Medscape is available in 5 Language Editions – Choose your Edition here.


Factor IX Deficiency Differential Diagnoses

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
Updated: Jun 17, 2016

Diagnostic Considerations

Other problems to be considered in the differential diagnosis of hemophilia B include the following:

  • Hemophilia A and von Willebrand disease
  • Other inherited coagulation disorders - Multiple vitamin K–dependent factor deficiencies and FXI deficiency
  • Acquired antibodies against FIX in persons with known hemophilia (for more information, see Medication)
  • Acquired antibodies against FIX in patients without hemophilia
  • Common coagulation disorders secondary to liver disease, warfarin sodium or heparin overdose, disseminated intravascular coagulation, dysproteinemias causing coagulopathies, and vitamin K deficiency

Differential Diagnoses

Contributor Information and Disclosures

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.


Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Additional Contributors

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, AMDA - The Society for Post-Acute and Long-Term Care Medicine, American Society of Hematology, Infectious Diseases Society of America, Phi Beta Kappa

Disclosure: Nothing to disclose.

  1. 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].

  2. 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].

  3. Smith SB, Gailani D. Update on the physiology and pathology of factor IX activation by factor XIa. Expert Rev Hematol. 2008 Oct. 1(1):87-98. [Medline]. [Full Text].

  4. 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].

  5. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001 Jun. 85(6):958-65. [Medline].

  6. 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.

  7. 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].

  8. 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].

  9. Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol. 2001 Feb. 112(2):264-74. [Medline].

  10. 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].

  11. Sidonio RF Jr, Gunawardena S, Shaw PH, Ragni M. Predictors of von Willebrand disease in children. Pediatr Blood Cancer. 2012 Jan 11. [Medline].

  12. 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].

  13. 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].

  14. 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.

  15. 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].

  16. 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].

  17. 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].

  18. 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].

  19. Poon MC. Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII. Haemophilia. 2006 Nov. 12 Suppl 4:61-9.

  20. 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.

  21. Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Huntingt). 2001 Sep. 15(9):1197-204, 1207; discussion 1207-8. [Medline].

  22. Fewell JG. Factor IX gene therapy for hemophilia. Methods Mol Biol. 2008. 423:375-82. [Medline].

  23. Ponder KP. Gene therapy for hemophilia. Curr Opin Hematol. 2006 Sep. 13(5):301-7. [Medline].

  24. Giangrande P. The Future of Hemophilia Treatment: Longer-Acting Factor Concentrates versus Gene Therapy. Semin Thromb Hemost. 2016 May 5. [Medline].

  25. 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].

  26. 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].

  27. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. 2001 Dec 8. 358(9297):1925-6. [Medline].

  28. 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.

  29. 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].

  30. 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].

  31. 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].

  32. 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.

  33. 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].

  34. 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].

  35. 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].

  36. 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].

  37. 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].

  38. 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].

  39. 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].

  40. 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].

  41. Economides DL, Kadir RA, Lee CA. Inherited bleeding disorders in obstetrics and gynaecology. Br J Obstet Gynaecol. 1999 Jan. 106(1):5-13. [Medline].

  42. The fibrinolytic system and thrombolytic agents. Bachmann F, ed. Fibrinolytics and Antifibrinolytics. New York, NY: Springer-Verlag; 2001. 3-15.

  43. Green D. Complications associated with the treatment of haemophiliacs with inhibitors. Haemophilia. 1999 Sep. 5 Suppl 3:11-7. [Medline].

  44. Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia. 1998 Sep. 4(5):704-13. [Medline].

  45. Kasper CK, Costa E, Silva M. Registry of Clotting Factor Concentrates. World Federation of Hemophilia. 1998:1-8.

  46. 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].

  47. 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].

  48. Lillicrap D. Molecular diagnosis of inherited bleeding disorders and thrombophilia. Semin Hematol. 1999 Oct. 36(4):340-51. [Medline].

