The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities
Department of Pediatrics
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.
DOI of Published Version
J Thromb Haemost. 2008 Feb;6(2):359-65. Epub 2007 Nov 15. doi 10.1111/j.1538-7836.2007.02838.x
Journal of thrombosis and haemostasis : JTH
Frelinger AL, Jakubowski JA, Li Y, Barnard MR, Linden MD, Tarnow I, Fox ML, Sugidachi A, Winters KJ, Furman MI, Michelson AD. (2008). The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities. Hematology/Oncology. https://doi.org/10.1111/j.1538-7836.2007.02838.x. Retrieved from https://escholarship.umassmed.edu/peds_hematology/100