von Willebrand Factor unfolding mediates platelet deposition in a model of high-shear thrombosis

TL;DR

This study develops a comprehensive 3-D thrombosis model incorporating vWF unfolding, validated against experimental and clinical benchmarks, to better understand high-shear thrombosis and bleeding disorders.

Contribution

It introduces a novel continuum model for vWF unfolding integrated into a multi-constituent thrombosis simulation, capturing complex flow effects and patient-specific deficiencies.

Findings

Model accurately reproduces thrombus formation and growth dynamics.

Simulations match clinical occlusion times for various vWD types.

The approach enables detailed analysis of shear-dependent thrombosis mechanisms.

Abstract

Thrombosis under high-shear conditions is mediated by the mechanosensitive blood glycoprotein von Willebrand Factor (vWF). vWF unfolds in response to strong flow gradients and facilitates rapid recruitment of platelets in flowing blood. While the thrombogenic effect of vWF is well recognized, its conformational response in complex flows has largely been omitted from numerical models of thrombosis. We recently presented a continuum model for the unfolding of vWF, where we represented vWF transport and its flow-induced conformational change using convection-diffusion-reaction equations. Here, we incorporate the vWF component into our multi-constituent model of thrombosis, where the local concentration of stretched vWF amplifies the deposition rate of free-flowing platelets and reduces the shear cleaning of deposited platelets. We validate the model using three benchmarks: in vitro model of atherothrombosis, a stagnation point flow, and the PFA-100, a clinical blood test commonly used for screening for von Willebrand Disease (vWD). The simulations reproduced the key aspects of vWF-mediated thrombosis observed in these experiments, such as the thrombus location, thrombus growth dynamics, and the effect of blocking platelet-vWF interactions. The PFA-100 simulations closely matched the reported occlusion times for normal blood and several hemostatic deficiencies, namely, thrombocytopenia, vWD Type 1, and vWD Type 3. Overall, the multi-constituent model of thrombosis presented in this work enables macro-scale 3-D simulations of thrombus formation in complex geometries over a wide range of shear rates and accounts for qualitative and quantitative hemostatic deficiencies in patient blood. The results also demonstrate the utility of the continuum model of vWF unfolding that could be adapted to other numerical models of thrombosis.