On physical examination, he appeared mildly overweight but otherwise healthy. His blood pressure was 128/76 mm Hg. He had no petechiae, ecchymoses, jaundice or hepatomegaly. He also had no clinical evidence of significant joint destruction or active arthritis except for a poor range of motion in his right ankle.

Discussion

Factor IX deficiency, also known as hemophilia B or Christmas Disease, presents similar clinical issues as the more common factor VIII deficiency, or hemophilia A. Both are X-linked inherited bleeding disorders, and so result in a 50% risk of disease in the sons of female carriers. Affected females may have a mild bleeding tendency, particularly if there is unbalanced lyonization or X chromosome inactivation favoring the mutated factor IX-containing X chromosome. Factor IX deficiency occurs in 1 out of 100,000 newborns, only 10% of the incidence of factor VIII deficiency. Approximately one-third represent de novo mutations, and so have no associated family history of a bleeding disorder. The factor IX gene, at q27.1 of the X chromosome, was cloned in 1982 and has 8 exons, which encode a single chain, 55 kilodalton pro-enzyme. To be functional, the factor IX pro-enzyme undergoes a vitamin K-dependent, posttranslational gamma-carboxylation. In clotting reactions, the gamma-carboxylated factor IX pro-enzyme is proteolytically cleaved and activated by either activated factor XI or activated factor VII.

Both the lack of bleeding episodes without physical trauma or surgery and the lack of detectable factor IX antibody in this patient are consistent with mild hemophilia B, which correlates with his factor IX levels being consistently above 10%. The patient's family history is consistent with X-linked inheritance, with clinical manifestations in the sons of female carriers.

As in this case, the treatment for significant bleeding episodes associated with any clotting factor deficiency is factor replacement. Although fresh frozen plasma (FFP) contains factor IX, the volume of FFP required for factor replacement is too great to be clinically useful. Prior to factor IX concentrates, prothrombin complex concentrates were used to supply factor IX, as well as factors II and X, and trace amounts of activated factors, including factor VII. Prothrombin complex concentrates, although still sometimes used in patients with factor IX inhibitors, carry a small risk of inappropriate thrombosis. In addition, factor replacements in the 1980s were often contaminated with hepatitis and human immunodeficiency viruses (HIV), leading to chronic infection and viral-associated disease in substantial numbers of factor deficient patients. Careful blood donor screening has subsequently lessened the chance of contaminated donor blood, particularly since concentrated factor products are pooled from many donors. Replacement products also undergo any of several viral inactivation strategies, including dry heat (80°C for 72 hours), pasteurization (60°C for 10 hours in solution), solvent/detergent treatment and sodium thiocyanate/ultrafiltration treatment, which effectively eliminates HIV and hepatitis B and C viruses, but may still contain Parvovirus B19 and possibly hepatitis A virus (solvent/detergent). Current purified factor IX products include the solvent/detergenttreated AlphaNine and the thiocyanate/ultrafiltrationtreated Mononine. Recently, a recombinant factor IX product, BeneFix, has become available. In addition to lacking contaminating viruses, BeneFix is free of serum albumin, which is found in blood donor-derived products and has the theoretical risk of transmitting prion diseases, like the neuro-degenerative Creutzfeld-Jacob disease.

Approximately 10 % of factor IX patients have inhibitory antibodies to factor IX. These generally only occur in patients with severe (<1%) factor IX deficiency, often associated with gene deletion mutations. Bypassing products include prothrombin complex concentrates and, more recently, recombinant activated factor VII (NovoSeven).

This patient had no detectable inhibitor and had an 11% factor IX activity. The dose of factor IX for BeneFix was calculated by the standard formula of a 1% U/dL rise in activity with 1 U/kg body weight infusion, with a dose correction multiplier of 1.2, which is thought to reflect the slightly decreased biological activity with the different post-translational processing of the recombinant factor IX protein. He was treated to replace up to 100% activity immediately pre-operatively and for 10 days post-operatively to allow for wound healing. Periodic factor IX activity levels were checked to insure the adequacy of factor replacement.

Submitted on April 1, 2005