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首页> 外文期刊>Journal of thrombosis and haemostasis: JTH >The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities.
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The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities.

机译：普拉格雷的活性代谢产物抑制二磷酸腺苷和胶原蛋白刺激的血小板促凝活性。

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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.
机译：背景：普拉格雷（Prasugrel）是与氯吡格雷和噻氯匹定同噻吩吡啶类的新型抗血小板前药。普拉格雷的代谢产生活性代谢产物R-138727，它是血小板P2Y（12）二磷酸腺苷（ADP）受体的拮抗剂，导致抑制ADP介导的血小板活化和聚集。 ADP还增强了血小板对胶原蛋白的反应，这两种激动剂有助于血小板促凝活性的产生。因此，我们检查了R-138727是否抑制ADP和胶原触发的血小板促凝活性。方法和结果：如全血流式细胞术所显示，R-138727抑制ADP加胶原蛋白刺激的血小板表面磷脂酰丝氨酸的表达以及ADP，胶原蛋白和ADP加胶原蛋白刺激的单核细胞血小板聚集体的组织因子（TF）表达。 R-138727减少了单核细胞-血小板聚集体的形成，从而进一步抑制了TF表达。 ADP，胶原蛋白和ADP加胶原蛋白可加速重新钙化的全血中凝血酶生成的动力学，R-138727可显着抑制这种加速。 R-138727（IC50 0.7 +/- 0.1 microM）也抑制了改良的血栓弹力图系统中的凝块强度。结论：普拉格雷的活性代谢产物R-138727除了其先前已知的对血小板活化和聚集的抑制作用外，还可以抑制全血中的血小板促凝活性（由血小板上的磷脂酰丝氨酸表达和单核细胞-血小板聚集体的TF表达确定）导致凝血酶生成延迟和血凝块发育受损的功能后果。

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