Mathematical analysis of mural thrombogenesis. Concentration profiles of platelet-activating agents and effects of viscous shear flow

Abstract

The concentration profiles of adenosine diphosphate (ADP), thromboxane A2 (TxA2), thrombin, and von Willebrand factor (vWF) released extracellularly from the platelet granules or produced metabolically on the platelet membrane during thrombus growth, were estimated using finite element simulation of blood flow over model thrombi of various shapes and dimensions. The wall fluxes of these platelet-activating agents were estimated for each model thrombus at three different wall shear rates (100 s-1, 800 s-1, and 1,500 s-1), employing experimental data on thrombus growth rates and sizes. For that purpose, whole human blood was perfused in a parallel-plate flow chamber coated with type l fibrillar human collagen, and the kinetic data collected and analyzed by an EPl-fluorescence video microscopy system and a digital image processor. It was found that thrombin concentrations were large enough to cause irreversible platelet aggregation. Although heparin significantly accelerated thrombin inhibition by antithrombin lll, the remaining thrombin levels were still significantly above the minimum threshold required for irreversible platelet aggregation. While ADP concentrations were large enough to cause irreversible platelet aggregation at low shear rates and for small aggregate sizes, TxA2 concentrations were only sufficient to induce platelet shape change over the entire range of wall shear rates and thrombi dimensions studied. Our results also indicated that the local concentration of vWF multimers released from the platelet alpha-granules could be sufficient to modulate platelet aggregation at low and intermediate wall shear rates (less than 1,000 s-1). The sizes of standing vortices formed adjacent to a growing aggregate and the embolizing stresses and the torque, acting at the aggregate surface, were also estimated in this simulation. It was found that standing vortices developed on both sides of the thrombus even at low wall shear rates. Their sizes increased with thrombus size and wall shear rate, and were largely dependent upon thrombus geometry. The experimental observation that platelet aggregation occurred predominantly in the spaces between adjacent thrombi, confirmed the numerical prediction that those standing vortices are regions of reduced fluid velocities and high concentrations of platelet-activating substances, capable of trapping and stimulating platelets for aggregation. The average shear stress and normal stress, as well as the torque, acting to detach the thrombus, increased with increasing wall shear rate. Both stresses were found to be nearly independent of thrombus size and only weekly dependent upon thrombus geometry. Although both stresses had similar values at low wall shear rates, the average shear stress became the predominant embolizing stress at high wall shear rates.

Fluid mechanics of arterial stenosis: Relationship to the development of mural thrombus

“…The process of thrombosis may be affected by a series of rheological and fluid dynamic parameters, including high rates of shear, areas of flow stagnation or recirculation, and turbulence (10,15). Transfer of platelets and other clotting factors to the vascular wall is accomplished through diffusive and convective mechanisms.…”

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

“…The flow disturbances at sites of severe stenosis may even lead to fatal occlusive thrombus formation in humans (12). Simulations indicate that plaque geometries induce gradients in pressure, flow velocity, and shear stress of the local blood flow, as a consequence of which autocrine agonists may get trapped that enhance platelet activation (13). However, the mechanisms dictating sheardependent platelet aggregation at sites of atherosclerotic stenosis remain poorly understood.…”

Effects of local geometry and fluid dynamics on regional platelet deposition on artificial surfaces.

“…To date, the vast majority of experimental observations includes flow visualization using latex beads; concentration profiles using freeze-capture methods; or bulk flow-type effects of high rates of fluid shear, areas of recirculation, and flow separation and reattachment on platelet aggregation and adhesion in flow chamber geometries that deviate greatly from those found in the circulation. The only direct correlations of local fluiddynamic events with platelet adhesion and aggregation on surfaces 9 " were obtained at extremely low Reynolds numbers to simulate flow in the microcirculation.…”