CANINE COAGULOPATHIES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Manv hereditary coagulopathies have been reported in dogs and few of these disorders have been characterized and serve as disease homologues to study the pathogenesis and to develop novel therapies including recombinant therapy and gene transfer. Fibrinogen Deficiency: We have identified a mixed breed dog with excessive post-operative hemorrhage due to a severe hypofibrinogenemia. This dog has severally prolonged screening coagulation times and by functional as well as protein assays very low fibrinogen levels. A lack of fibrinogen prevents the formation of any fibrin clot and also is expected to affect wound healing. This is the only animal with a naturally occurring hypofibrinogenemia, although transgenic mice have been produced. As we have access to this dog studies are planned to further characterize the biochemical and molecular basis of this defect. Factor VII Deficiency We have identified several Beagles in the pet population with a mild to moderate bleeding tendency due to a hereditary factor VII deficiency. These animals have persistently 5% of control factor VII activity and no inhibitor has been found. Other affected Beagles have been found in research animal colonies of pharmaceutical companies, while performing drug studies based upon a prolonged partial thromboplastin time. Recombinant human factor VII has recently been shown to be effective in a variety of coagulopathies including hemophilia as it can bypass the defect. Therefore the molecular characterization and establishment of a dog colony with factor VII deficiency would be highly desirable. These studies in collaboration with Mary Beth Callan VMD and Kathy High MD PhD at the Children Hospital of Philadelphia, led to the discover of a single missense mutation and a severally dysfunctional protein. A simple reliable DNA test has been developed to screen for carriers and factor VII deficient Beagles, thereby permitting the establishment of a colony to study novel gene transfer approaches. Hemophilia A: After the initial description of an inversion mutation in a factor VIII deficient dog colony similar to what is the major molecular mechanism in hemophilic humans, we have been examining other hemophilic dogs¿ DNA for this inversion in collaboration with Jay Lozier PhD at NIH. Of the five initiallydogs none had this form of a molecular defect and further studies are in progress. Factor XI Deficiency: We had earlier described factor XI deficiency in Kerry Blue Terriers which experience a delayed post-operative hemorrhagic diathesis. Recently we identified two deficient dogs from a major breeder and with cooperation we are planning to investigate the molecular defect. This should be readily achievable as the entire genomic sequence is now available from the canine genome project. There are still questions regarding the precise mode of inheritance (recessive verus incomplete dominant) and no other therapeutic options other than fresh frozen plasma are currently available. Although there are cattle with factor XI deficiency, this is the only naturally occurring animal suitable for further labortary investigations of novel therapeutic strategies. Von Willebrand Disease Doberman pinschers have a high prevalence of type I von Willebrand disease. Type I refers to the proportional deficiency of all multimeric sizes of von Willebrand factor. We have utilized this animal model to further characterize the effect of desmopressin, a vasopressin analog, which is commonly used in the treatment of human von Willebrand disease but its mechanism is poorly understood. We learned that the effect of desmopressin is not dependent on platelet associated von Willebrand factor and either not solely or not at all related to the multimeric size of the von Willebrand factor. Further mechanisms related to the endothelium are being examined.