Hemophilia B (Factor IX Deficiency) Questions & Answers

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11. Reijnen MJ, Maasdam D, Bertina RM, Reitsma PH. Haemophilia B Leyden: the effect of mutations at position +13 on the liver-specific transcription of the factor IX gene. Blood Coagul Fibrinolysis. 1994 Jun. 5 (3):341-8. [QxMD MEDLINE Link].

12. Goodeve AC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost. 2015 Jul. 13 (7):1184-95. [QxMD MEDLINE Link]. [Full Text].

13. Christophe OD, Lenting PJ, Cherel G, Boon-Spijker M, Lavergne JM, Boertjes R, et al. Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B. Blood. 2001 Sep 1. 98 (5):1416-23. [QxMD MEDLINE Link].

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15. Zdziarska J, Chojnowski K, Klukowska A, Łetowska 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. [QxMD MEDLINE Link].

16. Horava SD, Peppas NA. Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX. Ann Biomed Eng. 2016 Feb 16. [QxMD MEDLINE Link].

17. 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. 1994 Apr. 19(2):223-39. [QxMD MEDLINE Link].

18. Alam AU, Karkhaneh M, Attia T, Wu C, Sun HL. All-cause mortality and causes of death in persons with haemophilia: A systematic review and meta-analysis. Haemophilia. 2021 Nov. 27 (6):897-910. [QxMD MEDLINE Link].

19. [Guideline] Hanley J et al, on behalf of the UK Haemophilia Centre Doctors Organisation (UKHCDO). Emergency and out of hours care for patients with bleeding disorders – standards of care for assessment and treatment. UKHCDO. Available at http://www.ukhcdo.org/wp-content/uploads/2015/12/EmergencyCareStandardsFinalVersionJune2009-For-Website.pdf. April 2009; Accessed: December 21, 2022.

20. 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. [QxMD MEDLINE Link].

21. Berntorp E, Astermark J, Björkman S, Blanchette VS, Fischer K, Giangrande PL, et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia. 2003 May. 9 Suppl 1:1-4. [QxMD MEDLINE Link].

22. Ljung RC. Prophylactic infusion regimens in the management of hemophilia. Thromb Haemost. 1999 Aug. 82(2):525-30. [QxMD MEDLINE Link].

23. 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. 2011 Sep 7. 9:CD003429. [QxMD MEDLINE Link].

24. 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. 1998 Dec. 244(6):515-22. [QxMD MEDLINE Link].

25. Valentino LA, Rusen L, Elezovic I, Smith LM, Korth-Bradley JM, Rendo P. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia. 2014 Jan 13. [QxMD MEDLINE Link].

26. Hand L. Prophylaxis trumps on-demand dosing for hemophilia B in RCT. Medscape Medical News. January 31, 2014. [Full Text].

27. Otto MA. FDA Approves First Gene Therapy for Hemophilia B. Medscape Medical News. November 23, 2022. Available at https://www.medscape.com/viewarticle/984531.

28. Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016 Jan 11. [QxMD MEDLINE Link].

29. Windyga J, Solano Trujillo MH, Hafeman AE. BAX326 (RIXUBIS): a novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B. Ther Adv Hematol. 2014 Oct. 5 (5):168-80. [QxMD MEDLINE Link]. [Full Text].

30. Urasinski T, Stasyshyn O, Andreeva T, Rusen L, Perina FG, Oh MS, et al. Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial. Haemophilia. 2015 Mar. 21 (2):196-203. [QxMD MEDLINE Link].

31. Rebinyn (nonacog beta pegol; recombinant glycopegylated factor IX) [package insert]. Plainsboro, NJ: Novo Nordisk, Inc. 2017 June. Available at [Full Text].

32. 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. 2007 Aug. 205(2):256-65. [QxMD MEDLINE Link].

33. 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. 2002 Mar. 116(3):632-5. [QxMD MEDLINE Link].

34. 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. [QxMD MEDLINE Link].

35. McQuilten ZK, Barnes C, Zatta A, Phillips LE. Off-Label Use of Recombinant Factor VIIa in Pediatric Patients. Pediatrics. 2012 Jun. 129(6):e1533-e1540. [QxMD MEDLINE Link].

36. 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. 2009 Nov. 7(11):1809-15. [QxMD MEDLINE Link].

37. 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. 2006 Jan. 12(1):7-18. [QxMD MEDLINE Link].

38. Aggarwal A, Grewal R, Green RJ, Boggio L, Green D, Weksler BB, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia. 2005 Jan. 11(1):13-9. [QxMD MEDLINE Link].

39. Stachnik JM. Rituximab in the treatment of acquired hemophilia. Ann Pharmacother. 2006 Jun. 40(6):1151-7. [QxMD MEDLINE Link].

40. Personal communication with Dr. Troy H. Guthrie, Jr. MD, Medical Director Baptist Cancer Institute, Jacksonville, Florida.

41. Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results. Blood. 2019 Aug 23. 3 (21):3241-3247. [QxMD MEDLINE Link].

42. Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Eichler H, et al. Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors. Blood Adv. 2022 Jun 14. 6 (11):3422-3432. [QxMD MEDLINE Link]. [Full Text].

43. EU/3/17/1940. European Medicines Agency. Available at https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3171940. December 1, 2018; Accessed: August 23, 2022.

44. Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Adv. 2021 Jan 12. 5 (1):279. [QxMD MEDLINE Link]. [Full Text].

45. Lowes R. FDA OKs first cloned factor IX for bleeding prophylaxis. Medscape Medical News. June 27, 2013. Available at http://www.medscape.com/viewarticle/806996. Accessed: July 9, 2013.

46. US Food and Drug Administration. FDA approves first recombinant coagulation factor IX that is specifically indicated for routine use in preventing bleeding episodes (prophylaxis) [press release]. June 27, 2013. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm358918.htm. Accessed: July 9, 2013.

47. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013 Dec 12. 369(24):2313-23. [QxMD MEDLINE Link].

48. Brooks M. First Long-Acting Hemophilia B Drug (Alprolix) Clears FDA. Medscape Medical News. Mar 31 2014. [Full Text].

49. Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014 Jan. 20(1):65-72. [QxMD MEDLINE Link].

50. Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014 Jan. 20(1):65-72. [QxMD MEDLINE Link].

51. Duncan N, Kronenberger W, Roberson C, Shapiro A. VERITAS-Pro: a new measure of adherence to prophylactic regimens in haemophilia. Haemophilia. 2010 Mar. 16(2):247-55. [QxMD MEDLINE Link].

52. Hazendonk HCAM, Preijers T, Liesner R, Chowdary P, Hart D, Keeling D, et al. Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise. Haemophilia. 2018 Jul. 24 (4):611-618. [QxMD MEDLINE Link]. [Full Text].

53. Négrier C, Abdul Karim F, Lepatan LM, Lienhart A, López-Fernández MF, Mahlangu J, et al. Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery. Haemophilia. 2016 Jul. 22 (4):e259-66. [QxMD MEDLINE Link].

54. Curtin J, Santagostino E, Karim FA, Li Y, Seifert W, Négrier C. Simplifying surgery in haemophilia B: Low factor IX consumption and infrequent infusions in surgical procedures with rIX-FP. Thromb Res. 2020 Apr. 188:85-89. [QxMD MEDLINE Link].

55. Valentino LA, Cooper DL, Goldstein B. Surgical experience with rFVIIa (NovoSeven) in congenital haemophilia A and B patients with inhibitors to factors VIII or IX. Haemophilia. 2011 Jul. 17 (4):579-89. [QxMD MEDLINE Link].

56. 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. 2009 Nov. 15(6):1215-8. [QxMD MEDLINE Link].

57. Ingerslev HJ, Hindkjaer J, Jespersgaard C, Lind MP, Kølvraa S. [Preimplantation genetic diagnosis. The first experiences in Denmark]. Ugeskr Laeger. 2001 Oct 1. 163(40):5525-8. [QxMD MEDLINE Link].

58. Lissens W, Sermon K. Preimplantation genetic diagnosis: current status and new developments. Hum Reprod. 1997 Aug. 12(8):1756-61. [QxMD MEDLINE Link].

59. Wells D, Delhanty JD. Preimplantation genetic diagnosis: applications for molecular medicine. Trends Mol Med. 2001 Jan. 7(1):23-30. [QxMD MEDLINE Link].

60. Arruda VR, Samelson-Jones BJ. Obstacles and future of gene therapy for hemophilia. Expert Opin Orphan Drugs. 2015. 3 (9):997-1010. [QxMD MEDLINE Link].

61. Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20. 371 (21):1994-2004. [QxMD MEDLINE Link]. [Full Text].

62. Pipe SW, Recht M, Key NS, Leebeek FWG, Castaman G, Lattimore SU, et al. First data from the phase 3 HOPE-B gene therapy trial: Efficacy and safety of etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies. Presented December 8, 2020 at the 62nd American Society of Hematology Annual Meeting and Exposition. [Full Text].

63. Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, et al. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21. 387 (3):237-247. [QxMD MEDLINE Link]. [Full Text].

64. Croteau SE. Hemophilia A/B. Hematol Oncol Clin North Am. 2022 Aug. 36 (4):797-812. [QxMD MEDLINE Link].

65. Morishige S, Mizuno S, Ozawa H, Nakamura T, Mazahery A, Nomura K, et al. CRISPR/Cas9-mediated gene correction in hemophilia B patient-derived iPSCs. Int J Hematol. 2019 Oct 29. [QxMD MEDLINE Link].

66. Chen X, Niu X, Liu Y, Zheng R, Yang L, Lu J, et al. Long-term correction of haemophilia B through CRISPR/Cas9 induced homology-independent targeted integration. J Genet Genomics. 2022 Jun 9. [QxMD MEDLINE Link].

67. [Guideline] Hanley J, McKernan A, Creagh MD, Classey S, McLaughlin P, Goddard N, et al. Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia: A United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) guideline. Haemophilia. 2017 Jul. 23 (4):511-520. [QxMD MEDLINE Link]. [Full Text].

68. Hart DP, Matino D, Astermark J, Dolan G, d'Oiron R, Hermans C, et al. International consensus recommendations on the management of people with haemophilia B. Ther Adv Hematol. 2022. 13:20406207221085202. [QxMD MEDLINE Link]. [Full Text].

69. 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. 2009 Nov. 7(11):1824-31. [QxMD MEDLINE Link].

Robert A Zaiden, MD Adjunct Associate Professor, Division of Cancer Medicine, Baptist MD Anderson Cancer Center

Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology

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Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

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

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Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

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Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

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Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute

Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

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