FIBRINOGEN RECEPTORS IN HEREDITARY THROMBOPATHIA

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A platelet disorder in line-bred Basset Hounds with stress related bleeding has been detected. It has been labeled Basset Hound thrombopathia (BHT). This disorder has many characteristics in common with thrombasthenia in humans except for the presence of normal clot retraction. A primary, intrinsic failure of aggregation exists as in thrombasthenia, but there is evidence for a normal membrane content of glycoprotein (GP) IIb-IIIa. After preliminary studies, a hypothesis that fibrinogen receptors are abnormal in BHT was developed. It appears likely that the glycoprotein orientation or exposure, usually resulting in platelet-fibrinogen association and aggregation, is congenitally disturbed in BHT platelets. The specific aims of the program are to measure platelet fibrinogen binding, assay platelet ectosialyltransferase activity, conduct crossed immunoelectrophoresis and isolate functional GP IIb-IIIa complex for in vitro fibrinogen binding assay, and measure sugar membrane incorporation to determine post-ribosomal glycosylation. Utilization of 125I-fibrinogen binding, crossed immunoelectrophoresis, high resolution two-dimensional electrophoresis, ectosialyltransferase assays, and sialic acid quantitation may reveal the pathogenesis of BHT and substantially forward the understanding of the development of platelet membrane receptors. The isolation and recombination of hybrid complexes of BHT and normal glycoprotein IIb-IIIa subunits into functional and dysfunctional units should fix precisely the site of dysfunction. Because of the role of platelets in the initial response to vascular injury, this proposal is important in dissecting the platelet fibrinogen receptor and may, thereby, result in a better understanding of the phenomena of platelet aggregation.