Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model.
Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model.
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DOI：
10.1161/atvbaha.115.306528
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Storey RF
中科院分区：
文献类型：
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作者：
Thomas MR;Outteridge SN;Ajjan RA;Phoenix F;Sangha GK;Faulkner RE;Ecob R;Judge HM;Khan H;West LE;Dockrell DH;Sabroe I;Storey RF
临床研究表明，血小板P2Y12抑制剂可降低脓毒症的死亡率，尽管体内的潜在机制尚未明确。我们推测，P2Y12抑制剂可能通过抑制全身炎症及其促血栓形成作用来提高脓毒症的存活率。因此，我们确定了氯吡格雷和新型的、更有效的P2Y12抑制剂替卡格雷是否在实验人体模型中改变了这些反应。我们随机将30名健康志愿者分为替卡格雷(n=10)、氯吡格雷(n=10)和不服用抗血小板药物(对照组；n=10)。我们观察了抑制P2Y12对静脉注射大肠杆菌内毒素诱导的全身炎症反应的影响。两种P2Y12抑制剂都显著降低了血小板-单核细胞聚集的形成和主要致炎细胞因子的峰值水平，包括肿瘤坏死因子α、IL-6和CCL2。与氯吡格雷相比，替卡格雷还显著降低了IL-8和G-CSF的峰值水平，并提高了抗炎细胞因子IL-10的峰值水平。此外，替卡格雷改变了白细胞的运输。P2Y12抑制剂均抑制D-二聚体的生成，扫描电子显微镜显示替卡格雷也抑制纤维蛋白凝块超微结构的血栓前改变。P2Y12抑制剂对多种炎症和血栓形成机制的有效抑制表明，作为细菌内毒素诱导的全身炎症的中枢协调者，血小板具有至关重要的作用。这为临床研究中与P2Y12抑制剂相关的败血症患者的低死亡率提供了新的机制见解。
Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model. We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10) or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of E.coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major pro-inflammatory cytokines, including TNFα, IL-6 and CCL2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and G-CSF and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure. Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies.