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. 2024 Jan 3;8(3):102308. doi: 10.1016/j.rpth.2023.102308

The Evolution of Hemophilia Therapeutics: An Illustrated Review

María G Español 1,2,∗, Jessica N Mistretta 1, Michael D Tarantino 1,3, Jonathan C Roberts 1,3
PMCID: PMC11180375  PMID: 38883215

Abstract

Hemophilia is a rare genetic bleeding disorder historically associated with high morbidity and mortality. Some individuals with hemophilia suffer associated chronic joint disease, chronic pain, and other physical and mental health challenges. In the last 50 years, a better understanding of the pathophysiology of the disease has resulted in extraordinary therapeutic advances leading to enhanced quality of life and increased life expectancy.

We present an illustrated review of the evolution of hemophilia treatment from the development of non-factor therapies to gene therapy.

Keywords: Hemophilia, treatment, illustrated review, bleeding disorder, gene therapy, hemophilia treatment

Essentials

  • •

    Hemophilia is a bleeding disorder associated with high morbidity and mortality.

  • •

    Advances in hemophilia treatment have led to safer treatment options and a potential cure.

  • •

    Access to treatment and novel agents remains limited in low to middle-income countries.

Conclusions

Extraordinary advances have been made in the care of patients with hemophilia. A disease that once was associated with disabilities, high morbidity, and mortality today has a potential cure.

The evolution of hemophilia therapeutics has allowed these individuals to expand their horizons, setting personal goals never once thought attainable. Efforts continue to be made by international organizations to allow access to the standard of care and novel therapies to those living in low to middle income countries, to eventually realize a life without bleeds for the community worldwide.

Design

The manuscript was designed and created using Canva and BioRender.

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Disclosure of Interest

Dr. Michael D. Tarantino reports consulting fees from Pfizer, Sanofi, Sobi-Swedish Orphan Biovirtum, Takeda, Amgen, INC, Octapharma, Genentech, BioMarin, UCB Biosciences, Dova Pharmaceuticals, Novo Nordisk, and payment honoraria from Sobi, Genentech, Amgen, Novartis, BioMarin, and Sanofi.

Dr. Jonathan C. Roberts reports grants from Takeda and Genetech, consulting fees from CSL Behring, F. Hoffman-La Roche AG, Sanofi, HEMA Biologics, Novartis, Novo Nordisk, Pfizer, Takeda, and Genentech.

Dr. María G. Español reports participation on Sevenfact Advisory Board from HEMA biologics and payment honoraria from Octapharma.

Acknowledgments

The authors acknowledge support from The Dills Family Foundation Center for Research at The Bleeding & Clotting Disorders Institute.

Funding

The Dills Family Foundation Center for Research at The Bleeding & Clotting Disorders Institute.

Author contributions

All authors developed the concepts and images, wrote the manuscript, and approved the final content

Relationship Disclosure

M.D.T. reports consulting fees from Pfizer, Sanofi, Sobi–Swedish Orphan Biovitrum, Takeda, Amgen Inc, Octapharma, Genentech, BioMarin, UCB Biosciences, Dova Pharmaceuticals, Novo Nordisk and honoraria from Sobi, Genentech, Amgen, Novartis, BioMarin, and Sanofi. J.C.R. reports grants from Takeda and GeneTech and consulting fees from CSL Behring, F. Hoffman-La Roche AG, Sanofi, HEMA Biologics, Novartis, Novo Nordisk, Pfizer, Takeda, and Genentech. M.G.E. reports participation on Sevenfact Advisory Board for HEMA biologics and honoraria from Octapharma.

