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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL032853-04A2
Application #
3344370
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-12-01
Project End
1993-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Finch, C N; Lyle, V A; Cunningham, D et al. (1996) Expression of human platelet glycoprotein Ib beta in insect cells. Thromb Res 81:679-86
Beadling, W V; Herman, J H; Stuart, M J et al. (1995) Fetal bleeding in neonatal alloimmune thrombocytopenia mediated by anti-PlAl is not associated with inhibition of fibrinogen binding to platelet GPIIb/IIIa. Am J Clin Pathol 103:636-41
Pincus, M R; Carty, R P; Miller, J L (1994) Structural implications of the substitution of Val for Met at residue 239 in the alpha chain of human platelet glycoprotein Ib. J Protein Chem 13:629-33
Miller, J L; Lyle, V A; Cunningham, D (1992) Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease. Blood 79:439-46
Kroll, M H; Mendelsohn, M E; Miller, J L et al. (1992) Monoclonal antibody AG-1 initiates platelet activation by a pathway dependent on glycoprotein IIb-IIIa and extracellular calcium. Biochim Biophys Acta 1137:248-56
Pincus, M R; Dykes, D C; Carty, R P et al. (1991) Conformational energy analysis of the substitution of Val for Gly 233 in a functional region of platelet GPIb alpha in platelet-type von Willebrand disease. Biochim Biophys Acta 1097:133-9
Miller, J L; Cunningham, D; Lyle, V A et al. (1991) Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. Proc Natl Acad Sci U S A 88:4761-5
Kroll, M H; Claure, R E; Miller, J L (1990) The monoclonal antibody AG-1, a potent stimulator of human platelets, interacts with a low molecular weight GTP-binding protein. Biochem Biophys Res Commun 171:1252-7
Finch, C N; Miller, J L; Lyle, V A et al. (1990) Evidence that an abnormality in the glycoprotein Ib alpha gene is not the cause of abnormal platelet function in a family with classic Bernard-Soulier disease. Blood 75:2357-62
Miller, J L; Hustad, K O; Kupinski, J M et al. (1990) Increased platelet sensitivity to ristocetin is predicted by the binding characteristics of a GPIb/IX determinant. Br J Haematol 74:313-9

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