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首页> 外文期刊>Translational Stroke Research >Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice
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Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice

机译：抑制因子XII介导的因子XI的激活提供了针对小鼠实验性急性缺血性中风的保护作用。

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摘要

Blood coagulation factor XI (FXI) is an established risk factor for acute ischemic stroke (AIS) and thrombosis, but is also needed for normal hemostasis. Contact factor XII (FXII), an upstream activator of FXI, also contributes to experimental stroke, but is not required for hemostasis. We investigated whether selectively inhibiting FXII-mediated FXI activation, while leaving other FXI and FXII functions intact, could improve the outcome of experimental AIS in mice. Twenty-four hours before induction of AIS by placement of a filament into the internal carotid artery for 60 min, mice were anticoagulated with an antibody directed against the apple 2 domain of FXI. This antibody selectively reduces the prothrombotic activation of FXI by FXIIa but does not affect activated FXI or hemostatic activation of FXI by thrombin, thus leaving hemostasis intact in mice and primates. In this model of AIS/reperfusion injury, mice that received the antibody before AIS displayed less ischemic damage, manifested as reduced cerebral infarction and fibrin deposition (thrombosis), increased cortical reperfusion, and improved neurological behavior. Further, the antibody-anticoagulated mice had no detectable hemostasis impairment. Consistent with the neuroprotective phenotype of FXII-deficient mice, our data suggest that a single molecular event, FXII-mediated FXI activation, contributes to the development of experimental AIS.
机译：凝血因子XI（FXI）是急性缺血性卒中（AIS）和血栓形成的既定危险因素，但正常止血也需要。接触因子XII（FXII）是FXI的上游激活剂，也有助于实验性中风，但止血不是必需的。我们调查了是否选择性抑制FXII介导的FXI激活，同时保持其他FXI和FXII功能完好无损，可以改善小鼠实验性AIS的结果。通过将细丝置于颈内动脉内60分钟诱导AIS的二十四小时之前，用针对FXI苹果2结构域的抗体对小鼠进行抗凝。该抗体选择性地降低了FXIIa对FXI的促血栓形成的激活，但不影响凝血酶对FXI的激活或对FXI的止血激活，因此在小鼠和灵长类动物中均保持了止血作用。在这种AIS /再灌注损伤模型中，在AIS之前接受抗体的小鼠表现出更少的缺血性损伤，表现为脑梗死和纤维蛋白沉积（血栓形成）减少，皮质再灌注增加和神经行为改善。此外，抗体抗凝小鼠没有可检测的止血损伤。与FXII缺陷型小鼠的神经保护表型一致，我们的数据表明，FXII介导的FXI激活的单个分子事件有助于实验性AIS的发展。

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  • 来源
    《Translational Stroke Research》 |2012年第3期|381-389|共9页
  • 作者

    Philberta Y. Leung; Sawan Hurst; Michelle A. Berny-Lang; Norah G. Verbout; David Gailani; Erik I. Tucker; Ruikang K. Wang; Owen J. T. McCarty; András Gruber;

  • 作者单位

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Departments of Pathology and Medicine Vanderbilt University Nashville TN 37232 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Department of Bioengineering University of Washington Seattle WA 98195 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

    Department of Biomedical Engineering Oregon Health ampamp Science University 3303 SW Bond Ave Portland OR 97239 USA;

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  • 正文语种 eng
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  • 关键词

    Factor XI; Ischemia; Neuroprotection; Thrombolysis; Hemostasis;

    机译：XI因子;缺血;神经保护;溶栓;止血;

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