title: The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities.
abstract: Prasugrel is a novel antiplatelet prodrug of the same thienopyridine class as clopidogrel and ticlopidine. Metabolism of prasugrel generates the active metabolite R-138727, an antagonist of the platelet P2Y(12) adenosine diphosphate (ADP) receptor, leading to inhibition of ADP-mediated platelet activation and aggregation. ADP also enhances the platelet response to collagen, and these two agonists contribute to the generation of platelet procoagulant activity. We therefore examined whether R-138727 inhibits ADP- and collagen-triggered platelet procoagulant activities.
  
  
  
  As shown by whole blood flow cytometry, R-138727 inhibited surface phosphatidylserine expression on ADP plus collagen-stimulated platelets and tissue factor (TF) expression on ADP-, collagen-, and ADP plus collagen-stimulated monocyte-platelet aggregates. R-138727 reduced monocyte-platelet aggregate formation, thereby further inhibiting TF expression. ADP, collagen, and ADP plus collagen accelerated the kinetics of thrombin generation in recalcified whole blood and R-138727 significantly inhibited this acceleration. Clot strength in a modified thromboelastograph system was also inhibited by R-138727 (IC50 0.7 +/- 0.1 microM).
  
  
  
  In addition to its previously known inhibitory effects on platelet activation and aggregation, the active metabolite of prasugrel, R-138727, inhibits platelet procoagulant activity in whole blood (as determined by phosphatidylserine expression on platelets and TF expression on monocyte-platelet aggregates), resulting in the functional consequences of delayed thrombin generation and impaired clot development.
authors.affiliation: Center for Platelet Function Studies, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA. frelinger@platelets.org
authors.forename: A L
authors.initials: AL
authors.lastname: Frelinger
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: M R
authors.initials: MR
authors.lastname: Barnard
authors.forename: M D
authors.initials: MD
authors.lastname: Linden
authors.forename: I
authors.initials: I
authors.lastname: Tarnow
authors.forename: M L
authors.initials: ML
authors.lastname: Fox
authors.forename: A
authors.initials: A
authors.lastname: Sugidachi
authors.forename: K J
authors.initials: KJ
authors.lastname: Winters
authors.forename: M I
authors.initials: MI
authors.lastname: Furman
authors.forename: A D
authors.initials: AD
authors.lastname: Michelson
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D001711:Biotransformation; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors*; D001792:Blood Platelets / Q000187:drug effects*; D003018:Clot Retraction / Q000187:drug effects*; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D010718:Phosphatidylserines / Q000097:blood; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000493:pharmacokinetics*; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes / Q000493:pharmacokinetics*; D013916:Thrombelastography; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis
chemical_list: D017304:Annexin A5; D001779:Blood Coagulation Factors; C548576:P2RY12 protein, human; D010718:Phosphatidylserines; D010879:Piperazines; D011355:Prodrugs; D058919:Purinergic P2 Receptor Antagonists; C510685:R-138727; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; C049426:platelet procoagulant factor; D000244:Adenosine Diphosphate; D003094:Collagen; D013925:Thromboplastin; D013917:Thrombin; D000068799:Prasugrel Hydrochloride