Skip to main content

Advertisement

SpringerLink
Log in

Recent Advances in Haemophilia Management

  • Hematology/Oncology (C Cole, Section Editor)
  • Published:
Current Pediatrics Reports Aims and scope Submit manuscript

Abstract

Haemophilia is a life-threatening bleeding disorder characterised by recurrent, spontaneous bleeding episodes into muscles and joints leading to the development of painful, disabling haemophilic arthropathy. Significant improvements in the management of patients with haemophilia have occurred in the last four decades with the widespread availability of safe and effective clotting factor concentrates. Modern treatment of haemophilia is still associated with significant morbidity and recent advances in the care of patients with haemophilia including the development of modified clotting factor concentrates with extended half-life hold promise to significantly reduce the burden treatment of this bleeding disorder. The benefits of sophisticated clinical registries documenting patient reported outcomes, improvements in the management of patients who develop antibodies to infused clotting factor concentrate and a review of the current status of gene therapy for haemophilia are examples of advances in haemophilia management and will be reviewed in this manuscript.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110(3):815–25.

    Article  CAS  PubMed  Google Scholar 

  2. •• Lillicrap D, Fijnvandraat K, Santagostino E. Inhibitors—genetic and environmental factors. Haemophilia. 2014;20(4):87–93. This is an excellent summary providing the reader with a comprehensive reiview of inhibitor development in haemophilia.

  3. Gringeri A, Mantovani LG, Scalone L, Mannucci PM. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003;102(7):2358–63.

    Article  CAS  PubMed  Google Scholar 

  4. •• Dolan G, Makris M, Bolton-Maggs PH, Rowell JA. Enhancing haemophilia care through registries. Haemophilia. 2014;20(4):121–29. Highlights a number the benefits of clinical registries in a number of countiries around the world and describes in great detail the clinical benefit of collecting registry data. Has an excellent guide on the governance of clinical registries.

  5. •• 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;371(21):1994–2004. The most recent high level publication describing success of gene therapy in haemophilia.

  6. Lane S. Haemorrhagid diathesis. Lancet. 1840;1:185–8.

    Article  Google Scholar 

  7. Blanchette VS. Prophylaxis in the haemophilia population. Haemophilia. 2010;16(Suppl 5):181–8.

    Article  PubMed  Google Scholar 

  8. Nilsson IM, Hedner U, Ahlberg A. Haemophilia prophylaxis in Sweden. Acta Paediatr Scand. 1976;65(2):129–35.

    Article  CAS  PubMed  Google Scholar 

  9. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992;232(1):25–32.

    Article  CAS  PubMed  Google Scholar 

  10. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New Engl J Med. 2007;357(6):535–44.

    Article  CAS  PubMed  Google Scholar 

  11. Noe DA. A mathematical model of coagulation factor VIII kinetics. Haemostasis. 1996;26(6):289–303.

    CAS  PubMed  Google Scholar 

  12. Vlot AJ, Koppelman SJ, Meijers JC, et al. Kinetics of factor VIII-von Willebrand factor association. Blood. 1996;87(5):1809–16.

    CAS  PubMed  Google Scholar 

  13. Bjorkman S, Blanchette VS, Fischer K, et al. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost. 2010;8(4):730–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Bjorkman S, Folkesson A, Jonsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol. 2009;65(10):989–98.

    Article  PubMed  Google Scholar 

  15. Thompson AR. Factor IX concentrates for clinical use. Semin Thromb Hemost. 1993;19(1):25–36.

    Article  CAS  PubMed  Google Scholar 

  16. Yeoh ZH, Furmedge J, Ekert J, Crameri J, Curtis N, Barnes C. Central venous access device-related infections in patients with haemophilia. J Paediatr Child Health. 2013;49(3):242–5.

    Article  PubMed  Google Scholar 

  17. Valentino L, Ewenstein BM, Navikis R, Wilkes M. Central venous access devices in haemophilia: a meta-analysis. Haemophilia. 2004;10:134–46.

    Article  CAS  PubMed  Google Scholar 

  18. Price VE, Carcao M, Connolly B, et al. A prospective, longitudinal study of central venous catheter-related deep venous thrombosis in boys with hemophilia. J Thromb Haemost. 2004;2(5):737–42.

    Article  CAS  PubMed  Google Scholar 

  19. • Furmedge J, Lima S, Monagle P, Barnes C, Newall F. ‘I don’t want to hurt him.’ Parents’ experiences of learning to administer clotting factor to their child. Haemophilia. 2013;19(2):206–11. A paper describing qualitiative research involving the psychological trauma experienced by patients and their families in administering Homebase clotting factor concentrate. Gives the reader a good indication of the extent of the morbidity associated with treatment.

  20. Kang JS, Deluca PP, Lee KC. Emerging PEGylated drugs. Expert Opin Emerg Drugs. 2009;14(2):363–80.

    Article  CAS  PubMed  Google Scholar 

  21. Mehvar R. Modulation of the pharmacokinetics and pharmacodynamics of proteins by polyethylene glycol conjugation. J Pharm Pharm Sci. 2000;3(1):125–36.

