Platelet α-granules are required for occlusive high-shear-rate thrombosis
Platelet α-granules are required for occlusive high-shear-rate thrombosis
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DOI：
10.1182/bloodadvances.2020002117
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发表时间：
2020-07-01
期刊：
影响因子：
7.5
通讯作者：
Ku, David N.
中科院分区：
文献类型：
--
作者：
Kim, Dongjune A.;Ashworth, Katrina J.;Ku, David N.
血管性血友病因子（VWF）是诱发动脉血栓形成所必需的。在这项研究中，我们研究了血小板VWF在不表达血小板VWF （Nbeal2(-/-)）的小鼠高剪切下闭塞性血栓形成中的关键作用。通过计算机模拟、体外高剪切微流体和体内动脉血栓形成Folts模型，我们再现了狭窄血管病理血流下血小板动力学。计算流体动力学（cfd）基于动脉几何形状模拟狭窄的局部血流动力学。该模型预测剪切速率、血小板粘附时间和闭塞时间。这些预测在体内和体外都得到了验证。体外和体内血浆VWF和血小板VWF水平正常的野生型对照小鼠发生闭塞性血栓形成。在血浆VWF正常且血小板VWF缺失的Nbeal2（-/-）小鼠中没有形成闭塞性血栓。在Nbeal2（-/-）微流体实验中，通过添加外源性正常血小板和VWF来纠正闭塞性血栓形成。结合模型和实验数据，我们证明了a-颗粒中血小板VWF在高剪切条件下形成闭塞血栓的必要条件。这些结果可以启发新的针对病理条件的药物靶点，并预防动脉血栓形成。
von Willebrand factor (VWF) is essential for the induction of arterial thrombosis. In this study, we investigated the critical role of platelet VWF in occlusive thrombosis formation at high shear in mice that do not express platelet VWF (Nbeal2(-/-)). Using in silico modeling, in vitro high-shear microfluidics, and an in vivo Folts model of arterial thrombosis we reproduced the platelet dynamics that occur under pathological flow in a stenosed vessel. Computational fluid dynamics (CFDs) simulated local hemodynamics in a stenosis based on arterial geometries. The model predicted shear rates, time course of platelet adhesion, and time to occlusion. These predictions were validated in vitro and in vivo. Occlusive thrombosis developed in wild-type control mice that had normal levels of plasma VWF and platelet VWF in vitro and in vivo. Occlusive thrombosis did not form in the Nbeal2(-/-) mice that had normal plasma VWF and an absence of platelet VWF. Occlusive thrombosis was corrected in Nbeal2(-/-) microfluidic assays by the addition of exogenous normal platelets with VWF. Combining model and experimental data, we demonstrated the necessary requirement of platelet VWF in a-granules in forming an occlusive thrombus under high shear. These results could inspire new pharmacological targets specific to pathological conditions and prevent arterial thrombosis.