Platelet thrombus formation occurs when platelets become activated, secrete vasoactive and proaggregatory substances and aggregate. These platelet responses develop under flow conditions that modulate specific molecular interactions between platelet surface receptors and extracellular ligands. Previous studies demonstrate that pathological arterial wall shear stresses cause plasma von Willebrand factor (Vwf) to bind to the platelet glycoprotein (GP) Ib/IX/V and GPIIb-IIIa complexes, and that this binding leads to platelet activation associated with secretion and aggregation. The purpose of this proposal is to determine precisely the mechanisms by which large and unusually large Vwf multimers bind to platelets under shear, influence the threshold of shear-induced platelet-Vwf interaction, and signal the functional responses that lead to platelet thrombus formation. Elucidation of these mechanisms will involve studies on platelets from normal subjects, as well as on platelets from patients with thrombotic thrombocytopenic purpura (TTP) and other disorders. Systemic microvascular platelet aggregation, producing organ ischemia and thrombocytopenia, is the essential pathophysiologic event in patients with TTP. The precise explanation for excessive platelet activation and aggregation in vivo in this paradigm of arterial thrombosis is presently unknown. There is indirect evidence that Vwf multimers, especially unusually large Vwf forms, may be release from stimulated or injured endothelial cells in TTP. It is not known, however, if plasma Vwf multimers subsequently attach to platelets and induce aggregation in high shear stress regions of the microcirculation in TTP patients. The investigators will determine by direct flow cytometric analysis: whether or not Vwf binds to the platelets of TTP patients in vivo; and, if so, whether or not Vwf attachment to platelets occurs concurrently with the intravascular platelet activation, aggregation and thrombocytopenia that characterize TTP episodes in patients who have chronic relapsing, single episode and other types of TTP. They also will determine if the initiation, progression and recovery from incipient or severe TTP episodes correlates with: platelet-bound Vwf, platelet activation, platelet aggregation; and with the response of these platelet parameters in vitro shear stress.
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