A three-dimensional shear dependent continuum model of platelet aggregation under flow.

Abstract

Platelet aggregation under flow is a key component of hemostasis, strongly influenced by shear-dependent interactions mediated by von Willebrand factor (vWF). We present a three-dimensional continuum model that incorporates shear-dependent platelet adhesion, cohesion, and activation. The model tracks seven platelet species and integrates shear-dependent kinetics for vWF-mediated binding and activation. Parameterization was guided by microfluidic experiments under controlled shear rates (300/s and 1500/s) with platelet activation pathways inhibited. Simulations reproduce experimental aggregate growth and occlusion dynamics in both straight channels and physiologically relevant extravascular geometries, where shear rates exceed 8000/s. Functional forms for shear-dependent on- and off-rates were implemented using piecewise and nonlinear scaling: on-rates exhibit double-threshold behavior with saturation at high shear, while off-rates combine linear and exponential terms to capture bond lifetime changes under extreme shear. Simulations using these rate forms reproduced occlusion times within the experimentally observed range. Qualitative comparisons with microfluidic imaging further demonstrated that the model reproduces intrathrombus heterogeneity, including the core-shell architecture with activated platelets concentrated near the collagen surface and unactivated platelets forming an outer shell. These results provide mechanistic insight into how shear-dependent vWF-mediated interactions regulate thrombus growth and occlusion. By linking microfluidic data with continuum-scale modeling, this framework provides a computationally efficient platform to study shear-regulated platelet aggregation and its contribution to hemostatic occlusion under physiologic and pathologic flow conditions.