl cyclase activity in platelets and increases cyclic AMP concentrations, which inhibit Ca(2+)release and platelet aggregation induced by P2Y1 receptor activation. PGE1 is included in the VerifyNow P2Y12 assay to suppress P2Y1 induced platelet aggregation. We hypothesized that diabetes mellitus may be associated with altered response to PGE1 in subjects treated with clopidogrel. Subjects with established coronary artery disease who were taking clopidogrel 75 mg daily and aspirin for >14 days were enrolled (n = 96). Diabetic (n = 34) were compared with non-diabetic subjects (n = 62). VerifyNow P2Y12 assay and light transmittance aggregometry (LTA) were performed using ADP as agonist with and without addition of PGE1. Genomic DNA was genotyped for common cytochrome P450 (CYP) 2C19 variants using Taqman assays. Residual on-treatment platelet aggregation induced by 20 µM ADP was not significantly different between subjects with and without DM. Addition of 22 nM and 88 nM PGE1 to 20 µM ADP resulted in a significant reduction of maximal platelet aggregation (MPA). Residual LTA platelet aggregation with PGE1 and VerifyNow P2Y12 platelet reactivity were significantly higher in subjects with DM than those without DM and in carriers of CYP 2C19*2 polymorphism. We conclude that an impaired inhibitory response to PGE1 may contribute to the high platelet reactivity phenotype in subjects with DM treated with clopidogrel. Addition of PGE1 to ADP agonist platelet assays may identify subjects with blunted inhibitory response to prostaglandins and result in a higher proportion of subjects with DM being classified as non-responders.
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine , IN 46202, USA. rkreutz@iupui.edu
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Kreutz
authors.forename: Perry
authors.initials: P
authors.lastname: Nystrom
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kreutz
authors.forename: Jia
authors.initials: J
authors.lastname: Miao
authors.forename: Richard
authors.initials: R
authors.lastname: Kovacs
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D000527:Alprostadil / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000527:Alprostadil; D013988:Ticlopidine; D001241:Aspirin