论文标题
von willebrand因子展开的介导高剪切血栓形成模型中的血小板沉积
von Willebrand Factor unfolding mediates platelet deposition in a model of high-shear thrombosis
论文作者
论文摘要
高剪切条件下的血栓形成是由机械敏感的血糖蛋白von Willebrand因子（VWF）介导的。 VWF响应强流梯度而展开，并促进流动血液中血小板的快速募集。虽然VWF的血栓形成效应已得到充分认识，但其复杂流中的构象反应在很大程度上被从血栓形成的数值模型中省略了。我们最近提出了一个用于展开VWF的连续模型，在该模型中，我们使用对流扩散反应方程代表了VWF传输及其流动诱导的构象变化。在这里，我们将VWF组件纳入了血栓形成的多含量模型中，其中拉伸的VWF的局部浓度放大了自由流动的血小板的沉积速率，并减少了沉积血小板的剪切清洁。我们使用三个基准验证模型：动脉粥样硬化的体外模型，停滞点流量和PFA-100，这是一种通常用于筛查von Willbrand疾病（VWD）的临床血液测试。这些模拟再现了在这些实验中观察到的VWF介导的血栓形成的关键方面，例如血栓位置，血栓生长动力学以及阻断血小板-VWF相互作用的效果。 The PFA-100 simulations closely matched the reported occlusion times for normal blood and several hemostatic deficiencies, namely, thrombocytopenia, vWD Type 1, and vWD Type 3. Overall, the multi-constituent model of thrombosis presented in this work enables macro-scale 3-D simulations of thrombus formation in complex geometries over a wide range of shear rates and accounts for qualitative and患者血液中定量止血缺陷。结果还证明了VWF的连续模型展开的实用性，该模型可以适应其他数值的血栓形成模型。
Thrombosis under high-shear conditions is mediated by the mechanosensitive blood glycoprotein von Willebrand Factor (vWF). vWF unfolds in response to strong flow gradients and facilitates rapid recruitment of platelets in flowing blood. While the thrombogenic effect of vWF is well recognized, its conformational response in complex flows has largely been omitted from numerical models of thrombosis. We recently presented a continuum model for the unfolding of vWF, where we represented vWF transport and its flow-induced conformational change using convection-diffusion-reaction equations. Here, we incorporate the vWF component into our multi-constituent model of thrombosis, where the local concentration of stretched vWF amplifies the deposition rate of free-flowing platelets and reduces the shear cleaning of deposited platelets. We validate the model using three benchmarks: in vitro model of atherothrombosis, a stagnation point flow, and the PFA-100, a clinical blood test commonly used for screening for von Willebrand Disease (vWD). The simulations reproduced the key aspects of vWF-mediated thrombosis observed in these experiments, such as the thrombus location, thrombus growth dynamics, and the effect of blocking platelet-vWF interactions. The PFA-100 simulations closely matched the reported occlusion times for normal blood and several hemostatic deficiencies, namely, thrombocytopenia, vWD Type 1, and vWD Type 3. Overall, the multi-constituent model of thrombosis presented in this work enables macro-scale 3-D simulations of thrombus formation in complex geometries over a wide range of shear rates and accounts for qualitative and quantitative hemostatic deficiencies in patient blood. The results also demonstrate the utility of the continuum model of vWF unfolding that could be adapted to other numerical models of thrombosis.