    CAS  PubMed  Google Scholar 

  22. Ivens IA, Baumann A, McDonald TA, Humphries TJ, Michaels LA, Mathew P. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia. 2013;19(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  23. Negrier C, Knobe K, Tiede A, Giangrande P, Moss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011;118(10):2695–701.

    Article  CAS  PubMed  Google Scholar 

  24. Turecek PL, Bossard MJ, Graninger M, et al. BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation. Hamostaseologie. 2012;32(Suppl 1):S29–38.

    CAS  PubMed  Google Scholar 

  25. Tiede A, Friedrich U, Stenmo C, et al. Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa). J Thromb Haemost. 2011;9(6):1191–9.

    Article  CAS  PubMed  Google Scholar 

  26. Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol. 2011;22(6):868–76.

    Article  CAS  PubMed  Google Scholar 

  27. Shapiro AD, Ragni MV, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost. 2014;12(11):1788–800.

    Article  CAS  PubMed  Google Scholar 

  28. Shapiro AD, Ragni MV, Valentino LA, et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood. 2012;119(3):666–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Santagostino E, Negrier C, Klamroth R, et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012;120(12):2405–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Zollner SB, Raquet E, Muller-Cohrs J, et al. Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII. Thromb Res. 2013;132(2):280–7.

    Article  CAS  PubMed  Google Scholar 

  31. Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost. 1993;69(2):115–8.

    CAS  PubMed  Google Scholar 

  32. Lacroix-Desmazes S, Misra N, Bayry J, et al. Pathophysiology of inhibitors to factor VIII in patients with haemophilia A. Haemophilia. 2002;8(3):273–9.

    Article  CAS  PubMed  Google Scholar 

  33. DiMichele DM, Gorman PO, Kasper CK, Mannucci PM, Santagostino E, Hay CR. Continuous infusion of porcine factor VIII: stability, microbiological safety and clinical experience. Haemophilia. 2002;8(Suppl 1):9–12 discussion 28–32.

    Article  CAS  PubMed  Google Scholar 

  34. • Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119(6):1335–44. This manuscript describes the important study examining dosing in patients having immune tolerance therapy. The study highlights the difficulty of randomised trials and high quality research in haemophilia.

  35. Berntorp E, Shapiro A, Astermark J, et al. Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference. Haemophilia. 2006;12(Suppl 6):1–7.

    Article  PubMed  Google Scholar 

  36. Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood. 2007;109(2):546–51.

    Article  CAS  PubMed  Google Scholar 

  37. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost. 2007;5(9):1904–13.

    Article  CAS  PubMed  Google Scholar 

  38. Young G, Auerswald G, Jimenez-Yuste V, et al. When should prophylaxis therapy in inhibitor patients be considered? Haemophilia. 2011;17(5):e849–57.

    CAS  PubMed  Google Scholar 

  39. Barnes C, Brown SA, Curtin J, Dunkley S. When is enough…enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors. Haemophilia. 2014;20(4):e275–9.

    Article  CAS  PubMed  Google Scholar 

  40. Evatt B. World federation of hemophilia guide to developing a national patient registry. World Fed Hemophilia. 2005;1:1–22.

    Google Scholar 

  41. •• Blanchette VS, O’Mahony B, McJames L, Mahlangu JN. Assessment of outcomes. Haemophilia. 2014;20(4):114–20. An excellent and thorough manuscript describing the process of developing harmonised outcome measures in the management of haemophilia. Highlights the importance of outcome measures in assessing clinical effectiveness of therapy.

  42. Feldman BM, Funk SM, Bergstrom BM, et al. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score. Arthritis Care Res. 2011;63(2):223–30.

    Article  Google Scholar 

  43. •• High KH, Nathwani A, Spencer T, Lillicrap D. Current status of haemophilia gene therapy. Haemophilia. 2014;20(4):43–9. A comprehensive review of the status of haemophilia gene therapeutics describing both recent advances, but also where previous attempts gene therapy have been less successful.

  44. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122(1):23–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Roth DA, Tawa NE Jr, O’Brien JM, Treco DA, Selden RF. Factor VTTSG. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med. 2001;344(23):1735–42.

    Article  CAS  PubMed  Google Scholar 

  46. Cavazza A, Moiani A, Mavilio F. Mechanisms of retroviral integration and mutagenesis. Hum Gene Ther. 2013;24(2):119–31.

    Article  CAS  PubMed  Google Scholar 

  47. Rosner F. Haemophilia in the Talmud and rabbinic writings. Ann Intern Med. 1969;70:833–7.

    Article  CAS  PubMed  Google Scholar 

  48. Schramm W. The history of haemophilia—a short review. Thromb Res. 2014;134(Suppl 1):S4–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

Chris Barnes declares that he does not have any conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Henry Ekert Haemophilia Treatment Centre, Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, 3052, Australia

    Chris Barnes

Authors
  1. Chris Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chris Barnes.

Additional information

This article is part of the Topical Collection on Hematology/Oncology.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barnes, C. Recent Advances in Haemophilia Management. Curr Pediatr Rep 3, 154–159 (2015). https://doi.org/10.1007/s40124-015-0080-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40124-015-0080-1

Keywords

Search

Navigation