Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Haemophilia

Nature Reviews Disease Primers volume 7, Article number: 45 (2021) Cite this article

Subjects

Abstract

Haemophilia A and B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of levels of FVIII or FIX, which are determined by the type of the causative mutation in the genes encoding the factors (F8 and F9, respectively). The hallmark clinical characteristic, especially in untreated severe forms, is bleeding (spontaneous or after trauma) into major joints such as ankles, knees and elbows, which can result in the development of arthropathy. Intracranial bleeds and bleeds into internal organs may be life-threatening. The median life expectancy was ~30 years until the 1960s, but improved understanding of the disorder and development of efficacious therapy based on prophylactic replacement of the missing factor has caused a paradigm shift, and today individuals with haemophilia can look forward to a virtually normal life expectancy and quality of life. Nevertheless, the potential development of inhibitory antibodies to infused factor is still a major hurdle to overcome in a substantial proportion of patients. Finally, gene therapy for both types of haemophilia has progressed remarkably and could soon become a reality.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Initiation and amplification of the clotting cascade.
Fig. 2: Pathophysiology of haemophilic arthropathy.
Fig. 3: Outcome measures in haemophilia.

Similar content being viewed by others

References

  1. Berntorp, E. & Shapiro, A. D. Modern haemophilia care. Lancet 379, 1447–1456 (2012). This is an easily accesible review of the fundamentals of modern haemophilia care. Still relevant despite publication year.

    PubMed  Google Scholar 

  2. Biggs, R. & Macfarlane, R. G. Haemophilia and related conditions: a survey of 187 cases. Br. J. Haematol. 4, 1–27 (1958).

    CAS  PubMed  Google Scholar 

  3. White, G. C. 2nd et al. Definitions in hemophilia. Thromb. Haemost. 85, 560 (2001).

    CAS  PubMed  Google Scholar 

  4. Fischer, K. et al. Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry. Haemophilia 20, e280–e286 (2014).

    CAS  PubMed  Google Scholar 

  5. WFH. Report on the Annual Global Survey 2019 http://www1.wfh.org/publications/files/pdf-1806.pdf (2020). The WFH Global Survey gives a good and up to date picture of demographics for haemophilia and other rare bleeding disorders worldwide.

  6. van den Berg, H. M. et al. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood 134, 317–320 (2019).

    PubMed  Google Scholar 

  7. Oldenburg, J. & Levy, G. G. Emicizumab prophylaxis in hemophilia a with inhibitors. N. Engl. J. Med. 377, 2194–2195 (2017).

    PubMed  Google Scholar 

  8. Mahlangu, J. et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N. Engl. J. Med. 379, 811–822 (2018).

    CAS  PubMed  Google Scholar 

  9. Gollomp, K. L., Doshi, B. S. & Arruda, V. R. Gene therapy for hemophilia: progress to date and challenges moving forward. Transfus. Apher. Sci. 58, 602–612 (2019). This paper is a must-read for those who want to learn the story of gene therapy in haemophilia.

    PubMed  Google Scholar 

  10. Nathwani, A. C. Gene therapy for hemophilia. Hematol. Am. Soc. Hematol. Educ. Program. 2019, 1–8 (2019).

    Google Scholar 

  11. Larsson, S. A. Life expectancy of Swedish haemophiliacs, 1831-1980. Br. J. Haematol. 59, 593–602 (1985).

    CAS  PubMed  Google Scholar 

  12. Mauser-Bunschoten, E. P., Fransen Van De Putte, D. E. & Schutgens, R. E. Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy. Haemophilia 15, 853–863 (2009).

    CAS  PubMed  Google Scholar 

  13. Stonebraker, J. S., Bolton-Maggs, P. H., Soucie, J. M., Walker, I. & Brooker, M. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 16, 20–32 (2010).

    CAS  PubMed  Google Scholar 

  14. Hassan, S. et al. Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018. J. Thromb. Haemost. 19, 645–653 (2021).

    PubMed  Google Scholar 

  15. Colvin, B. T. et al. European principles of haemophilia care. Haemophilia 14, 361–374 (2008). This article discusses important principles that should be followed by all haemophilia centres.

    CAS  PubMed  Google Scholar 

  16. UKHCDO. Annual Report. Bleeding disorder statistics for 2014/2015. http://www.ukhcdo.org/wp-content/uploads/2019/04/2015_UKHCDO_Annual_Report_2014_15_Data.pdf (2015).

  17. EAHAD. EUHASS newest annual reports. https://eahad.org/euhass-newest-annual-report-published/ (2018).

  18. Stonebraker, J. S., Bolton-Maggs, P. H., Michael Soucie, J., Walker, I. & Brooker, M. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 18, e91–e94 (2012).

    CAS  PubMed  Google Scholar 

  19. MacLean, P. E., Fijnvandraat, K., Beijlevelt, M. & Peters, M. The impact of unaware carriership on the clinical presentation of haemophilia. Haemophilia 10, 560–564 (2004).

    CAS  PubMed  Google Scholar 

  20. Biggs, R. et al. Christmas disease: a condition previously mistaken for haemophilia. Br. Med. J. 2, 1378–1382 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hoffman, M. & Monroe, D. M. III A cell-based model of hemostasis. Thromb. Haemost. 85, 958–965 (2001).

    CAS  PubMed  Google Scholar 

  22. Vehar, G. A. et al. Structure of human factor VIII. Nature 312, 337–342 (1984). This paper really paves the road for molecular biology techniques in haemophilia, such as recombinant FVIII products and gene therapy.

    CAS  PubMed  Google Scholar 

  23. Mannucci, P. M. & Tuddenham, E. G. The hemophilias—from royal genes to gene therapy. N. Engl. J. Med. 344, 1773–1779 (2001). This is a frequently cited paper on haemophilia history up to contemporary issues.

    CAS  PubMed  Google Scholar 

  24. Rogaev, E. I., Grigorenko, A. P., Faskhutdinova, G., Kittler, E. L. & Moliaka, Y. K. Genotype analysis identifies the cause of the “royal disease”. Science 326, 817 (2009).

    CAS  PubMed  Google Scholar 

  25. