Hemophilia B Medication
- Author: Robert A Zaiden, MD; Chief Editor: Steven C Dronen, MD, FAAEM more...
Medication Summary
Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, CNS, trauma related, GI, GU, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).
One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is approximately 100 mL/kg. To find the number of units of factor IX needed to correct the factor IX activity level, use the following:
Units factor IX = (weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)
The difference between the desired factor IX activity level and the patient's native factor IX activity level is expressed as a fraction. For example, if 100% activity is desired and the patient’s native activity is 5%, the calculation is as follows:
100% - 5% = 95% or 0.95
As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the emergency department with a serious upper GI bleed. The desired factor IX activity level is 100%. The dose of factor IX to administer to the patient would be calculated as follows:
Units factor IX = (80 kg)(100 mL/kg)(1 U factor IX/mL)(.99) = 7920
The next dose should be administered 24 hours after the first and is one half of the initial calculated dose.
Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for major hemorrhage.
Factor Ix-containing Products
Class Summary
These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to hemorrhage or preventing hemorrhage.
Factor IX (BeneFIX, Mononine, AlphaNine SD)
This synthetic factor IX is a recombinant product using no human products for stabilization.
Plasma-derived prothrombin complex concentrates (Human) (Bebulin, Profilnine SD),
These pooled plasma products (high purity) replace deficient FIX and other factors in the complex.
Fresh frozen plasma (FFP)
Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.
Coagulation Factor VIIa (Recombinant)
Class Summary
These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.
Factor VIIa, recombinant
This agent is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.
Antifibrinolytics
Class Summary
These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. These agents are used in prophylaxis for oral surgery and in the treatment of excessive bleeding in the oral mucosa that results from local fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).
Epsilon aminocaproic acid (Amicar)
This is a lysine analog that binds to natively produced plasmin, reducing its fibrinolytic activity.
This agent inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.
This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.
Tranexamic acid (Cyklokapron)
Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.
Antihemophilic Agents
Class Summary
These agents are used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.
These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.
These agents raise endogenous FVIII levels in mild hemophilia A. Increases as much as 3-fold from the baseline are observed, with peak responses at 30-60 minutes after infusion.[23]
These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.
Anti-inhibitor coagulant complex (FEIBA VH)
This agent binds to exposed tissue factor and directly activates FX.
Desmopressin (DDAVP, Stimate)
The main effect of desmopressin is enhancement of water reabsorption in the kidney and smooth muscle constriction. It causes a dose-dependent increase in plasma FVIII and plasminogen activator.
This agent increases the cellular permeability of collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur, even after first dose, but the drug can be effective again after several days.
Human antihemophilic factor (Hemofil M, Koate-DVI)
FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.
Recombinant human antihemophilic factor (Recombinate, Kogenate, Helixate, Advate)
FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.
Plasma-derived prothrombin complex concentrates/Factor IX complex concentrates (Bebulin, Profilnine SD)
This agent replaces deficient FIX and other factors in the complex.
Plasma-derived coagulation factor IX concentrate (Alpha Nine SD, Mononine, BeneFIX)
This agent replaces deficient FIX and other factors in the complex. AlphaNine SD and Mononine contain only FIX. BeneFIX is a recombinant product.
Monoclonal Antibodies
Class Summary
These agents are monoclonal antibodies directed against the CD20 antigen on B cells. They are recommended as second-line therapy in the treatment of factor IX inhibitors, especially in cases with high inhibitor titers.
Rituximab (Rituxan)
Rituximab binds to, and mediates destruction of, B-cells, thereby decreasing production of inhibitors and autoimmunization.
Venkateswaran L, Wilimas JA, Jones DJ, Nuss R. Mild hemophilia in children: prevalence, complications, and treatment. J Pediatr Hematol Oncol. Jan-Feb 1998;20(1):32-5. [Medline].
Loveland KA, Stehbens J, Contant C, Bordeaux JD, Sirois P, Bell TS, et al. Hemophilia growth and development study: baseline neurodevelopmental findings. J Pediatr Psychol. Apr 1994;19(2):223-39. [Medline].
Jones PK, Ratnoff OD. The changing prognosis of classic hemophilia (factor VIII "deficiency"). Ann Intern Med. Apr 15 1991;114(8):641-8. [Medline].
Chorba TL, Holman RC, Strine TW, Clarke MJ, Evatt BL. Changes in longevity and causes of death among persons with hemophilia A. Am J Hematol. Feb 1994;45(2):112-21. [Medline].
Ewenstein BM, Wong WY, Schoppmann A. Bypassing agent prophylaxis for preventing arthropathy in patients with inhibitors. Haemophilia. Jan 2010;16(1):179-80. [Medline].
Berntorp E, Astermark J, Björkman S, Blanchette VS, Fischer K, Giangrande PL, et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia. May 2003;9 Suppl 1:1-4. [Medline].
Ljung RC. Prophylactic infusion regimens in the management of hemophilia. Thromb Haemost. Aug 1999;82(2):525-30. [Medline].
Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. Sep 7 2011;9:CD003429. [Medline].
Miners AH, Sabin CA, Tolley KH, Lee CA. Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease. J Intern Med. Dec 1998;244(6):515-22. [Medline].
Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL Jr, Reynolds TC, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. Aug 2007;205(2):256-65. [Medline].
Siddiqui MA, Scott LJ. Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders. Drugs. 2005;65(8):1161-77. [Medline].
Coppola A, Margaglione M, Santagostino E, Rocino A, Grandone E, Mannucci PM, et al. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost. Nov 2009;7(11):1809-15. [Medline].
Carcao M, St Louis J, Poon MC, Grunebaum E, Lacroix S, Stain AM, et al. Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience. Haemophilia. Jan 2006;12(1):7-18. [Medline].
Aggarwal A, Grewal R, Green RJ, Boggio L, Green D, Weksler BB, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia. Jan 2005;11(1):13-9. [Medline].
Stachnik JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother. Jun 2006;40(6):1151-7. [Medline].
Personal communication with Dr. Troy H. Guthrie, Jr. MD, Medical Director Baptist Cancer Institute, Jacksonville, Florida.
Duncan N, Kronenberger W, Roberson C, Shapiro A. VERITAS-Pro: a new measure of adherence to prophylactic regimens in haemophilia. Haemophilia. Mar 2010;16(2):247-55. [Medline].
Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, Schutgens R, Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment. Haemophilia. Nov 2009;15(6):1215-8. [Medline].
Ingerslev HJ, Hindkjaer J, Jespersgaard C, Lind MP, Kølvraa S. [Preimplantation genetic diagnosis. The first experiences in Denmark]. Ugeskr Laeger. Oct 1 2001;163(40):5525-8. [Medline].
Lissens W, Sermon K. Preimplantation genetic diagnosis: current status and new developments. Hum Reprod. Aug 1997;12(8):1756-61. [Medline].
Wells D, Delhanty JD. Preimplantation genetic diagnosis: applications for molecular medicine. Trends Mol Med. Jan 2001;7(1):23-30. [Medline].
Chuah MK, Collen D, VandenDriessche T. Gene therapy for hemophilia. J Gene Med. Jan-Feb 2001;3(1):3-20. [Medline].
Castaman G, Mancuso ME, Giacomelli SH, Tosetto A, Santagostino E, Mannucci PM, et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. Nov 2009;7(11):1824-31. [Medline].
Adamson S, Charlebois T, O'Connell B, Foster W. Viral safety of recombinant factor IX. Semin Hematol. Apr 1998;35(2 Suppl 2):22-7. [Medline].
Aronson DL. Cause of death in hemophilia A patients in the United States from 1968 to 1979. Am J Hematol. Jan 1988;27(1):7-12. [Medline].
Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis. Oct 2009;20(7):517-23. [Medline].
Bogdanova N, Markoff A, Pollmann H, Nowak-Göttl U, Eisert R, Wermes C, et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. Sep 2005;26(3):249-54. [Medline].
Coagulation Factor VII a (Recombinant) [package insert]. Denmark: Novo Nordisk; 2006. [Full Text].
Konkle BA, Kessler C, Aledort L, Andersen J, Fogarty P, Kouides P, et al. Emerging clinical concerns in the ageing haemophilia patient. Haemophilia. Nov 2009;15(6):1197-209. [Medline].
O'Connell N, Mc Mahon C, Smith J, Khair K, Hann I, Liesner R, et al. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors. Br J Haematol. Mar 2002;116(3):632-5. [Medline].
| Classification | Factor Activity, % | Cause of Hemorrhage |
| Mild | >5-40 | Major trauma or surgery |
| Moderate | 1-5 | Mild-to-moderate trauma |
| Severe | < 1 | Spontaneous, hemarthrosis |
| Indication or Site of Bleeding | Factor level Desired, % | FIX Dose, IU/kg* | Comment |
| Severe epistaxis; mouth, lip, tongue, or dental work | 20-50 | 20-50 | Consider aminocaproic acid (Amicar), 1-2 d |
| Joint (hip or groin) | 40 | 40 | Repeat transfusion in 24-48 h |
| Soft tissue or muscle | 20-40 | 40 | No therapy if site small and not enlarging (transfuse if enlarging) |
| Muscle (calf and forearm) | 30-40 | 40 | None |
| Muscle deep (thigh, hip, iliopsoas) | 40-60 | 40-60 | Transfuse, repeat at 24 h, then as needed |
| Neck or throat | 50-80 | 50-80 | None |
| Hematuria | 40 | 40 | Transfuse to 40% then rest and hydration |
| Laceration | 40 | 40 | Transfuse until wound healed |
| GI or retroperitoneal bleeding | 60-80 | 60-80 | None |
| Head trauma (no evidence of CNS bleeding) | 50 | 50 | None |
| Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) | 100 | 100 | Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
| Trauma with bleeding, surgery† | 80-100 | 100 | 10-14 d |
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