Abstract

An excessive von Willebrand factor (VWF) secretion, coupled with a moderate to severe deficiency of ADAMTS13 activity, serves as a linking mechanism between inflammation to thrombosis. The former facilitates platelet adhesion to the vessel wall and the latter is required to cleave VWF multimers. As a result, the ultra-large VWF (UL-VWF) multimers released by Weibel–Palade bodies remain uncleaved. In this study, using a computational model based on first principles, we quantitatively show how the uncleaved UL-VWF multimers interact with the blood cells to initiate microthrombosis. We observed that platelets first adhere to unfolded and stretched uncleaved UL-VWF multimers anchored to the microvessel wall. By the end of this initial adhesion phase, the UL-VWF multimers and platelets make a mesh-like trap in which the red blood cells increasingly accumulate to initiate a gradually growing microthrombosis. Although high-shear rate and blood flow velocity are required to activate platelets and unfold the UL-VWFs, during the initial adhesion phase, the blood velocity drastically drops after thrombosis, and as a result, the wall shear stress is elevated near UL-VWF roots, and the pressure drops up to 6 times of the healthy condition. As the time passes, these trends progressively continue until the microthrombosis fully develops and the effective size of the microthrombosis and these flow quantities remain almost constant. Our findings quantitatively demonstrate the potential role of UL-VWF in coagulopathy.

中文翻译：

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超大血管性血友病因子多聚体在凝血病中的数值研究

摘要

冯维勒布兰德因子 (VWF) 分泌过多，加上 ADAMTS13 活性中度至重度缺乏，是炎症与血栓形成之间的联系机制。前者促进血小板粘附到血管壁，后者需要裂解 VWF 多聚体。因此，Weibel-Palade 体释放的超大 VWF (UL-VWF) 多聚体仍未被切割。在这项研究中，我们使用基于第一原理的计算模型，定量展示了未切割的 UL-VWF 多聚体如何与血细胞相互作用以引发微血栓形成。我们观察到血小板首先粘附到锚定在微血管壁上的未折叠和拉伸的未切割的 UL-VWF 多聚体上。在初始粘附阶段结束时，UL-VWF 多聚体和血小板形成网状陷阱，红细胞在其中不断积累，从而引发逐渐生长的微血栓形成。虽然激活血小板和展开 UL-VWF 需要高剪切速率和血流速度，但在初始粘附阶段，血栓形成后血流速度急剧下降，导致 UL-VWF 附近的壁剪切应力升高根，压力下降达健康状态的6倍。随着时间的推移，这些趋势逐渐持续，直到微血栓形成完全发展并且微血栓形成的有效尺寸和这些流量保持几乎恒定。我们的研究结果定量证明了 UL-VWF 在凝血障碍中的潜在作用。