Replacement of factor IX is essential for the prevention and treatment of hemorrhage in hemophilia B. Earlier forms of replacement therapy were crude preparations of donated plasma that were often only partially effective. The production of highly concentrated factor IX preparations had a major impact in the management of hemophilia B, facilitating home therapy, early treatment of bleeds, amelioration of joint damage, and a marked improvement in quality of life. However, their use was associated with serious complications:

1. Transfusion-transmitted infection (TTI)

The use of donated plasma in the management of hemophilia led to the transmission of infectious agents to recipients. Hepatitis B and non-A-non-B hepatitis (later recognized as hepatitis C) were shown to be very common in individuals with hemophilia. In the early 1980s, the catastrophe of HIV transmission through blood products emerged in the hemophilic population, and 60-80% of severe hemophiliacs in Europe and the United States were infected. The risk of TTI was highest with concentrates prepared from larger donor pools. The concentrates that had led to a major improvement in the quality of life of these individuals had also caused the tragedy of transfusion-transmitted infection, which had become the leading cause of death in this population. The risks of TTI have been greatly reduced by measures such as blood donor exclusion policies and virucidal treatment of concentrates.

2. Inhibitor development

The use of FIX replacement therapy may lead to the development of neutralizing antibodies (inhibi-

tors) against FIX and may render the individual refractory to further treatment. Inhibitors may appear transiently in children with hemophilia but persist in approximately 1.5-3% of severely affected hemophilia B patients. In such cases, hemorrhage may be life threatening or may lead to more severe muscu-loskeletal complications. There is a strong association between inhibitor development and underlying genetic defect (discussed later). The inhibitors may disappear with immune tolerance strategies and bleeding episodes in inhibitor patients may respond to treatment with recombinant FVIIa.

3. Thrombosis

Earlier FIX concentrates also contained large amounts of the other vitamin K-dependent coagulation factors: II, VII, and X; the intravenous infusion of these factors: which patients with hemophilia B are not deficient in, led to high plasma levels and thrombotic complications. With the development of high-purity FIX concentrates, thrombosis became far less common.

Recent Developments in Therapy

Recombinant factor IX

The cloning and expression of the factor IX gene led to the development of recombinant factor IX concentrate, which has no exposure to human protein and minimal exposure to animal protein. Pharmacokinetic and efficacy studies have demonstrated satisfactory in vivo recovery although substantially lower than for plasma-derived factor IX concentrate probably because of minor posttranslational differences. Recombinant factor IX concentrate is now widely used.


The availability of safer products has also led to a change in therapeutic strategy in that prophylaxis of bleeding is now widely used, particularly in children. This necessitates the intravenous administration of factor IX in doses of 25-40 u/kg twice weekly and leads to a marked reduction in spontaneous bleeding episodes and an improvement in quality of life.[4]

Gene therapy

Hemophilia B (and A) is well suited for gene therapy because it is entirely due to a single gene defect, the therapeutic window is broad, and there are good animal models. Clinical studies on hemophilia B have been performed using autologous skin fibroblasts transduced with FIX retroviral vector and adenovirus-associated gene transfer by intramuscular and hepatic artery infusion. Results of such studies are moderately encouraging, but major challenges remain particularly in improving and maintaining expression of factor IX and ensuring safety. Several new approaches to gene therapy are in development and promise to make a major contribution to the treatment of hemophilia.[5]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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