  49. 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].

  50. 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].

  51. 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].

  52. 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].

  53. Santagostino E, Fasulo MR. Hemophilia A and Hemophilia B: Different Types of Diseases?. Semin Thromb Hemost. 2013 Sep 8. [Medline].

  54. 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].

  55. 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].

  56. Tedgard U, Ljung R, McNeil TF. Reproductive choices of haemophilia carriers. Br J Haematol. 1999 Aug. 106(2):421-6. [Medline].

  57. Teitel JM. Recombinant factor VIIa versus aPCCs in haemophiliacs with inhibitors: treatment and cost considerations. Haemophilia. 1999 Sep. 5 Suppl 3:43-9. [Medline].

  58. 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.

  59. Tock B, Drohan W, Hess J, et al. Haemophilia and advanced fibrin sealant technologies. Haemophilia. 1998 Jul. 4(4):449-55. [Medline].

  60. 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].

  61. 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].

  62. 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].

Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
Major components of the factor IX structure.
Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.
The hemostatic pathway: role of factor IX.
Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.
Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)
Possible genetic outcomes in individuals carrying the hemophilic gene.
Teenage boy with bleeding into right thigh, both knees, and ankles.
Older adult man with chronic fused extended knee following open drainage of right knee bleed many years previously.
Severe bilateral hemophilic arthropathy and muscle wasting. Three puncture sites demonstrate attempts to aspirate a recent bleed into the knee joint.
Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the knees. Findings are of advanced hemophilic arthropathy.
Chronic severe arthritis, fusion, and loss of cartilage and joint space with deformities in the elbow. Findings are of advanced hemophilic arthropathy.
Hemophilic knee at surgery with synovial proliferation caused by repeated bleeding and requiring synovectomy.
Large amount of vascular synovium removed during knee surgery.
Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, would show diffuse deposits. Iron-laden macrophages are present.
Male patient presenting with a slowly expanding abdominal and flank mass with increasing pain, inability to eat, weight loss, and weakness of the lower extremity.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by the pseudocyst.
Dissection of a pseudocyst.
Transected pseudocyst with old chocolate brown–black blood.
Large pseudocyst involving left proximal femur.
Transected pseudocyst (following disarticulation of the lower left extremity because of vascular compromise, nerve damage, loss of bone, and nonfunctional lower left extremity) showing old black-brown blood, residual muscle, and bone.
Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
Extensive spontaneous abdominal wall hematoma and thigh hemorrhage in a previously healthy older man with an acquired factor VIII inhibitor.
Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
Application of Velcro tourniquet followed by self-infusion of concentrate as part of home therapy.
Quality of life at summer camp.
Table 1. Correlation Between Severity of Bleeding and the Level of Basal FIX Activity
SeverityFunctional FIX Levels, %Bleeding and Hemarthroses
Severe≤ 1Lifelong spontaneous hemorrhages and hemarthroses starting in infancy
Moderate2-5Hemorrhage secondary to minor trauma or surgery; occasional spontaneous hemarthrosis
Mild6-25Hemorrhage secondary to trauma, surgery, or precipitated by the use of drugs such as nonsteroidal anti-inflammatory drugs
Table 2. Rough Guidelines for Treatment Using Factor IX Concentrates
Type of HemorrhageDesired FIX Activity, % of NormalDuration of Therapy, Days
Minor -



superficial large


Moderate -

Hematoma with dissection

Oral/mucosal hemorrhages and epistaxis hematuria*


(2-5 in oral hemorrhages)

Dental extraction(s)*50-1002-5
Major -



GI tract bleeding,

CNS bleeding surgery

~100 until bleeding is controlled; then taper to minimum required to prevent rebleed7-10

(5-10 in

oral hemorrhages)

*Concomitant administration of EACA or tranexamic acid (both fibrinolytic inhibitors) can help reduce the dose of clotting factor replacement required to treat such bleeds.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.