DESCRIPTION: (Adapted from investigator's abstract). Colonies of animals with inherited coagulation and platelet function defects are maintained for genetic, biochemical, and physiological studies; production of agents for coagulation tests; and evaluation of hemostasis. These include dos with hemophilia A, hemophilia B, von Willebrand's disease (vWD), factor VII deficiency, thrombasthenia, and thrombopathia. Studies with these naturally occurring animal models examine basic mechanisms of hemostasis and thrombosis in comparison to analogous human diseases. The continued diagnosis, characterization and maintenance of animal models of spontaneous hemorrhagic and thrombotic diseases is a major objective for the next period. Our research efforts will focus on: (1) utilization of well-defined canine models of vWD and hemophilia to study the FVIII/vWF complex including determination of the complementary DNA sequence for the canine vWF gene; (2) the action of thyroid hormone (T4) on vWF gene expression; and (3) continue ongoing characterization studies related to signaling pathways in thrombopathic platelets. Consultation about the comparative aspects of hemostasis research and bleeding disorders as well as collaboration with other investigators in research projects will also continue. Reagents, genetic material and other animal products will be provided based on availability. Specific aims for the period include: comparative molecular genetic analysis of canine and human von Willebrand factor/vWF; establish whether endothelial cells are the exclusive site of synthesis, storage, and release of canine vWF; identify functional domains of canine vWF; examine the stability of canine FVIII coagulant in the absence of vWF in type III canine vWD; utilize a new sensitive ELISA assay to characterize vWF in a variety of species and assess vWF gene expression and the thyroid endocrine axis in mutant hypothyroid mice. Platelet studies will focus on definition of the biochemical defect of canine thrombopathia, specifically the role of cAMP in regulating platelet signal transduction.