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Platelets have been shown to be a main contributor to thrombus formation in stenotic arteries leading to acute coronary syndromes. It is thought that increased activation and adhesion of platelets under variable shear and complex flow conditions contribute to thrombosis. The objective of this work was to evaluate the relationship between asymmetric stenosis hemodynamics and platelet adhesion using in-vitro models developed to properly simulate physiological conditions. In this study, platelet rich plasma was circulated through stenotic and straight coronary artery models. Adhesion results were obtained by post-perfusion fluorescent labelling and imaging of adhered platelets. Analysis of platelet area coverage has shown maximum adhesion occurs in the distal region of the stenosis. Most likely this is due to increased exposure time of platelets to the wall of the recirculation zone following the stenosis and that exposure being directly after a period of high shear stress. This result gives us a better understanding of the importance of both shear and flow conditions in coronary artery thrombosis.

Motivated by the physiological phenomena of collapse and flow limitation for a serial pulmonary artery stenosis, we investigated the three-dimensional influence of spatial configuration on the wall motion and hemodynamic. Our numerical study focused on the effect of two geometrical parameters: the relative distance and the angular orientation between the two stenoses. The collapse of a compliant arterial stenosis may cause flow choking, which would limit the flow reserve to major vital vascular beds such as the lungs, potentially leading to a lethal ventilation-perfusion mismatch. Flow through a stenotic vessel is known to produce flow separation downstream of the throat. The eccentricity of a stenosis leads to asymmetric flow where the high velocity jets impinge on the sidewall, thereby inducing significant dissipation. The additional viscous dissipation causes a higher pressure drop for a flow through a stenotic vessel, than in a straight compliant vessel. It is likely that some particular morphology would have a higher vulnerability to the fluid induced instability of buckling (divergence), under physiological pulsatile flow. It was found that fluid pressure distribution have substantial implication for the downstream wall motion, under conditions of strong coupling between nonlinear vessel geometries, and their corresponding asymmetric flow. The three-dimensional fluid structure interaction problem is solved numerically by a finite element method based on the Arbitrary Lagrangian Eulerian formulation, a natural approach to deal with the moving interface between the flow and vessel. The findings of this investigation reveal that the closeness between stenoses is a substantial indication of wall collapse at the downstream end. Moreover, the results suggest a close link between the initial angular orientation of the distal stenosis (i.e. the constriction direction) and the subsequent wall motion at the downstream end. For cases showing evidence of preferential direction of wall motion, it was found that the constricted side underwent greater cumulative displacement than the straight side, suggestive of significant wall collapse.

Bibliography: leaves 249-279. / xv, 279 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--The University of Adelaide, Dept. of Applied Mathematics, 1999

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Atherothrombosis can induce acute myocardial infarction and stroke by progressive stenosis of a blood vessel lumen to full occlusion. The goal of this research is to determine what shear rates are pertinent to an occluding blood vessel, the rate of thrombus growth relative to wall shear rates, and to develop a predictive model for estimating length of time to thrombus occlusion for a given atherosclerotic lesion. Computational studies of severely stenotic idealized vessels were performed to investigate the wall shear rates that may exist. The study shows that maximum shear rates in severe short stenoses were found to exceed 250,000 1/s (9,500 dynes/cm2). We utilize an in vitro experiment consisting of blood flow through a collagen coated stenosis to study the rate of thrombus growth. Growth is monitored through light microscopy and a camera. Computational fluid dynamics are used to determine shear rates along the thrombus surface as it grows. We found a strong positive correlation between thrombus growth rates and shear rates up to 6,000 1/s after a log-log transformation (r=0.85, p<0.0001). Growth rates at pathologic shear rates were typically 2-4 times greater than for physiologic shear rates below 400 s-1. To determine whether transport or kinetic binding limits the rate of thrombus growth, a computational model of platelet transport was developed. The model allows for thrombus growth by occluding computational cells. We show that thrombus is transport rate-limited for shear rates below 6,000 1/s, while it is more likely to be kinetic rate-limited for higher shear rates. Predictions of occlusion times based on the model demonstrate that increases in stenosis severity results in decreased time to occlusion.

Arterial thrombus forms from the capture and accumulation of circulating platelets on a stenosis. As the thrombus grows, the lumen becomes further stenotic producing very high shear rates as the blood velocities increase through the narrowed cross-section. This study explores the molecular binding conditions that may occur under these pathologic shear conditions where circulating platelets must adhere quickly and with strong bonds. Platelets binding in an arterial stenosis of >75% are subject to drag forces exceeding 10,000 pN. This force can be balanced by 100 simultaneous GPIb-vWFA1 bonds of 100 pN each. The number and density of GPIb on platelets is sufficiently high; however, platelet capture under high shear would require the density of A1 receptors to be increased to over 416 per square micron. A computational model is used to determine platelet capture as a function of shear rate, surface receptor density, surface contact and kinetic binding rate. A1 density could be increased by a combination of vWF events of: i) plasma vWF attach to the thrombus surface and elongate under shear; ii) the elongated vWF strands create a net with 3-D pockets; and iii) additional vWF is released from mural platelets by activation under shear. With all three events, A1 density matches the existing high GPIbα densities to provide sufficient multivalency for capture at 100,000 s-1 with greater than 170 bonds per platelet. If the on-rate is greater than 108 M-1s-1, then a platelet could be captured within 15 microseconds, the amount of time available to form bonds before the platelet is swept away. This mechanism of platelet capture allows for the rapid platelet accumulation in atherothombosis seen clinically and in high shear experiments.

Photochromic Molecular Flow Visualization is an in vitro, experimental technique that uses high speed image acquisition combined with an ultraviolet laser to capture instantaneous flow profiles. It is particularly adept at measuring near wall velocities which are necessary for accurate wall shear rate measurements. This thesis describes the implementation and validation of the technique at McGill. The system was used to investigate the wall shear rate patterns in an idealized 50% asymmetric stenosis model under steady flow for Reynolds numbers 206, 99 and 50. A large recirculation zone with flow reattachment was seen downstream of the stenosis with maximum shear values occurring slightly upstream of peak stenosis for Reynolds number 206. This information is vital to ongoing dynamic cell culture experiments aimed at understanding the progression of atherosclerosis.

Errata has been inserted inside back pages. / Bibliography: leaves 180-186. / viii, 186 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Effects of stenoses on characteristics such as pressure drops, flow velocities and shearing stresses on the arterial walls are examined and their significance on the progression of arterial diseases is discussed. / Thesis (Ph.D.)--University of Adelaide, Dept. of Applied Mathematics, 1996

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