The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities

J Thromb Haemost. 2008 Feb;6(2):359-65. doi: 10.1111/j.1538-7836.2007.02838.x. Epub 2007 Nov 15.

Abstract

Background: 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.

Methods and results: 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).

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Annexin A5 / metabolism
  • Biotransformation
  • Blood Coagulation Factors / antagonists & inhibitors*
  • Blood Platelets / drug effects*
  • Clot Retraction / drug effects*
  • Collagen / pharmacology
  • Humans
  • Monocytes / metabolism
  • Phosphatidylserines / blood
  • Piperazines / pharmacokinetics*
  • Piperazines / pharmacology*
  • Platelet Activation / drug effects*
  • Prasugrel Hydrochloride
  • Prodrugs / pharmacokinetics*
  • Purinergic P2 Receptor Antagonists*
  • Receptors, Purinergic P2Y12
  • Thiophenes / pharmacokinetics*
  • Thrombelastography
  • Thrombin / biosynthesis
  • Thromboplastin / biosynthesis

Substances

  • Annexin A5
  • Blood Coagulation Factors
  • P2RY12 protein, human
  • Phosphatidylserines
  • Piperazines
  • Prodrugs
  • Purinergic P2 Receptor Antagonists
  • R-138727
  • Receptors, Purinergic P2Y12
  • Thiophenes
  • platelet procoagulant factor
  • Adenosine Diphosphate
  • Collagen
  • Thromboplastin
  • Thrombin
  • Prasugrel Hydrochloride