PATHOBIOLOGY OF HUMAN FACTOR IX: STRUCTURE AND FUNCTION

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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.