Factor IX Deficiency Treatment & Management
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
Highly purified factor IX (FIX) concentrates are now available. These include monoclonal antibody–purified plasma-derived FIX (pdFIX; Immunine and Mononine) and recombinant FIX (rFIX).
A review of the global experience with pdFIX and rFIX products showed that the two types of products have comparable reliability, tolerability, and clinical efficacy. Serious adverse effects occur rarely with either product. The major difference was variable pharmacokinetics, with a similar half-life but an approximately 25-30% lower in vivo recovery after rFIX, particularly in younger children (in children <16 y, according to Poon ; in children <15 y, according to Roth et al ).
Data obtained from a survey of several French hemophilia centers and presented at the International Society of Thrombosis and Haemostasis meeting in July 2001 showed an average recovery of 61% for rFIX use versus 85% for pdFIX. Initial dosing of FIX for both inpatient and outpatient treatment is on the basis of standard guidelines (Indiana Hemophilia & Thrombosis Center).
Worldwide, only 25 patients with allergic reactions have been reported to the manufacturer of rFIX, with mild-to-moderate skin and respiratory reactions in most of the patients. Of 5 patients with anaphylaxis, some developed an inhibitor, and no fatalities were reported. Three thrombotic events were reported: two were catheter related and the third was a transient ischemic event in a 14-year-old patient who did well when continued on rFIX. Seventeen of 4500 patients had red cell agglutination when blood was withdrawn into the catheter or syringe containing rFIX; this practice must be avoided.
Development of inhibitors is a serious matter affecting 1.5–3% of patients with hemophilia B. Thus, successful eradication of inhibitor may be challenging and require rituximab, with or without desensitization therapy.
Although many reports exist of the successful use of different continuous infusion regimens of FIX, ongoing data collection and studies will allow development of a standardized regimen in the future. Potential benefits include the ability to mimic the physiologic state and reduction in product usage, providing much-needed economic savings.
Although administration of clotting factor in prophylaxis has been shown to be beneficial for both hemophilia A and B, it is more commonly used with hemophilia A than hemophilia B. The reasons for this are unclear.
In children who are starting therapy for the first time or in persons with hemophilia who are HIV negative, recombinant products are used whenever possible because of their presumed higher viral safety. Note that approximately 25% of the lots of human albumin containing first-generation recombinant factor VIII (rFVIII) concentrates have been found to be positive for transfusion-transmitted virus (TTV) from contaminated human serum albumin. All of the second-generation rFVIII preparations (free from human albumin) were negative for the virus.
It is important to understand the pharmacokinetics of factor IX. Factor IX in vivo recovery is also relatively short, possibly due to its reversible binding to endothelium and possibly to platelets. There is considerable pharmacokinetic variability of factor IX between products (particularly between plasma-derived factor IX and recombinant factor IX), and between individuals.
Factor replacement in patients with hemophilia B should be guided by an experienced hematologist who is familiar with treating patients with coagulation disorders.
The location and severity of bleeding determine the dose and duration of factor replacement therapy.
The first dose should be 20-80 IU/kg, depending on the FIX level necessary to treat the specific clinical condition. Approximately 50% of the first dose is administered approximately every 24 hours to maintain the initial level of FIX
If therapy is to last for more than 2 days or is occurring for the first time, FIX levels should be obtained immediately after the first dose, with a subsequent trough level taken to determine appropriate dose and frequency of replacement therapy based on in vivo response to a specific product. Children and surgical patients require closer monitoring of FIX levels because of known variable pharmacokinetics and a lack of a steady state, respectively.
Preservation of the hemostatic plug formed in the presence of adequate levels of FIX at the time of surgery (ie, dental extraction) can be achieved by inhibiting fibrinolysis with epsilon-aminocaproic acid (EACA) or tranexamic acid (Cyklokapron) administered orally or intravenously as needed. Inhibitors of fibrinolysis, such as EACA or tranexamic acid, can be used in combination with factor replacement to prevent bleeding from mucosal sites, including after dental extractions or sinus surgery.
Following a surgical procedure, fibrinolytic inhibitors are continued, then tapered as the wound heals. A single dose can be used to prevent bleeding from minor procedures. However, fibrinolytic inhibitors are not of value in the treatment of hemarthroses or deep-seated bleeding. The prolonged use of fibrinolytic inhibitors in joint and deep hematomas can lead to persistence (lack of absorption) of the clot with negative consequences.
