A Mechanistic Model of Acute Platelet Accumulation in Thrombogenic Stenoses

Abstract

Thrombosis on an atherosclerotic lesion can cause heart attack or stroke. Thrombosis may be triggered by plaque rupture or erosion, creating a thrombogenic stenosis. To measure and model this situation, collagen-coated stenoses have been exposed to nonanticoagulated blood in a baboon ex vivo shunt. The maximum rate of platelet accumulation, measured using a gamma camera, was highest in the throat region of moderate and severe stenoses, and increased with increasing stenosis severity. A species transport model of platelet accumulation was developed, which included mechanisms of convection, shear-enhanced diffusion, near-wall platelet concentration, and a kinetic model of platelet activation and aggregation. The model accurately reproduced the average spatial pattern and time rate of platelet accumulation in the upstream and throat regions of the stenosis, where shear-enhanced diffusivity increased platelet transport in the stenosis throat. Downstream of the throat where flow is complicated by recirculation, the model computed a transport-limited region with lower than measured platelet accumulation, suggesting that fluid-phase platelet activation may significantly affect both transport and adhesion rates in the poststenotic region. This model may provide an initial quantitative estimate of the likelihood of occlusive thrombus in individual patients due to plaque erosion, artery spasm, incomplete angioplasty, or plaque rupture.

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

“…Fluid dynamic studies from the 1990s reported that stenotic regions influenced platelet aggregation by way of flow perturbations and recirculation zones (19,20). In particular, collagen ligands in combination with extremely high shear rates were used to detect poststenotic aggregate formation (21,22). However, in the present study, the flow conditions in the microfluidics channel were flow in straight channels.…”

Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress

“…In experiments with ␥ w ranging from a value found in normal arterioles (2000 s Ϫ1 ) to a value found at points of lumen restriction in atherosclerotic coronary arteries (40 000 s Ϫ1 ), 14,26,27 we observed that a single DAP positioned either within the platelet body or at the upstream end of a tether could be the only membrane area anchored to the surface. In the former cases it acted as a pivot during rotational or flip movements ( Figure 1E; Movie S5); in the latter, it held the whole platelet body stationary ( Figure 1F; Movie S6).…”

A Quasi-Mechanistic Mathematical Representation for Blood Viscosity

“…Above this range, blood can be considered Newtonian. The aggregability of RBCs, in turn, is dependent on the concentration of plasma proteins, especially large molecules like fibrinogen and Dextran, the hematocrit, as well as the size, shape, and rigidity of RBCs [6,7,27]. The functional dependence of deformability includes the rigidity of the RBC as well as the hematocrit-since greater packing requires more net energy to deform the cells.…”

“…The latter property is important for simulating rheological anomalies that may occur in disease. The former property is important to account for the effect of hemodilution or hemo-concentration, as well as the non-uniform distribution of red blood cells in several situations, such as capillary tubes [1], plasma skimming [2], bifurcations [3], rotary blood pumps [4], and sudden expansions [5][6][7]. Several of the models presented in Tables 1 and 2 exhibit mathematical discontinuities with respect to shear rate and/or hematocrit.…”