SIPA in 10 milliseconds: VWF tentacles agglomerate and capture platelets under high shear

Area of Science:

• Biophysics
• Hematology
• Computational Biology

Background:

• Shear-induced platelet aggregation (SIPA) occurs at high shear rates (10,000 s-1) in stenotic arteries, potentially causing occlusive thrombosis.
• The interaction between nonactivated platelets and von Willebrand factor (VWF) via glycoprotein Ib-A1 binding drives SIPA in pathological shear environments.
• Visualizing SIPA at molecular and cellular resolutions under high shear rates is experimentally challenging.

Purpose of the Study:

• To elucidate the flow-mediated biophysics of VWF and platelet assembly into mural microthrombi under high shear conditions.
• To understand the rapid bonding dynamics of shear-induced platelet aggregation.
• To investigate the influence of VWF concentration and molecular weight on SIPA.

Main Methods:

• Employed a validated multiscale in silico model incorporating measured molecular kinetics.
• Utilized a thrombosis-on-a-chip device to simulate flow conditions.
• Analyzed VWF elongation, platelet agglomeration, and mural capture dynamics.

Main Results:

• SIPA initiates with VWF elongation, followed by platelet agglomeration via soluble VWF entanglement, and subsequent capture by immobilized VWF.
• The entire SIPA process occurs within milliseconds, with aggregates traveling hundreds of microns before capture.
• Increased soluble VWF concentration significantly elevates SIPA rates, correlating with in vitro occlusion rates.
• VWF molecular weight dictates aggregate morphology: normal VWF forms clusters/elongated aggregates, while ultra-long VWF results in loose aggregates.

Conclusions:

• The study provides a mechanistic understanding of SIPA, detailing the sequence of VWF elongation, platelet agglomeration, and capture.
• Computational modeling successfully replicates experimental observations of SIPA dynamics and VWF concentration effects.
• Phase diagrams of SIPA offer biomechanistic insights into thrombotic and hemostatic events related to platelet aggregation and capture.