Parker H. Petit Institute for Bioengineering and Biosciences, and.
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA.
Blood Adv. 2022 Apr 26;6(8):2453-2465. doi: 10.1182/bloodadvances.2021005692.
Shear-induced platelet aggregation (SIPA) occurs under elevated shear rates (10 000 s-1) found in stenotic coronary and carotid arteries. The pathologically high shear environment can lead to occlusive thrombosis by SIPA from the interaction of nonactivated platelets and von Willebrand factor (VWF) via glycoprotein Ib-A1 binding. This process under high shear rates is difficult to visualize experimentally with concurrent molecular- and cellular-resolutions. To understand this fast bonding, we employ a validated multiscale in silico model incorporating measured molecular kinetics and a thrombosis-on-a-chip device to delineate the flow-mediated biophysics of VWF and platelets assembly into mural microthrombi. We show that SIPA begins with VWF elongation, followed by agglomeration of platelets in the flow by soluble VWF entanglement before mural capture of the agglomerate by immobilized VWF. The entire SIPA process occurs on the order of 10 milliseconds with the agglomerate traveling a lag distance of a few hundred microns before capture, matching in vitro results. Increasing soluble VWF concentration by ∼20 times in silico leads to a ∼2 to 3 times increase in SIPA rates, matching the increase in occlusion rates found in vitro. The morphology of mural aggregates is primarily controlled by VWF molecular weight (length), where normal-length VWF leads to cluster or elongated aggregates and ultra-long VWF leads to loose aggregates seen by others' experiments. Finally, we present phase diagrams of SIPA, which provides biomechanistic rationales for a variety of thrombotic and hemostatic events in terms of platelet agglomeration and capture.
剪切诱导的血小板聚集（SIPA）发生在狭窄的冠状动脉和颈动脉中发现的升高的剪切速率（10,000 s-1）下。病理上高剪切环境可通过 SIPA 导致闭塞性血栓形成，这是由于非激活血小板与 von Willebrand 因子（VWF）通过糖蛋白 Ib-A1 结合相互作用引起的。在高剪切速率下，该过程很难通过具有同时的分子和细胞分辨率的实验来可视化。为了理解这种快速结合，我们采用了经过验证的多尺度计算模型，该模型结合了测量的分子动力学和血栓形成在芯片设备，以描绘 VWF 和血小板组装到壁微血栓中的流动介导的生物物理学。我们表明，SIPA 始于 VWF 伸长，然后在可溶性 VWF 缠结的作用下，血小板在流中聚集，然后通过固定化的 VWF 捕获聚集物。整个 SIPA 过程在 10 毫秒左右发生，聚集物在捕获之前会滞后几毫米的距离，与体外结果匹配。在计算机模拟中，可溶性 VWF 浓度增加约 20 倍，导致 SIPA 速率增加约 2 到 3 倍，与体外发现的闭塞速率增加相匹配。壁聚集物的形态主要受 VWF 分子量（长度）控制，其中正常长度的 VWF 导致聚集或伸长的聚集物，而超长的 VWF 导致其他人实验中看到的松散聚集物。最后，我们展示了 SIPA 的相图，该相图为血小板聚集和捕获的各种血栓形成和止血事件提供了生物力学原理。
