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

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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.