Factor IX protein, although present in a very low concentration in plasma, is essential for hemostasis. Patients with congenital deficiency of factor IX, hemophilia B, have a bleeding disorder with a prevalence of 5 per 100,000 males. These patients require an inordinate supply of donor blood products to control their bleeding and thus lead nearly normal lives. Acquired factor IX defects are uncommon by themselves but accompany the depression of other vitamin K-dependent clotting factors in liver disease and in patients on oral anticoagulants. Management of bleeding in the acquired defects is much more difficult. In order to function in clotting, factor IX must be converted to an active form, factor IXa. Just how this occurs either normally or pathologically is poorly understood as are the means of limiting its activity. Since factor IX activation is one of the initial steps of a long series of biochemical reactions which lead to clotting, it provides excellent potential for either setting off or controlling the very common disorders of thrombosis. A greater understanding of interactions between this plasma protein, blood platelets (the clotting cells) and the innner walls of the blood vessels is needed. It is proposed that elucidating the functional abnormalities and structural bases of hemophilic (abnormal) factor IX proteins will provide insights into the role of this clotting protein in normal blood clotting and thrombosis. Antibody techniques to purify abnormal factor IX proteins from patients' plasmas are being developed. The abnormal factor IX proteins will be labeled with a trace of radioactivity and studied by sensitive immunochemical methods. Characterization will include micro-screening tests for: 1) their ability to be converted from an inactive precursor to the active form, 2) their ability to be broken down by certain enzymes, 3) their functional properties as enzymes and 4) their interactions with cofactors. We will also be able to assess for unstable variants which are cleared more rapidly than normal from the circulation. Studies of hemophilic factor IX genes will be used to determine what is wrong with the structure of a given hemophilic factor IX protein by identifying the abnormality in the genetic code.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL031193-01A2
Application #
3342232
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Weinmann, A F; Schoof, J M; Thompson, A R (1996) Clinical correlates among 49 families with hemophilia A and factor VIII gene inversions. Am J Hematol 51:192-9
Kim, D J; Thompson, A R; Nash, D R et al. (1995) Factors XWenatchee I and II: compound heterozygosity involving two variant proteins. Biochim Biophys Acta 1271:327-34
Kim, D J; Thompson, A R; James, H L (1995) Factor XKetchikan: a variant molecule in which Gly replaces a Gla residue at position 14 in the light chain. Hum Genet 95:212-4
Chen, S H; Schoof, J M; Weinmann, A F et al. (1995) Heteroduplex screening for molecular defects in factor IX genes from haemophilia B families. Br J Haematol 89:409-12
Thompson, A R; Chen, S H (1994) Germ line origins of de novo mutations in hemophilia B families. Hum Genet 94:299-302
Chen, S H; Schoof, J M; Scott, C R et al. (1993) Five novel factor IX mutations in unrelated hemophilia B families. Hum Mol Genet 2:599-600
Thompson, A R; Chen, S H (1993) Characterization of factor IX defects in hemophilia B patients. Methods Enzymol 222:143-69
Weinmann, A F; Reiner, A P; Thompson, A R (1993) A polymorphic MseI site 5' to the factor IX gene varies among ethnic groups. Hum Mol Genet 2:486
Reiner, A P; Stray, S M; Thompson, A R (1992) Three missense mutations in Arg codons of the factor VIII genes of mild to moderately severe hemophilia A patients. Thromb Res 66:93-9
Thompson, A R; Schoof, J M; Weinmann, A F et al. (1992) Factor IX mutations: rapid, direct screening methods for 20 new families with hemophilia B. Thromb Res 65:289-95

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