References

  • 1.Matuk-Villazon O., Roberts J.C., Corrales-Medina F.F. Hemophilia: The Past, the Present, and the Future. Pediatr Rev. 2021 Dec 1;42(12):672–683. doi: 10.1542/pir.2020-004143. PMID: 34850178. [DOI] [PubMed] [Google Scholar]
  • 2.World Federation of Hemophilia World Federation of Hemophilia Report on the Annual Global Survey. 2022. https://elearning.wfh.org/resource/report-on-the-annual-global-survey-2022/
  • 3.Miller C.H., Soucie J.M., Byams V.R., Payne A.B., Sidonio R.F., Jr., Buckner T.W., Bean C.J. Women and girls with haemophilia receiving care at specialized haemophilia treatment centres in the United States. Haemophilia. 2021 Nov;27(6):1037–1044. doi: 10.1111/hae.14403. Epub 2021 Sep 4. PMID: 34480812; PMCID: PMC8663793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Females Inheriting Hemophilia | Causes of Hemophilia. https://www.ihtc.org/women-with-hemophilia
  • 5.Weyand A.C., Sidonio R.F., Jr., Sholzberg M. Health issues in women and girls affected by haemophilia with a focus on nomenclature, heavy menstrual bleeding, and musculoskeletal issues. Haemophilia. 2022 May;28(Suppl 4 Suppl 4):18–25. doi: 10.1111/hae.14535. PMID: 35521724; PMCID: PMC9321707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Nascimento B., Goodnough L.T., Levy J.H. Cryoprecipitate therapy. Br J Anaesth. 2014 Dec;113(6):922–934. doi: 10.1093/bja/aeu158. Epub 2014 Jun 27. PMID: 24972790; PMCID: PMC4627369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Kasper C.K. Judith Graham Pool and the discovery of cryoprecipitate. Haemophilia. 2012 Nov;18(6):833–835. doi: 10.1111/hae.12042. PMID: 23106944. [DOI] [PubMed] [Google Scholar]
  • 8.Franchini M. The modern treatment of haemophilia: a narrative review. Blood Transfus. 2013 Apr;11(2):178–182. doi: 10.2450/2012.0166-11. Epub 2012 Jul 4. PMID: 22790275; PMCID: PMC3626468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., Carcao M., Mahlangu J., Ragni M.V., Windyga J., Llinás A., Goddard N.J., Mohan R., Poonnoose P.M., Feldman B.M., Lewis S.Z., van den Berg H.M., Pierce G.F. WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug;26(Suppl 6):1–158. doi: 10.1111/hae.14046. Epub 2020 Aug 3. Erratum in: Haemophilia. 2021 Jul;27(4):699. PMID: 32744769. [DOI] [PubMed] [Google Scholar]
  • 10.Marchesini E., Morfini M., Valentino L. Recent Advances in the Treatment of Hemophilia: A Review. Biologics. 2021 Jun 15;15:221–235. doi: 10.2147/BTT.S252580. PMID: 34163136; PMCID: PMC8214539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.COOMBES R. BAD BLOOD. BMJ. 2007;334(7599):879–880. doi: 10.1136/BMJ.39195.621528.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Pappenheim K. UK inquiry should establish why contaminated blood products were given to people with haemophilia. BMJ. 1999 Jul 3;319(7201):52–53. doi: 10.1136/bmj.319.7201.52a. PMID: 10390467; PMCID: PMC1116150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Klamroth R., Gröner A., Simon T.L. Pathogen inactivation and removal methods for plasma-derived clotting factor concentrates. Transfusion. 2014 May;54(5):1406–1417. doi: 10.1111/trf.12423. Epub 2013 Sep 30. PMID: 24117799; PMCID: PMC7169823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.MASAC Hemophilia & Coagulation Disorder Treatments | NBDF. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-276-masac-recommendations-concerning-products-licensed-for-the-treatment-of-hemophilia-and-selected-disorders-of-the-coagulation-system
  • 15.Schwarzinger I., Pabinger I., Korninger C., Haschke F., Kundi M., Niessner H., Lechner K. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol. 1987 Mar;24(3):241–245. doi: 10.1002/ajh.2830240303. PMID: 3103425. [DOI] [PubMed] [Google Scholar]