Fibrinolytic inhibitors are used as follows:
A dose of EACA, 5 g orally or IV, is administered immediately before the surgical procedure along with a dose of FIX, followed by 1 g per hour postoperatively until the decision is made to taper the dose over the next 5 days.
Tranexamic acid can be administered in a dose of 1.5 g every 6-8 hours for 5 days; this drug is not available in the United States.
Administration of these fibrinolytic inhibitors is contraindicated in patients with hematuria who are receiving or have recently received an FIX product because of the risk of an acute persistent thrombus obstructing the ureters and causing acute hydronephrosis.
Nonnarcotic and narcotic analgesics are used to relieve pain. Narcotic analgesics are used to manage severe acute pain, such as occurs with joint bleeding or perioperatively. Chronic persistent pain of chronic joint disease can be difficult to manage.
Ideally, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with a bleeding disorder because the addition of platelet dysfunction caused by the drugs can potentiate bleeding. However, because of the persistent demand by individuals with hemophilia, cyclooxygenase 2 (COX-2) inhibitors may be tried with caution because of a lack of efficacy of nonnarcotic pain relievers in severe arthritis. Use of NSAIDs by individuals with hemophilia has increased in an attempt to relieve the severe joint pain of chronic arthritis.
Several approaches to gene therapy have been undertaken in treating patients with hemophilia B or A with severe deficiency. Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.
The most successful and least toxic method of introducing the gene remains to be determined. The use of an attenuated adenoviral vector, although associated with high short-term expression in a canine model of hemophilia, led to liver toxicity, thrombocytopenia, and an antibody to the factor due to an immunologic response to the vector. An additional question is the appropriate in vivo–vector dose to be administered; evidence is emerging for the need for a minimum threshold dose. Features of gene therapy research have included the following:
Short-term correction resulting from high gene expression in the neonatal period following in utero injection of an adenoviral murine vector has been accomplished with FVIII.
Use of a parvovirus, use of transduced endothelial cells, or the possibility of cutaneous gene therapy are being explored in animal models and in humans.
Development of antibodies to replaced proteins is a major problem, and the possibility of using CTLA4-Ig to block T-cell function to prevent antibody response has been explored in murine models of hemophilia A.
Possible approaches to gene therapy include ex vivo gene therapy, in which the cells to be injected are modified to secrete FIX or FVIII and then are reimplanted into the recipient, and in vivo gene therapy, in which cells modified to secrete the missing factor are packaged in immunoprotected devices and implanted in recipients.
Gene therapy with a variety of vectors has been tested in humans, with the most successful method still to be determined. Gene therapy studies were halted following the death of a patient treated for a metabolic disorder. Reevaluation of the type of vector, dose, route, and toxicity of the different approaches to gene therapy was undertaken. Oligonucleotides possibly can be used in vivo to correct point mutations. Advantages and disadvantages of several approaches to gene therapy in individuals with hemophilia and other patients have been updated in two recent publications.[20, 21]
Gene therapy with viral-based vectors has had efficacy limited by immune responses against the viral components.
Gene therapy remains promising.[7, 23, 22] Sadly, however, current techniques produce factor levels well short of those achieved by prophylaxis with longer-acting products, and gene therapy is unlikely ever to be an inexpensive treatment option.
In humans, one hemophilia B patient achieved 10% of normal activity after liver-directed gene therapy with a single-stranded adeno-associated virus vector expressing human factor IX, but expression fell at 1 month. Thus, gene therapy may be viewed as successful in a patient with hemophilia B, but expression was unstable, probably due to an immune response. Abrogating immune responses may be the next important hurdle for achieving long-lasting gene therapy.
Appropriate preoperative evaluation includes an activated partial thromboplastin time (aPTT) mixing test after incubation for 1-2 hours at 37°C with pooled normal plasma to exclude an inhibitor, followed by administration of an appropriate preoperative dose of concentrate, followed by appropriate postoperative treatment.
