The role of thrombosis in various acute coronary syndromes has been firmly established by pathological findings, angiography, and intraoperative fiberoptic angioscopy; thrombotic deposits apparently evolve from disrupted atherosclerotic plaque. The mechanism by which plaque rupture leads to a thrombus in the vicinity of stenotic lesions is not fully understood, but clearly involves the local blood rheology, the composition of the exposed vascular material and the activation of certain blood factors. The main objectives of the present grant proposal is to evaluate the importance of flow, vascular and blood factors in the evolution of thrombosis resulting from complicated atherosclerotic plaque rupture. Selected degrees of stenosis will be produced with vascular substrates (or purified components thereof) and exposed to whole blood in a well-characterized flow chamber. Various techniques will be used to evaluate platelet and fibrin deposition on the surface, including: 111-In-labelled platelets and 125-I labelled fibrinogen, morphometric evaluation of platelet and fibrin formation by both light and electron microscopy, and generation of fibrinopeptide A in effluent blood. Both a biological and laboratory approach to understanding the local velocity and mass transport profiles will be adopted. Biologically, stenotic narrowings ranging from 0 to 90% occlusion will be exposed to blood. Flow rates will be varied to simulate coronary flow. Concomitantly, a scaled-up model of the perfusion chambers will be utilized to measure flow profiles and mass transport values in the stenotic region by means of a video camera recording system. The contribution of the substrate will be investigated with materials intended to mimic various degrees of vascular damage, including normal vessels (endothelialized, de- endothelialized and stripped tunica media), atherosclerotic vessels and atherosclerotic plaque components, such as collagen Type I and III, tissue factor and various lipids. Blood factors will be studied by using animals with von Willebrand's disease or hyperlipidemia. Immunological probes, such as antibodies to vWF and platelet membrane glycoproteins Ib and IIb - IIIa and synthetic polypeptides will be used to probe specific mechanisms of thrombus formation. The elucidation of the specific pathways for the evolution of thrombotic deposits on stenotic lesions may help develop a rational approach to future therapeutic strategies in patients with coronary atherosclerotic disease.
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