  • 16.Witmer C., Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol. 2013 Feb;4(1):59–72. doi: 10.1177/2040620712464509. PMID: 23610614; PMCID: PMC3629762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Abdi A., Bordbar M.R., Hassan S., Rosendaal F.R., van der Bom J.G., Voorberg J., Fijnvandraat K., Gouw S.C. Prevalence and Incidence of Non-neutralizing Antibodies in Congenital Hemophilia A- A Systematic Review and Meta-Analysis. Front Immunol. 2020 May 7;11:563. doi: 10.3389/fimmu.2020.00563. PMID: 32457734; PMCID: PMC7221178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Male C., Andersson N.G., Rafowicz A., Liesner R., Kurnik K., Fischer K., Platokouki H., Santagostino E., Chambost H., Nolan B., Königs C., Kenet G., Ljung R., Van den Berg M. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica. 2021 Jan 1;106(1):123–129. doi: 10.3324/haematol.2019.239160. PMID: 31919092; PMCID: PMC7776246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Tieu P., Chan A., Matino D. Molecular Mechanisms of Inhibitor Development in Hemophilia. Mediterr J Hematol Infect Dis. 2020 Jan 1;12(1) doi: 10.4084/MJHID.2020.001. PMID: 31934311; PMCID: PMC6951349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Antonarakis S.E., Rossiter J.P., Young M., Horst J., de Moerloose P., Sommer S.S., Ketterling R.P., Kazazian H.H., Jr., Négrier C., Vinciguerra C., Gitschier J., Goossens M., Girodon E., Ghanem N., Plassa F., Lavergne J.M., Vidaud M., Costa J.M., Laurian Y., Lin S.W., Lin S.R., Shen M.C., Lillicrap D., Taylor S.A., Windsor S., Valleix S.V., Nafa K., Sultan Y., Delpech M., Vnencak-Jones C.L., Phillips J.A. 3rd, Ljung R.C., Koumbarelis E., Gialeraki A., Mandalaki T., Jenkins P.V., Collins P.W., Pasi K.J., Goodeve A., Peake I., Preston F.E., Schwartz M., Scheibel E., Ingerslev J., Cooper D.N., Millar D.S., Kakkar V.V., Giannelli F., Naylor J.A., Tizzano E.F., Baiget M., Domenech M., Altisent C., Tusell J., Beneyto M., Lorenzo J.I., Gaucher C., Mazurier C., Peerlinck K., Matthijs G., Cassiman J.J., Vermylen J., Mori P.G., Acquila M., Caprino D., Inaba H. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 1995 Sep 15;86(6):2206–2212. PMID: 7662970. [PubMed] [Google Scholar]
  • 21.Schwaab R., Brackmann H.H., Meyer C., Seehafer J., Kirchgesser M., Haack A., Olek K., Tuddenham E.G., Oldenburg J. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost. 1995 Dec;74(6):1402–1406. PMID: 8772209. [PubMed] [Google Scholar]
  • 22.Mahlangu J., Oldenburg J., Callaghan M.U., Shima M., Mancuso M.E., Trask P., Recht M., Garcia C., Yang R., Lehle M., Macharia H., Asikanius E., Levy G.G., Kruse-Jarres R., von Mackensen S. Health-related quality of life and health status in persons with haemophilia A with inhibitors: A prospective, multicentre, non-interventional study (NIS) Haemophilia. 2019 May;25(3):382–391. doi: 10.1111/hae.13731. Epub 2019 Apr 24. PMID: 31016855; PMCID: PMC6850115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kearney S., Raffini L.J., Pham T.P., Lee X.Y., von Mackensen S., Landorph A., Takedani H., Oldenburg J. Health-related quality-of-life and treatment satisfaction of individuals with hemophilia A treated with turoctocog alfa pegol (N8-GP): a new recombinant extended half-life FVIII. Patient Prefer Adherence. 2019 Apr 9;13:497–513. doi: 10.2147/PPA.S196103. PMID: 31040652; PMCID: PMC6460998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Usuba K., Price V.E., Blanchette V., Abad A., Altisent C., Buchner-Daley L., Carneiro J.D.A., Feldman B.M., Fischer K., Grainger J., Holzhauer S., Luke K.H., Meunier S., Ozelo M., Tang L., Antunes S.V., Villaça P., Wakefield C., Wharfe G., Wu R., Young N.L. Impact of prophylaxis on health-related quality of life of boys with hemophilia: An analysis of pooled data from 9 countries. Res Pract Thromb Haemost. 