SUMMARY

Platelet accumulation under high shear rates at the site of atherosclerotic plaque rupture leads to myocardial infarction and stroke. To address the need for risk stratification and therapy monitoring, the overall objective the present study is to design a physiologically relevant device for the routine assessment of high-shear thrombosis and develop an improved model of shear induced platelet accumulation that incorporates the concentration of plasma protein von Willebrand factor and the vWF-A1 platelet-binding domain availability. First, the effects of arterial-like flow pulsatility on high shear platelet accumulation will be investigated. Subsequently, a microfluidic test section and fluid handling system will be developed to investigate shear induced platelet accumulation with small (<10 mL) blood volumes. To demonstrate the dependence of thrombus formation on vWF concentration, the test section will be used to quantify thrombus formation in a blood analog with a range of concentrations of vWF, both with and without fibrinogen. To demonstrate that platelet binding site availability increase with shear rate, the test section will also be used to perfuse platelet poor plasma over platelet-coated collagen at shear rates from 500 to 100 000 s-1. Fluorescently labeled A1 domains on platelet-bound vWF will be imaged using super-resolution microscopy techniques to quantify A1 domain availability as a function of shear rate. Incorporation of the results into a model of the effects of vWF and other plasma protein concentration in high shear occlusive thrombus formation may serve to identify targets for future therapies, and in conjunction with high shear platelet function testing, may be used to evaluated patient-specific risk of ischemic events and to monitor patient response to treatment.