Modeling the flow behavior of blood cells and von Willebrand factor in primary hemostasis

本研究的目的是为了更好地理解VWF、血小板和其他血流中的血细胞之间复杂的相互作用所导致的原发性止血过程。初始凝块的形成受到各种血流条件的影响，包括血流速率、红细胞压积（红细胞的体积分数）和红细胞之间的聚集（红细胞）。此外，VWF和血小板在血管横截面内的分布也起着重要作用，因为VWF和血小板都需要靠近血管壁才能粘附。VWF和血小板在血流中向血管壁的迁移（或边缘化）是由红细胞介导的，在之前的资助期已经进行了研究。利用所建立的血流模型和获得的VWF和血小板的粘附结果，我们将首先研究血小板和VWF在血流中粘附到模拟损伤部位的壁上。此外，血小板粘附到壁结合的VWF将被研究，这将导致VWF的进一步拉伸和血小板结合。在第二步中，将研究拉伸的VWF与自由流动的血小板的自发结合，这可能导致血栓样聚集体的形成。特别是，聚集体形成对粘附相互作用、VWF特性和流动特性的依赖将被研究，其中粘附相互作用的差异可能对应于VWF的某些突变，这对血管性血友病有影响。作为最后一步，我们将研究血管壁初始血凝块的形成，它类似于VWF/血小板网络，模拟初级止血栓。将使用VWF、血小板和红细胞在不同流动条件下的三组分混合物来研究血液凝固情况。我们的研究将基于一种中尺度流体动力学模拟技术-平滑耗散粒子动力学-该技术先前已被证明可以正确地模拟血液流动和软物体（例如聚合物，VWF）在流动中的行为。我们将与该计划的其他实验和理论项目密切互动，并期望我们的模拟将有助于更好地理解实验结果，并阐明与原发性止血有关的生物和物理机制。

The aim of this proposal is to better understand the primary hemostasis process with the intricate interplay of VWF, platelets and other blood cells in flow. The formation of an initial clot is affected by various blood flow conditions - including flow rate, hematocrit (volume fraction of red blood cells), and aggregation between red blood cells (RBCs). ln addition, the distribution of VWF andplatelets within a vessel cross-section plays an important role, since both VWF and platelets need tobe in close proximity to a vessel wall in order to adhere. The migration (or margination) of VWF and platelets toward vessel walls in blood flow is mediated by RBCs and has been investigated in the previous funding period. Using the developed blood flow model and the obtained results for margination of VWF and platelets, we will investigate first the adhesion of platelets and VWF in blood flow to a wall mimicking an injury site. Furthermore, platelet adhesion to a wall-bound VWF will be studied, which Ieads to further stretching of VWF and platelet binding. ln the second step, spontaneaus binding of stretched VWF to freely flowing platelets, which may Iead to the formation of thrombus-like aggregates, will be investigated. ln particular, the dependence of aggregate formation on adhesion interactions, VWF properties, and flow characteristics will be studied, where the differences in adhesion interactions may correspond to certain mutations of VWF, withimplications for the von Willebrand disease. As a final step, we will investigate the formation of an initial blood clot at a vessel wall, which resembles a VWF/platelet network and mimics primary hemostatic plug. Blood clotting will be investigated using a three-component mixture of VWF, platelets and RBCs for different flow conditions. Our investigations will be based on a mesoscalehydrodynamics simulation technique - smoothed dissipative particles dynamics - which has been shown previously to properly model blood flow and the behavior of soft objects (e.g., polymers, VWF) under flow. We will closely interact with other experimental and theoretical projects of the program and expect that our simulations will Iead to much better understanding of experimental results and to elucidation of biological and physical mechanisms involved in primary hemostasis.