GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice
GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice
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DOI：
10.1182/blood-2013-12-543074
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发表时间：
2014-05-22
期刊：
影响因子：
20.3
通讯作者：
Vivien, Denis
中科院分区：
文献类型：
--
作者：
Le Behot, Audrey;Gauberti, Maxime;Vivien, Denis
血小板糖蛋白（Gp） IIb/IIIa与血浆蛋白的相互作用介导动脉血栓中血小板交联。然而，GpIIb/IIIa抑制剂在心肌梗死或缺血性卒中后不能分散血小板聚集物。这些结果表明闭塞性血栓的稳定性涉及其他尚未确定的机制。在本研究中，我们研究了闭塞血栓形成过程中驱动血小板交联的机制。通过计算流体动力学模拟和体内血栓形成模型，我们证明了闭塞血栓的内部结构是不均匀的，主要由血栓生长过程中普遍存在的流变条件决定。与依赖GpIb / iiia的血栓形成的第一步不同，我们的研究结果表明，动脉管腔的关闭是由GpIb α -血管性血友病因子（VWF）相互作用介导的。因此，使用GpIb α - vwf抑制剂破坏血小板交联可以恢复血管通畅，改善缺血性中风小鼠模型的预后，尽管血栓对纤维蛋白溶解或传统抗血栓药物具有抗性。总的来说，我们的研究表明，阻断GpIb α - vwf相互作用可以通过特异性地分解闭塞性血栓的外层来恢复闭塞性血栓形成后的血管通畅，闭塞性血栓的外层是由在非常高的剪切速率下形成的血小板聚集体组成的。
Interactions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth. Unlike the first steps of thrombus formation, which are GpIIb/IIIa-dependent, our findings reveal that closure of the arterial lumen is mediated by GpIb alpha-von Willebrand Factor (VWF) interactions. Accordingly, disruption of platelet cross-linking using GpIb alpha-VWF inhibitors restored vessel patency and improved outcome in a mouse model of ischemic stroke, although the thrombi were resistant to fibrinolysis or traditional antithrombotic agents. Overall, our study demonstrates that disruption of GpIb alpha-VWF interactions restores vessel patency after occlusive thrombosis by specifically disaggregating the external layer of occlusive thrombi, which is constituted of platelet aggregates formed under very high shear rates.