Targeting platelets in acute experimental stroke - Impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding
Targeting platelets in acute experimental stroke - Impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding
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DOI：
10.1161/circulationaha.107.691279
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发表时间：
2007-05-01
期刊：
影响因子：
37.8
通讯作者：
Stoll, Guido
中科院分区：
文献类型：
--
作者：
Kleinschnitz, Christoph;Pozgajova, Miroslava;Stoll, Guido
背景 - 缺血性脑卒中是一种常见且严重的疾病，治疗选择有限。血小板可通过其糖蛋白（GP）Ib受体与血管性血友病因子结合而黏附于缺氧的脑内皮细胞。内皮下基质蛋白的暴露通过胶原蛋白与血小板的GPVI受体结合进一步促进血小板牢固附着于血管壁。在本研究中，我们探讨了GPIb、GPVI以及聚集受体GPIIb/IIIa在小鼠实验性脑卒中中的致病作用。
方法与结果 - 通过向大脑中动脉短暂闭塞1小时的小鼠静脉注射100μg单克隆抗体p0p/B的Fab片段，实现了对GPIbα的完全阻断。在大脑中动脉短暂闭塞24小时后，通过2,3,5 - 氯化三苯基四氮唑染色评估脑梗死体积。在大脑中动脉闭塞前1小时接受抗GPIbα Fab治疗的小鼠中，与对照组相比，缺血性病变减少至约40%（分别为28.5±12.7立方毫米对比73.9±17.4立方毫米；P < 0.001）。在大脑中动脉闭塞后1小时应用抗GPIbα Fab同样减少了脑梗死体积（24.5±7.7立方毫米；P < 0.001）并改善了神经功能状态。类似地，GPVI的耗竭显著减小了梗死体积，但程度较轻（49.4±19.1立方毫米；P < 0.05）。重要的是，通过系列磁共振成像显示，血小板活化早期步骤的阻断并未伴随出血并发症的增加。相反，用抗GPIIb/IIIa F(ab)(2)片段阻断血小板聚集的最终共同通路对脑卒中面积和功能结局没有积极影响，但在大脑中动脉短暂闭塞后以剂量依赖的方式增加了脑出血的发生率和死亡率。
结论 - 我们的数据表明，对血小板黏附和聚集的关键信号通路的选择性阻断对脑卒中结局和出血并发症有不同的影响。抑制血小板黏附于缺血内皮和内皮下基质的早期步骤可能为急性脑卒中提供一种新的安全治疗策略。
Background - Ischemic stroke is a frequent and serious disease with limited treatment options. Platelets can adhere to hypoxic cerebral endothelial cells by binding of their glycoprotein ( GP) Ib receptor to von Willebrand factor. Exposure of subendothelial matrix proteins further facilitates firm attachment of platelets to the vessel wall by binding of collagen to their GPVI receptor. In the present study, we addressed the pathogenic role of GPIb, GPVI, and the aggregation receptor GPIIb/IIIa in experimental stroke in mice.Methods and Results - Complete blockade of GPIb alpha was achieved by intravenous injection of 100 mu g Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery occlusion. At 24 hours after transient middle cerebral artery occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining. In mice treated with anti-GPIb alpha Fab 1 hour before middle cerebral artery occlusion, ischemic lesions were reduced to approximate to 40% compared with controls (28.5 +/- 12.7 versus 73.9 +/- 17.4 mm(3), respectively; P < 0.001). Application of anti-GPIb alpha Fab 1 hour after middle cerebral artery occlusion likewise reduced brain infarct volumes (24.5 +/- 7.7 mm(3); P < 0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4 +/- 19.1 mm(3); P < 0.05). Importantly, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)(2) fragments had no positive effect on stroke size and functional outcome but increased the incidence of intracerebral hemorrhage and mortality after transient middle cerebral artery occlusion in a dose-dependent manner.Conclusions - Our data indicate that the selective blockade of key signaling pathways of platelet adhesion and aggregation has a different impact on stroke outcome and bleeding complications. Inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix may offer a novel and safe treatment strategy in acute stroke.