The Effect of von Willebrand Disease on Platelet Adhesion Dynamics: Correlating a Multiscale Platelet Model to in Vitro Results

Objective: Von Willebrand Disease (VWD), the most common inherited bleeding disorder affecting 0.1% to 1% of the population, causes extensive mucocutaneous bleeding across various clinical contexts. Von Willebrand Factor (vWF) plays a critical role in hemostasis by mediating platelet adhesion under high shear stress conditions. We simulated platelet-vWF interactions to investigate adhesion dynamics in VWD using a multiscale modeling approach combining Dissipative Particle Dynamics (DPD) and Coarse-Grained Molecular Dynamics (CGMD). Methods: Our platelet model provides high-resolution insights into adhesion mechanics by representing the platelet as a complex, deformable cellular entity comprising intricate membrane and subcellular components that capture the nuanced biomechanical behavior of platelets under flow conditions. Results: Simulations under 30 dyne/cm2 shear stress revealed a threshold effect: platelets failed to complete flipping and adhesion below 40% vWF density, mirroring Type 1 VWD clinical manifestations. We identified asymmetric platelet flipping dynamics with longer lift-off periods compared to reattachment periods, and revealed a distinct temporal lag between the platelet's vertical positioning and minimum bond force/contact area configurations. In vitro experiments supported these computational findings, demonstrating a significant reduction in platelet residence duration and translocation distance as vWF surface densities decreased. Conclusions: This work provides quantitative insights into the molecular mechanisms underlying platelet adhesion in VWD through our advanced CGMD model. Significance: Our findings establish a comprehensive framework for understanding cellular adhesion processes in biofluid environments, potentially informing therapeutic strategies for bleeding disorders and thrombotic conditions.