The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities
Department of Pediatrics
Medical Subject Headings
Adenosine Diphosphate; Annexin A5; Biotransformation; Blood Coagulation Factors; Blood Platelets; Clot Retraction; Collagen; Humans; Monocytes; Phosphatidylserines; Piperazines; Platelet Activation; Prodrugs; *Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Thrombelastography; Thrombin; Thromboplastin
Hematology | Oncology | Pediatrics
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.
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Citation: J Thromb Haemost. 2008 Feb;6(2):359-65. Epub 2007 Nov 15. doi 10.1111/j.1538-7836.2007.02838.x