Abstract

Objectives and specific aims are: 1) To develop and characterize a recently developed rat model of thrombotic thrombocytopenic purpura (TTP) induced by a snake venom, botrocetin. The program includes ascertainment of the pathology and pathophysiology of the condition and comparison with the human disease. Alterations in hemostasis, plasma factor VIII complex, platelet function and endothelium, will be determined. Evolution and resolution of microvascular thrombi will be examined. Searches will be made for chemical agents that may prevent or alter the course of the syndrome. Possible mechanisms by which venom coagglutinin induces the disorder will be investigated; (2) To maintain inbred colonies of bleeder animals (von Willebrand disease dogs; hemophilia A and B dogs) as animal models on the corresponding human diseases; to study the genetics and pathophysiology of these diseases in animals and extend the studies, as appropriate to the human counterpart; to determine the comparative effectiveness of different plasma procoagulant fractions, particularly those of the factor VIII complex, both plasma-derived and recombinant as available, in correcting the several defects in these inherited bleeding disorders, as modified by varying gene dosages of the vWD and hemophilia A genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL001648-45
Application #
3334100
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1974-10-01
Project End
1993-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
45
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Kay, M A; Landen, C N; Rothenberg, S R et al. (1994) In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc Natl Acad Sci U S A 91:2353-7
Lozier, J N; Brinkhous, K M (1994) Gene therapy and the hemophilias. JAMA 271:47-51
Kay, M A; Rothenberg, S; Landen, C N et al. (1993) In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science 262:117-9
Nichols, T C; Bellinger, D A; Reddick, R L et al. (1993) The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A. Blood 81:2644-51
Nichols, T C; Bellinger, D A; Davis, K E et al. (1992) Porcine von Willebrand disease and atherosclerosis. Influence of polymorphism in apolipoprotein B100 genotype. Am J Pathol 140:403-15
Nichols, T C; Bellinger, D A; Reddick, R L et al. (1991) Role of von Willebrand factor in arterial thrombosis. Studies in normal and von Willebrand disease pigs. Circulation 83:IV56-64
Eaton Jr, L A; Read, M S; Brinkhous, K M (1991) Glycoprotein Ib bioassays. Activity levels in Bernard-Soulier syndrome and in stored blood bank platelets. Arch Pathol Lab Med 115:488-93
Brinkhous, K M; Reddick, R L; Read, M S et al. (1991) von Willebrand factor and animal models: contributions to gene therapy, thrombotic thrombocytopenic purpura, and coronary artery thrombosis. Mayo Clin Proc 66:733-42
Nichols, T C; Bellinger, D A; Tate, D A et al. (1990) von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis. Arteriosclerosis 10:449-61
Axelrod, J H; Read, M S; Brinkhous, K M et al. (1990) Phenotypic correction of factor IX deficiency in skin fibroblasts of hemophilic dogs. Proc Natl Acad Sci U S A 87:5173-7

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