2019 Apr 23;3(3):397–404. doi: 10.1002/rth2.12202. PMID: 31294327; PMCID: PMC6611476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Cheung Y.T., Lam P.H., Lam H.H.W., Ma C.T., Leung A.W.K., Wong R.S.M., Li C.K. Treatment Adherence and Health-Related Quality of Life in Patients with Hemophilia in Hong Kong. Int J Environ Res Public Health. 2022 May 26;19(11):6496. doi: 10.3390/ijerph19116496. PMID: 35682087; PMCID: PMC9180237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Gupta N., Benbouzid A., Belhani M., El Andaloussi M., Maani K., Wali Y., Benchikh El Fegoun S., Saad H.A., Mahlangu J. HAEMOcare: The First International Epidemiological Study Measuring Burden of Hemophilia in Developing Countries. TH Open. 2019 Jun 27;3(2):e190–e199. doi: 10.1055/s-0039-1688414. PMID: 31259302; PMCID: PMC6598083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Graf L. Extended Half-Life Factor VIII and Factor IX Preparations. Transfus Med Hemother. 2018 Apr;45(2):86–91. doi: 10.1159/000488060. Epub 2018 Mar 21. PMID: 29765290; PMCID: PMC5939656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Seth Chhabra E., Liu T., Kulman J., Patarroyo-White S., Yang B., Lu Q., Drager D., Moore N., Liu J., Holthaus A.M., Sommer J.M., Ismail A., Rabinovich D., Liu Z., van der Flier A., Goodman A., Furcht C., Tie M., Carlage T., Mauldin R., Dobrowsky T.M., Liu Z., Mercury O., Zhu L., Mei B., Schellenberger V., Jiang H., Pierce G.F., Salas J., Peters R. BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood. 2020 Apr 23;135(17):1484–1496. doi: 10.1182/blood.2019001292. PMID: 32078672; PMCID: PMC7180082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Mannucci P.M. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Haemost. 2023 Mar;21(3):403–412. doi: 10.1016/j.jtha.2022.12.029. PMID: 36858789. [DOI] [PubMed] [Google Scholar]
  • 30.Sun H.L., Yang M., Poon M.C., Lee A., Robinson K.S., Sholzberg M., Wu J., Iorio A., Blanchette V., Carcao M., Klaassen R.J., Jackson S. The impact of extended half-life factor concentrates on patient reported health outcome measures in persons with hemophilia A and hemophilia B. Res Pract Thromb Haemost. 2021 Oct 11;5(7) doi: 10.1002/rth2.12601. PMID: 34667922; PMCID: PMC8505988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Kitazawa T., Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity. Int J Hematol. 2020;111:20–30. doi: 10.1007/s12185-018-2545-9. [DOI] [PubMed] [Google Scholar]
  • 32.Callaghan M.U., Negrier C., Paz-Priel I., Chang T., Chebon S., Lehle M., Mahlangu J., Young G., Kruse-Jarres R., Mancuso M.E., Niggli M., Howard M., Bienz N.S., Shima M., Jiménez-Yuste V., Schmitt C., Asikanius E., Levy G.G., Pipe S.W., Oldenburg J. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021 Apr 22;137(16):2231–2242. doi: 10.1182/blood.2020009217. PMID: 33512413; PMCID: PMC8065240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.MASAC Documents | National Hemophilia Foundation. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents
  • 34.Jenkins P.V., Bowyer A., Burgess C., Gray E., Kitchen S., Murphy P., Platton S., Riddell A., Chowdary P., Lester W. Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline. Haemophilia. 2020 Jan;26(1):151–155. doi: 10.1111/hae.13903. Epub 2019 Dec 20. PMID: 31859415. [DOI] [PubMed] [Google Scholar]
  • 35.Peyvandi F., Kenet G., Pekrul I., Pruthi R.K., Ramge P., Spannagl M. Laboratory testing in hemophilia: Impact of factor and non-factor replacement therapy on coagulation assays. J Thromb Haemost. 2020 Jun;18(6):1242–1255. doi: 10.1111/jth.14784. Epub 2020 Apr 23. PMID: 32115865. [DOI] [PubMed] [Google Scholar]
