MOLECULAR MECHANISMS OF PLATELET THROMBOSIS UNDER FLOW

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About 50% of all deaths from illness in the United States each year are caused by thrombi, predominantly composed of platelets, in coronary or cerebral arteries. Although tissue plasminogen activator tPA and streptokinase have been useful in restoring blood flow in acutely occluded coronary arteries, presently available prophylactic agents (e.g., aspirin and ticlopidine) are only moderately effective in preventing the development or recurrence of arterial thrombi in the heart or brain. In order to improve the therapy of arterial thrombotic disorders, basic mechanisms involved in the induction and control of platelet thrombus formation must be better understood. Model systems capable of following in real-time shear stress-induced direct platelet activation and aggregation, as well as platelet-subendothelial adhesion and subsequent aggregation under flow, would be especially useful for this type of study. The use of human blood components and flowing conditions more closely analogous to those encountered in vivo in normal and pathological arteries would improve the in vitro evaluation of prospective anti-arterial thrombotic substances. We propose to utilize our existing real-time flow model of exposed subendothelium for the study of: the interaction of endothelial cell-derived unusually large von Willebrand factor (vWF) multimers with human fibrillar collagen type I (which predominates in atherosclerotic subendothelium) and human collagen type VI (another vWF-binding collagen), and the resulting effects on platelet adhesion; the contribution to thrombosis on collagens I and VI of vWF released from platelets; and the effects on platelet thrombosis of tPA-mediated vWF proteolysis. We will also construct real-time flow models of platelet thrombosis that include endothelial cells and, in order to simulate more closely pathological events that occur in vivo. These latter flow models will enable us to analyze: subendothelial exposure, vWF-mediated platelet-subendothelial adhesion, and subsequent aggregation in a model of vascular injury that includes surrounding endothelial cells; direct shear stress-induced vWF- mediated platelet aggregation in a model of constricted arteries under pathological flow conditions in the presence of intact endothelium; and the modulating effects on vWF-mediated events in these flow models of endothelial cell products (prostacyclin, tissue plasminogen activator, nitric oxide or activity ecto-adenosine diphosphatase).