Mechanobiology of shear-induced platelet aggregation leading to occlusive arterial thrombosis: a multiscale in silico analysis

TL;DR

This paper presents a multiscale computational model that simulates shear-induced platelet aggregation (SIPA) in arteries, providing insights into the rapid formation of thrombi under high shear conditions relevant to heart attacks and strokes.

Contribution

The study introduces a novel multiscale in silico model that directly resolves cell- and molecule-level dynamics of SIPA, validated against experimental data.

Findings

Model accurately reproduces microfluidic SIPA experiments

Platelet aggregates form within milliseconds, matching in vivo shear conditions

Provides a cross-scale tool for studying biophysical mechanisms of SIPA

Abstract

Occlusive thrombosis in arteries causes heart attacks and strokes. The rapid growth of thrombus at elevated shear rates (~10,000 1/s) relies on shear-induced platelet aggregation (SIPA) thought to come about from the entanglement of von Willebrand factor (VWF) molecules. The mechanism for SIPA is not yet understood in terms of cell- and molecule-level dynamics in fast-flowing bloodstreams. Towards this end, we develop a multiscale computational model to recreate SIPA in silico, where the suspension dynamics and interactions of individual platelets and VWF multimers are resolved directly. The platelet-VWF interaction via GP1b-A1 bonds is prescribed with intrinsic binding rates theoretically derived and informed by single-molecule measurements. The model is validated against existing microfluidic SIPA experiments, showing good agreement with the in vitro observations in terms of the morphology, traveling distance, and capture time of the platelet aggregates. Particularly, the capture of aggregates can occur in a few milliseconds, comparable to the platelet transit time through pathologic arterial stenotic sections and much shorter than the time for shear-induced platelet activation. The multiscale SIPA simulator provides a cross-scale tool for exploring the biophysical mechanisms of SIPA in silico that are difficult to access with single-molecule measurements or micro-/macro-fluidic assays only.