Basset Hound thrombopathy (BHT) is a hereditary defect in linebred dogs in which there is a severe hemorrhagic diathesis. In initial studies, glycoprotein IIb-IIIa content, 125-labeled fibrinogen binding, gold-labeled fibrinogen binding, electron micrographic morphology, platelet counts and clot retraction were found to be normal. Aggregation of BHT platelets does not occur in response to adenosine diphosphate (ADP), platelet activating factor (PAF), or A23187; is reversible in response to epinephrine; and complete in response to phorbol myristate acetate (PMA) or concentrations of thrombin greater than 0.1 U/ml. Release of dense granule contents induced by thrombin or PMA is normal but neither A23187 or epinephrine is able to induce significant release. ADP and PAF induce release of a normal quantity of ATP, but the rate of release is increased. These results suggest that BHT platelets aggregate and release only when the phospho-inositide hydrolysis pathway can be bypassed. The working hypothesis proposes that there is a defect in the inositol phospholipid second messenger system. In preliminary studies, cytoplasmic ionized Ca2+ (Cai2+) fluxes in Quin 2-loaded platelets incubated with ADP, PAF, thrombin or A23187 are normal.
Specific aims designed to methodically investigate the pathways of platelet activation include further measurement of cytoplasmic Cai2+ fluxes, assessment of the effects of the protein kinase C inhibitor H-7, measurement of thromboxane A2 production, assessment of 20 and 40-47 kDa protein phosphorylation, isolation of protein kinase C, measurement of diacylglycerol production and isolation of phospholipase A2. The overall aim of the program is to characterize the molecular abnormality responsible for the platelet aggregation and secretion defect in BHT and to investigate the stimulus-response coupling phenomena in the platelet.
| Patterson, W R; Estry, D W; Schwartz, K A et al. (1989) Absent platelet aggregation with normal fibrinogen binding in basset hound hereditary thrombopathy. Thromb Haemost 62:1011-5 |
| Patterson, W R; Kunicki, T J; Bell, T G (1986) Two-dimensional electrophoretic studies of platelets from dogs affected with basset hound hereditary thrombopathy: a thrombasthenia-like aggregation defect. Thromb Res 42:195-203 |
| Mattson, J C; Estry, D W; Bell, T G et al. (1986) Defective contact activation of platelets from dogs with basset hound hereditary thrombopathy. Thromb Res 44:23-38 |
| Padgett, G A; Bell, T G; Patterson, W R (1986) Genetic disorders affecting reproduction and periparturient care. Vet Clin North Am Small Anim Pract 16:577-86 |