Small studies have established the efficacy of using lower than usually recommended doses of FIX concentrate, administered as an intermittent bolus infusion after major surgical procedures. Preoperatively, FIX was used in a dose of 77 U/kg to achieve a presurgical level of 107% (range 50-104%). Between days 1 and 3 after surgery, an average of 23 U/kg/d was used with an average trough value of FIX of 34% (range 11-52%). After day 4, an average of 18 U/kg/d of FIX was used until wound healing occurred. This resulted in a significant reduction in overall factor used without hemostatic inadequacy. Such data underscore the importance of defining the least amount of factor replacement necessary to obtain and maintain adequate hemostasis.
The use of fibrin sealants (ie, fibrin glue, fibrin adhesive), which consist of fibrinogen and thrombin with variable incorporation of factor XIII (FXIII) and fibrinolytic inhibitors, has helped improve surgical hemostasis markedly, thereby permitting necessary high-risk surgery (eg, pseudotumors, surgery in patients with hemophilia with inhibitors). This technology reduces or eliminates the need for prolonged replacement using expensive clotting factor concentrates and may eliminate or reduce the need for hospitalization.
In total, the measures result in improved quality of life in patients with hemophilia, while achieving a reduction in medical care costs. Bovine thrombin used in these preparations may result in development of inhibitors to several factors, including thrombin and FV, as it has in other postoperative states.
Warn patients to avoid any antiplatelet drug starting 1 week prior to surgery and in the immediate postoperative period to minimize the risk of bleeding.
The use of ice packs at surgical sites may be beneficial to reduce the size of the surgical site hematoma.
See the list below:
Hematologist, including general medical evaluation
Psychiatrist, particularly in the management of HIV-related issues 
Geneticist for genetic testing and counseling for family members
Activity recommendations depend on such factors as joint disease and resolution of bleed into joints and muscles. Appropriate use of physical therapy is advised.
Chavali S, Sharma A, Tabassum R, Bharadwaj D. Sequence and structural properties of identical mutations with varying phenotypes in human coagulation factor IX. Proteins. 2008 Apr 7. [Medline].
Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost. 2009 Oct. 102(4):634-44. [Medline].
Bauer KA, Kass BL, ten Cate H, et al. Factor IX is activated in vivo by the tissue factor mechanism. Blood. 1990 Aug 15. 76(4):731-6. [Medline].
Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001 Jun. 85(6):958-65. [Medline].
Roberts HR, Monroe DM III, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. Beutler E, Lichtman M, Coller B, et al, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill Professional; 2001. 2001: 1409-34.
Zdziarska J, Chojnowski K, Klukowska A, Letowska M, Mital A, Podolak-Dawidziak M, et al. Therapeutic properties and safety of recombinant factor VIII and factor IX. Pol Arch Med Wewn. 2009 Jun. 119(6):403-9. [Medline].
Quadros L, Ghosh K, Shetty S. A common G10430A mutation (Gly 60 Ser) in the factor IX gene describes the presence of moderate and mild hemophilia B in the majority of the Gujarati population. Ann Hematol. 2007 May. 86(5):377-9. [Medline].
Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol. 2001 Feb. 112(2):264-74. [Medline].
Kulkarni R, Lusher JM, Henry RC, Kallen DJ. Current practices regarding newborn intracranial haemorrhage and obstetrical care and mode of delivery of pregnant haemophilia carriers: a survey of obstetricians, neonatologists and haematologists in the United States, on behalf of the National Hemop. Haemophilia. 1999 Nov. 5(6):410-5. [Medline].
Sidonio RF Jr, Gunawardena S, Shaw PH, Ragni M. Predictors of von Willebrand disease in children. Pediatr Blood Cancer. 2012 Jan 11. [Medline].
Christophe OD, Lenting PJ, Cherel G, et al. Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B. Blood. 2001 Sep 1. 98(5):1416-23. [Medline].
Park CH, Seo JY, Kim HJ, Jang JH, Kim SH. A diagnostic challenge: mild hemophilia B with normal activated partial thromboplastin time. Blood Coagul Fibrinolysis. 2010 Jun. 21(4):368-71. [Medline].
Poon MC. Clotting Factor IX in Hemophilia B: Global Experience. Paper presented at: XVIII Congress of the International Society on Thrombosis and Haemostasis. July 6-12, 2001. Paris, France.
Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood. 2001 Dec 15. 98(13):3600-6. [Medline].
Gamerman S, Singh AM, Makhija M, Sharathkumar A. Successful eradication of inhibitor in a patient with severe haemophilia B and anaphylaxis to factor IX concentrates: is there a role for Rituximab® and desensitization therapy?. Haemophilia. 2013 Aug 28. [Medline].
Escobar M, Sallah S. Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis. J Thromb Haemost. 2013 Aug. 11(8):1449-53. [Medline].
Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. 2001 Oct 15. 98(8):2571-3. [Medline].
Poon MC. Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII. Haemophilia. 2006 Nov. 12 Suppl 4:61-9.
Hedner U, Ginsburg D, Lusher JM, High KA. Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. Hematology (Am Soc Hematol Educ Program). 2000. 241-65.
Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Huntingt). 2001 Sep. 15(9):1197-204, 1207; discussion 1207-8. [Medline].
Fewell JG. Factor IX gene therapy for hemophilia. Methods Mol Biol. 2008. 423:375-82. [Medline].
Ponder KP. Gene therapy for hemophilia. Curr Opin Hematol. 2006 Sep. 13(5):301-7. [Medline].
Giangrande P. The Future of Hemophilia Treatment: Longer-Acting Factor Concentrates versus Gene Therapy. Semin Thromb Hemost. 2016 May 5. [Medline].
Treisman GJ, Angelino AF, Hutton HE. Psychiatric issues in the management of patients with HIV infection. JAMA. 2001 Dec 12. 286(22):2857-64. [Medline].
Lin CN, Kao CY, Miao CH, Hamaguchi N, Wu HL, Shi GY, et al. Generation of a novel factor IX with augmented clotting activities in vitro and in vivo. J Thromb Haemost. 2010 May 21. [Medline].
Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. 2001 Dec 8. 358(9297):1925-6. [Medline].
MediView. Recombinant therapy enhances safety and quality of life for hemophilia patients. Paper presented at: 53rd Annual Meeting of the National Hemophilia Foundation. November 16, 2001:Nashville, Tennessee.
Rigas B, Hasan I, Rehman R, et al. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. 2001 Dec 8. 358(9297):1961-2. [Medline].
Urwin PJ, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang. 2016 May. 110 (4):310-6. [Medline].
Jackson GS, Burk-Rafel J, Edgeworth JA, Sicilia A, Abdilahi S, Korteweg J, et al. Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study. JAMA Neurol. 2014 Apr. 71 (4):421-8. [Medline].
Feuerstein GZ, Nichols AJ, Church WR. Novel murine monoclonal antifactor IX/IXa (BC2) is a potent anticoagulant with "self limiting" inhibition of hemostasis. Circulation. 1997. 96:142.
Kjalke M, Monroe DM, Hoffman M, et al. Active site-inactivated factors VIIa, Xa, and IXa inhibit individual steps in a cell-based model of tissue factor-initiated coagulation. Thromb Haemost. 1998 Oct. 80(4):578-84. [Medline].
Spanier TB, Oz MC, Minanov OP, et al. Heparinless cardiopulmonary bypass with active-site blocked factor IXa: a preliminary study on the dog. J Thorac Cardiovasc Surg. 1998 May. 115(5):1179-88. [Medline].
Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost. 2012 Feb. 38(1):79-94. [Medline].
Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1995 Jun 16. 270(24):14477-84. [Medline].
Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. 1996 Sep 15. 88(6):2093-100. [Medline].
Bouma BN, von dem Borne PA, Meijers JC. Factor XI and protection of the fibrin clot against lysis--a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost. 1998 Jul. 80(1):24-7. [Medline].
Brooks M. A review of canine inherited bleeding disorders: biochemical and molecular strategies for disease characterization and carrier detection. J Hered. 1999 Jan-Feb. 90(1):112-8. [Medline].
Broze GJ Jr, Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. 1996 Nov 15. 88(10):3815-23. [Medline].
Economides DL, Kadir RA, Lee CA. Inherited bleeding disorders in obstetrics and gynaecology. Br J Obstet Gynaecol. 1999 Jan. 106(1):5-13. [Medline].
