Background: Shear-induced platelet aggregation (SIPA) under elevated shear rates (~10,000 1/s) is a major hallmark of occlusive arterial thrombosis. SIPA specific to elevated shear rates is independent of platelet activation while exclusively controlled by von Willebrand Factor (VWF). Current in vitro and in vivo assays lack resolution to capture the sub-cellular dynamics of SIPA within ultra-fast time scale of 10 ms and pathologically high shear rates. Prior in silico thrombosis models tend to ignore the presence of VWF.

Aims: Develop an in silico biophysical model to create SIPA, where the dynamics and interaction of individual VWF polymers and platelets are resolved directly.

Methods: The dynamics of platelet and VWF are computed through a multiscale blood flow solver. The GP1b-A1 binding kinetics are created from single-molecule measurements. The times to form a platelet agglomerate that is then captured at the wall are used as the end points for quantifying the rate of SIPA. A microfluidic thrombosis-on-a-chip platform is used to validate the in silico predictions.

Results: Results show that platelet agglomerates form in the flow prior to surface adherence (Figure A). Subsequent capture of the agglomerate creates a SIPA process within ~10 ms, equivalent to the transit time through an atherosclerotic stenosis. Increasing soluble VWF concentration by 20x in the model leads to 2~3x increase SIPA rates. This matches the increase in occlusion rates observed in vitro. (Figure B).

(A) In silico formation of a platelet aggregate entangled by VWF polymers through forming GP1bα-A1 bonds on a thrombogenic surface pre-coated with immobilized VWF. (B) Increment of SIPA rate (in terms of agglomeration rate and capture rate) or occlusion rate with respect with the elevation of soluble VWF concentration.

Conclusions: A multiscale in silico model for high shear-induced platelet aggregation pertinent to arterial thrombosis is developed and validated against in vitro experiments of macroscopic occlusion rates. The in silico thrombotic model can be used to precisely design VWF-targeting drugs to control agglomeration or capture of platelets in arterial thrombosis.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/agglomeration-and-then-capture-within-10-ms-creates-shear-induced-platelet-aggregation-controlled-by-von-willebrand-factor-concentration/