PB0799 - Multi-scale modeling of SIPA showing VWF agglomeration and capture of platelets with high shear

Background: Pathologically high shear rate conditions can allow platelets to aggregate on collagen or VWF surfaces. This process is difficult to visualize experimentally with concurrent molecular- and cellular-resolutions.

Aims: Demonstrate physics of agglomeration and capture in first 10 ms.

Methods: We created a multi-scale computational model of VWF protein folding, the non-equilibrium molecular kinetics of A1-GPIb, and high shear rate convection to delineate the flow-mediated biophysics of VWF and platelets assembly into mural micro-thrombi (Figure 1). The in silico predictions are compared to experimental observations of SIPA in an in vitro microfluidic chamber.

Results: We show that high shear initially creates VWF elongation. The VWF then wraps around platelets passing the strings to cause a local agglomeration in the flow. The soluble VWF entanglement occurs before mural capture of the agglomerate by immobilized VWF. Increasing soluble VWF concentration by ~20x in silico leads to a 2~3x increase in SIPA rates, matching the increase in occlusion rates found in vitro. The morphology of mural aggregates is primarily controlled by VWF molecular weight (length), where normal-length VWF leads to cluster or elongated aggregates and ultra-long VWF leads to loose aggregates seen by others’ experiments. The entire SIPA process occurs on the order of 10 ms with the agglomerate travelling a lag distance of a few hundred microns before capture, matching in vitro results. Finally, we present phase diagrams of SIPA which provides biomechanistic rationales for a variety of thrombotic and hemostatic events in terms of platelet agglomeration and capture (Figure 2).

Conclusion(s): The model captures the early biophysics of SIPA under pathologically high shear rates to provide a mechanistic explanation for rapid platelet accumulation and VWF-related thrombotic pathologies. sVWF tentacles reach out to collect platelets in the flow while iVWF tentacles capture the agglomerates in 10 ms.