The fibrinolytic system and thrombolytic agents. Bachmann F, ed. Fibrinolytics and Antifibrinolytics. New York, NY: Springer-Verlag; 2001. 3-15.
Green D. Complications associated with the treatment of haemophiliacs with inhibitors. Haemophilia. 1999 Sep. 5 Suppl 3:11-7. [Medline].
Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia. 1998 Sep. 4(5):704-13. [Medline].
Kasper CK, Costa E, Silva M. Registry of Clotting Factor Concentrates. World Federation of Hemophilia. 1998:1-8.
Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost. 1998 Dec. 80(6):912-8. [Medline].
Knobe KE, Persson KE, Sjörin E, Villoutreix BO, Ljung RC. Functional analysis of the factor IX epidermal growth factor-like domain mutation Ile66Thr associated with mild hemophilia B. Pathophysiol Haemost Thromb. 2006. 35(5):370-5. [Medline].
Lillicrap D. Molecular diagnosis of inherited bleeding disorders and thrombophilia. Semin Hematol. 1999 Oct. 36(4):340-51. [Medline].
Mosnier LO, von dem Borne PA, Meijers JC, et al. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost. 1998 Nov. 80(5):829-35. [Medline].
Qian J, Collins M, Sharpe AH, Hoyer LW. Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood. 2000 Feb 15. 95(4):1324-9. [Medline].
Racoosin JA, Kessler CM. Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series. Haemophilia. 1999 Jul. 5(4):266-9. [Medline].
Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. 1995 Nov. 96(5):2534-8. [Medline].
Santagostino E, Fasulo MR. Hemophilia A and Hemophilia B: Different Types of Diseases?. Semin Thromb Hemost. 2013 Sep 8. [Medline].
Shapiro AD, Gilchrist GS, Hoots WK, et al. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost. 1998 Nov. 80(5):773-8. [Medline].
Srivastava A, Chandy M, Sunderaj GD, et al. Low-dose intermittent factor replacement for post-operative haemostasis in haemophilia. Haemophilia. 1998 Nov. 4(6):799-801. [Medline].
Tedgard U, Ljung R, McNeil TF. Reproductive choices of haemophilia carriers. Br J Haematol. 1999 Aug. 106(2):421-6. [Medline].
Teitel JM. Recombinant factor VIIa versus aPCCs in haemophiliacs with inhibitors: treatment and cost considerations. Haemophilia. 1999 Sep. 5 Suppl 3:43-9. [Medline].
Thomson AR. Molecular biology of F IX. Colman RW, George JN, Hirsh J, et al, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott-Raven Pub; 2001. 123-34.
Tock B, Drohan W, Hess J, et al. Haemophilia and advanced fibrin sealant technologies. Haemophilia. 1998 Jul. 4(4):449-55. [Medline].
Warrier I, Ewenstein BM, Koerper MA, et al. Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol. 1997 Jan-Feb. 19(1):23-7. [Medline].
Wildgoose P, Nemerson Y, Hansen LL, et al. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood. 1992 Jul 1. 80(1):25-8. [Medline].
Wang QY, Hu B, Liu H, Tang L, Zeng W, Wu YY, et al. A genetic analysis of 23 Chinese patients with hemophilia B. Sci Rep. 2016 Apr 25. 6:25024. [Medline].
|Severity||Functional FIX Levels, %||Bleeding and Hemarthroses|
|Severe||≤ 1||Lifelong spontaneous hemorrhages and hemarthroses starting in infancy|
|Moderate||2-5||Hemorrhage secondary to minor trauma or surgery; occasional spontaneous hemarthrosis|
|Mild||6-25||Hemorrhage secondary to trauma, surgery, or precipitated by the use of drugs such as nonsteroidal anti-inflammatory drugs|
|Type of Hemorrhage||Desired FIX Activity, % of Normal||Duration of Therapy, Days|
Hematoma with dissection
Oral/mucosal hemorrhages and epistaxis hematuria*
(2-5 in oral hemorrhages)
GI tract bleeding,
CNS bleeding surgery
|~100 until bleeding is controlled; then taper to minimum required to prevent rebleed||7-10
|*Concomitant administration of EACA or tranexamic acid (both fibrinolytic inhibitors) can help reduce the dose of clotting factor replacement required to treat such bleeds.|