The present proposal represents the continuation of this laboratory's long-term commitment to the study of von Willebrand factor (vWF) interactions with platelets in general and of the basic and clinical aspects of Platelet-type von Willebrand's disease (vWD) in particular. Platelet-type vWD is a recently recognized bleeding disorder sharing a number of features with previously studied von Willebrand syndrome disordrs, but distinguished by primary abnormalities of the blood platelet. In particular, platelets from these patients bear exposed receptors on their surfaces that bind vWF circulating in the plasma. The proposed studies seek to determine the molecular basis of the receptor abnormalities on the platelet surface. Aggregation and 125I-vWF binding studies will be performed following incubation of patient platelets with monoclonal antibodies of well-defined specificity to platelet glycoproteins, in order to identify the receptors responsible for the spontaneous vWF binding. Two-dimensional gel, crossed immunoelectrophoretic, and peptide-mapping techniques will be employed to determine structural abnormalities of the membranes of the patient platelets. Monoclonal antibodies with specificities to the abnormal antigenic determinants will be developed, to be used both in affinity chromatography of the abnormal receptors and in in vitro models of possible future therapy for this disorder. An effort will be made to improve the current therapy of Platelet-type vWD by the administration of relatively low doses of 1-desamino-8-D-arginine vasopressin (DDAVP). In the course of these studies, plasma vWF following the DDAVP administration will be analyzed to learn if, in addition to having an abnormality of platelets, patients with Platelet-type vWD may additionally possess a primary abnormality of plasma vWF. The proposed studies may reasonably be expected to provide new knowledge directly beneficial to the care of patients with this disorder, in addition to providing much new information pertaining to the more general subject of vWF-platelet interactions.
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