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Hemophilia B (factor IX deficiency, Christmas Disease) results from mutations in the Factor IX gene, which is located on the long arm of the X-chromosome. Hemophilia B occurs in the general population at one-sixth the incidence of Hemophilia A, affecting approximately 1 in 30,000 male births. The severity of Hemophilia B is classified according the baseline Factor IX level. Severity of Hemophilia B
Concentrates Containing Factor IX Factor IX concentrates can be prepared from large pools of human plasma or synthesized by recombinant DNA techniques. Two types of plasma derived Factor IX concentrates are available: prothrombin complex concentrates and purified Factor IX concentrates. Improved viral depletion processes and donor screening practices have greatly reduced the risk of HIV and hepatitis B and C transmission. Viral depletion methods include dry heat at 80oC for 72 hours, solvent-detergent, vapor heat (pasteurization) and sodium thiocyanate plus ultrafiltration. Factor IX purification also removes virus particles. In spite of these safeguards, plasma derived Factor IX concentrates still carry a slight risk of viral or prion transmission. The following table contains a list of Factor IX products available in the United States.
Prothrombin complex concentrates contain coagulation Factors II, VII, IX and X. Factor IX specific activity is low; less than 5 units of Factor IX per mg of protein. These complexes have been associated with arterial and venous thrombosis including DIC, deep venous thrombosis, pulmonary embolism, and myocardial infarction. Patients at greatest risk for developing thrombotic complications are those who are immobile, have crush injuries, liver disease, or massive hemorrhage. Thrombotic risk is greatest when large amounts of prothrombin complex are given to raise the plasma Factor IX level above 50%. In these situations, it is safer to use purified Factor IX concentrate. Purified Factor IX concentrates are produced by multiple chromatography or immunoaffinity chromatography. These purification steps remove extraneous plasma proteins, activated coagulation factors, and viruses. They have higher Factor IX specific activity, approximately 200 units per mg of protein. The FDA licensed Recombinant Factor IX (BeneFIX) in February 1997. It is produced in Chinese hamster ovary (CHO) cells by co-transfection with a plasmid coding for human recombinant FIX plasmid and a plasmid for the paired amino acid cleaving enzyme (PACE). PACE improves the cell's efficiency of converting a precursor peptide to Factor IX. Cells are grown in a medium that is free of animal and human derived proteins. The final product is stabilized with sucrose. BeneFIX is virtually free of risk of transmission of human bloodborne viruses and prions. Hemophilia B Treatment Recommendations The Medical and Scientific Advisory Council of the National Hemophilia Foundation considers recombinant Factor IX concentrate to be the treatment of choice for young and newly diagnosed patients. Recombinant or purified Factor IX concentrates, rather than prothrombin complex concentrates, are recommended in clinical situations associated with a higher risk of thromboembolic complications such as surgery or severe hemorrhage requiring treatment 1 to 2 times per day. The increased purity of these products largely eliminates the risk of thrombotic complications. HIV seropositive patients with hemophilia B should be treated with purified or recombinant Factor IX concentrates to prevent immune suppression. Dosage Guidelines for Factor IX Replacement Bleeding from hemophilia B is clinically indistinguishable from hemophilia A. Indications for Factor IX replacement are similar to Factor VIII. General guidelines are:
Dosage Guidelines for Factor IX Replacement
Patients undergoing dental procedures such as tooth extractions should receive antifibrinolytic therapy with aminocaproic acid (Amicar) in conjunction with factor replacement. Treatment should be started the evening prior to the procedure and continued for 5 to10 days. Amicar loading dose is 200 mg/kg and maintenance dose is 100 mg/Kg every 6 hours. Loading dose should not exceed 10g and maintenance dose should not exceed 30g per day. Children with severe hemophilia B should begin receiving prophylactic therapy at one to two years of age prior to the onset of frequent bleeding. The treatment goal is to keep the trough Factor IX level above 1% between doses. This goal can usually be accomplished by giving 40-100 units of BeneFIX/kg twice weekly. Factor IX Dosage Calculation & Administration The number of Factor IX units in each lot of concentrate is printed on each vial. The lyophilized concentrate is suspended in sterile water and administered intravenously with a syringe and filter within three hours after reconstitution. The following formula is used to calculate the number of factor IX units needed; Body weight (kg) X desired Factor IX increase (%) X 1.0 1.0 represents the factor IX volume of distribution; one unit of Factor IX should raise plasma levels by 0.01 U/mL or 1%. For example, if you want to raise a 70 kg patient's factor IX level from 0 to 50% the following formula would be used: 70 kg X 50% X 1.0 = 3500 units of Factor IX. The circulating half-life of Factor IX ranges from 20 to 24 hours. Daily or every other day dosing is usually adequate, but each patient's therapy needs to be individualized by following Factor IX levels. A citrate (blue top) tube should be drawn before the loading dose to determine the baseline level, 1 hour after the dose to determine the peak level, and immediately before the next dose to determine the trough level. Caution must be exercised in calculating the dosage of recombinant Factor IX. BeneFIX has lower recovery values than plasma derived Factor IX concentrate due to differences in the post-translational modification of the final protein. In some cases the observed rise in Factor IX level may only be 50% of the expected value. Therefore, higher doses of BeneFIX may be required. The BeneFIX package insert recommends the following dosage calculation: # Factor IX Units required = Body weight (kg) X desired Factor IX increase (%) x 1.2 However, because of the wide variation in recovery between individuals a factor greater than 1.2 may be necessary. Factor IX Inhibitors Inhibitors develop in only 1 to 4% of persons with hemophilia B. Approximately 40% have titers less than 5 BU, while the majority has higher titers. Patients with low titers, less than 10 Bethesda units, can be treated with sufficient quantities of Factor IX concentrate to overwhelm the inhibitor. Recombinant Factor VIIa (NovoSeven) received FDA approval and became commercially available on April 19, 1999. NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. Factor VIIa complexes with tissue factor at the site of injury and induces activation of Factor X, resulting in clot formation. The recommended dose is 90 ug/kg by IV bolus given every two hours until hemostasis is achieved. For severe bleeds, dosing should be continued at 3 to 6 hour intervals to maintain hemostasis. Recombinant Factor VIIa is supplied in three sizes: 1200, 2400 and 4800 ug/vial. |
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