  • 36.Pasi K.J., Lissitchkov T., Mamonov V., Mant T., Timofeeva M., Bagot C., Chowdary P., Georgiev P., Gercheva-Kyuchukova L., Madigan K., Van Nguyen H., Yu Q., Mei B., Benson C.C., Ragni M.V. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort. J Thromb Haemost. 2021. Jun;19(6):1436–1446. doi: 10.1111/jth.15270. Epub 2021 May 18. PMID: 33587824; PMCID: PMC8251589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Chowdary P. Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab. Drugs. 2018 Jun;78(9):881–890. doi: 10.1007/s40265-018-0922-6. Erratum in: Drugs. 2018 Jun;78(9):891. PMID: 29845491; PMCID: PMC6013504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Arruda V.R., Samelson-Jones B.J. Obstacles and future of gene therapy for hemophilia. Expert Opin Orphan Drugs. 2015;3(9):997–1010. doi: 10.1517/21678707.2015.1069179. Epub 2015 Jul 18. PMID: 26900534; PMCID: PMC4756761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Leebeek F.W.G., Miesbach W. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood. 2021 Sep 16;138(11):923–931. doi: 10.1182/blood.2019003777. PMID: 34232980. [DOI] [PubMed] [Google Scholar]
  • 40.Nathwani A.C. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):1–8. doi: 10.1182/hematology.2019000007. PMID: 31808868; PMCID: PMC6913446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Pierce G.F., Haffar A., Ampartzidis G., Peyvandi F., Diop S., El-Ekiaby M., van den Berg H.M. First-year results of an expanded humanitarian aid programme for haemophilia in resource-constrained countries. Haemophilia. 2018 Mar;24(2):229–235. doi: 10.1111/hae.13409. Epub 2018 Mar 14. PMID: 29537123. [DOI] [PubMed] [Google Scholar]
  • 42.Ghosh K., Ghosh K. Management of Haemophilia in Developing Countries: Challenges and Options. Indian J Hematol Blood Transfus. 2016 Sep;32(3):347–355. doi: 10.1007/s12288-015-0562-x. Epub 2015 Jun 18. PMID: 27429529; PMCID: PMC4930749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Pierce G.F., Adediran M., Diop S., Dunn A.L., El Ekiaby M., Kaczmarek R., Konkle B.A., Pipe S.W., Skinner M.W., Valentino L.A., Robinson F., Ampartzidis G., Martin J., Haffar A. Achieving access to haemophilia care in low-income and lower-middle-income countries: expanded Humanitarian Aid Program of the World Federation of Hemophilia after 5 years. Lancet Haematol. 2022 Sep;9(9):e689–e697. doi: 10.1016/S2352-3026(22)00209-5. PMID: 36055333. [DOI] [PubMed] [Google Scholar]
  • 44.Liu Z., Feng J., Fang Y., Cheng Y., Li S. Barriers to prophylactic treatment among patients with haemophilia A in Shandong Province, China: a qualitative study. Orphanet J Rare Dis. 2023 Aug 3;18(1):226. doi: 10.1186/s13023-023-02838-8. PMID: 37537616; PMCID: PMC10398971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Ndoumba-Mintya A., Diallo Y.L., Tayou T.C., Mbanya D.N. Optimizing Haemophilia Care in Resource-Limited Countries: Current Challenges and Future Prospects. J Blood Med. 2023 Feb 20;14:141–146. doi: 10.2147/JBM.S291536. PMID: 36846349; PMCID: PMC9951595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Mbanya D.N., Diop S., Ndoumba Mintya A.N., El Kiaby M. Hemophilia care in Africa: Status and challenges. Transfus Clin Biol. 2021 May;28(2):158–162. doi: 10.1016/j.tracli.2021.01.008. Epub 2021 Jan 27. PMID: 33515729. [DOI] [PubMed] [Google Scholar]
  • 47.Humanitarian Aid – WFH - World Federation of Hemophilia. https://wfh.org/humanitarian-aid/
  • 48.Annual Global Survey – WFH - World Federation of Hemophilia. https://wfh.org/research-and-data-collection/annual-global-survey/ [DOI] [PubMed]

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