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

Abstract

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). 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. 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. This work provides quantitative insights into the molecular mechanisms underlying platelet adhesion in VWD through our advanced CGMD model. Our findings establish a comprehensive framework for understanding cellular adhesion processes in biofluid environments, potentially informing therapeutic strategies for bleeding disorders and thrombotic conditions.