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ABSTRACT

  • The activated form of factor IX (F.IXa), a vitamin K-dependent protein made exclusively in the liver, is an enzyme required for amplification in the series of reactions leading to blood clot formation. Factor IX deficiency (hemophilia B or Christmas disease) results in a bleeding disorder, phenotypically identical to the more common Hemophilia A, which results from a deficiency of factor VIII.

  • Clinically, the disease exists in severe (F.IX levels <1 percent normal), moderate (1 to 5 percent), and mild (6 to 30 percent) forms. The major symptom of the disease is spontaneous bleeding into joints and soft tissues. Bleeding at others sites is less common but can be life or limb threatening; for example, intracranial or compartmental syndrome bleeding.

  • A detailed and extensive database of mutations resulting in hemophilia B that includes more than 1918 patient entries as of mid 2000 (www.kcl.ac.uk/ip/petergreen/haemBdatabase.html) provides information about all known mutations.

  • Treatment options include replacement of the missing protein with purified or recombinant F.IX protein and most recently gene therapy. Complications of treatment include thrombogenicity, blood-borne viral diseases, and the development of an inhibitory F.IX antibody. The presence of an anti-F.IX inhibitory antibody is clinically problematic and treated acutely by delivery of proteins (recombinant Factor VIIa) that bypass the requirement for F.IX. In addition, initiation of immune tolerance regimens (daily injection of high doses of F.IX) is designed to eradicate the inhibitory antibody.

  • Murine and canine models of hemophilia B facilitate testing of novel therapies such as gene therapy.

HISTORICAL PERSPECTIVE

Hemophilia B, also called factor IX deficiency or Christmas disease, is an X-linked blood clotting disorder caused by a deficiency of the vitamin K-dependent blood procoagulant protein factor IX (F.IX). Hemophilia B occurs in approximately 1 in 30,000 live male births and is clinically indistinguishable from the more common hemophilia A, which is caused by a deficiency of factor VIII (F.VIII), which in the activated state, serves as the catalytic cofactor for the activated factor F.IX (F.IXa).

Hemophilia is thought to be the first X-linked genetic disease described; the Talmud vindicates abstention from circumcision, a mandated Jewish ritual in the newborn male, when the mother had a history of two sons who had died at circumcision.1 John Conrad Otto from the Philadelphia Dispensary is said to have given the first description of hemophilia in the modern day literature in 1813 and the name “hemophilia” is attributed to Hopff in 1828,6 and Schönlein in 1839.1 The distinction between the two hemophilia disorders, later shown to be F.VIII and F.IX deficiencies, was discovered in 1952 when Aggeler et al. in San Francisco,2 Biggs, MacFarlane et al. in Oxford,3 and Schulman and Smith in New York4 noted the difference between samples from patients with classic hemophilia, deficient in antihemophiliac factor (F.VIII), and a subset of other hemophilia patients.5,6 The term “Christmas disease” refers to one of the initial reports of F.IX deficiency in a family with the surname Christmas; the report appeared in the 1952 Christmas number of the British Medical Journal.3 Detailed study of procoagulant protein functions later revealed that the activated form of F.VIII (F.VIIIa) is a cofactor for the activated form of F.IX (F.IXa) ...

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