The aim of this research is to apply state of the art rheological techniques and transport phenomena models to the study of specific problems in coagulation and thrombosis.
Five specific aims are proposed for investigation. Endothelial cells which line blood vessels are subjected to shear stresses due to blood flow and mechanical strain due to the pressure pulse acting on the compliant wall. The effect of both stress and strain on intracellular arachadonic acid metabolism and protein synthesis and secretion will be determined. Specific target proteins have been identified tissue plasminogen activator, plasminogen activator inhibitor - type 1, fibronectin and von Willebrand factor. Each of these proteins is important in thrombosis and synthesized by endothelial cells. Preliminary data show dramatic effects of arterial shear stress on TPA synthesis and secretion. A continuing question is the problem of how the mechanical signal is transduced to effect intracellular changes. We will utilize epi- fluorescent video microscopy and digital image processing to study stress effects on calcium fluxes and intracellular pH. Again, preliminary data show striking calcium transients in response to changes in flow. Our equipment can determine both multicellular averages and single cell changes in fluorescence. An important question to be answered is the importance of stress (or strain) magnitude versus the rate of change of stress (or strain). Since arterial blood flow is inherently pulsatile, in vivo application of our in vitro results will require this knowledge. The biochemical control of thrombus formation on model damaged blood vessel and biomaterial surfaces will be investigated. Our hypothesis is that blood flow greatly modulates the local concentration of important activating species near growing thrombi. Our clearly results predicted an important role for thrombin in platelet recruitment even in the presence in heparin. We will combine epi-fluorescence video microscopy and mathematical modelling to study the role of specific coagulation factors and fluid mechanics in mural thrombus formation and embolization.
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