Use of blood and its products for the treatment of bleeding disorders carries the risk for transmission of viral diseases such as non A, non B hepatitis and AIDS. The longterm objectives of this proposal are to establish the clinical efficacy and mechanism(s) of action of thyroid hormones in the treatment of hereditary and/or acquired hemostatic defects. A unique colony of dogs with well- characterized inherited defects and a clinical population of dogs referred for bleeding problems will be utilized. Thyroid dysfunction produces a number of hemostatic and immunohematologic abnormalities in man and dogs which can be corrected by oral thyroid therapy, but the mode(s) of action of thyroid hormones in these situations are unknown.
The specific aims of this application are: 1) To evaluate the effect and mode(s) of action of thyroid hormones on hemostatic parameters in dogs with VWD (types I and III); hemophilias A and B, and a thrombopathia similar to Glanzmann's thrombasthenia. 2) Establish hemostatic responses to thyroid hormones in a clinical population of dogs with thyroid dysfunction and/or polyglandular autoimmune syndrome. 3) Determine the effectiveness of thyroid hormone and/or DDAVP therapy for treatment of dogs with VWD and/or thyroid dysfunction and a bleeding tendency. These goals will be achieved by establishing whether thyroid hormone therapy i) results in quantitative and/or qualitative changes in plasma factors essential for normal hemostasis (e.g. the FVIII complex); ii) enhances platelet production, availability and/or reactivity; iii) reduces levels of antithyroid antibodies present in autoimmune thyroiditis which may interfere with hemostasis; and iv) alters endothelial cell metabolism. Specific assays will be used to monitor changes in coagulation factors. The levels of FVIII:C, VWF:Ag and VWF:RCoF will be correlated with alterations in cuticle (toe nail) bleeding times and FVIII multimeric profiles. Platelet adhesion, aggregation, secretion and glass-bead retention (two-stage method) will be determined as will changes in platelet biochemistry including adenine nucleotide ratios, serotonin content, thromboxane A2 generation, cyclic AMP content and fibrinogen receptor availability. Finally, synthesis and release of VWF from cultured endothelial cells will be studied in the presence and absence of thyroid hormones.
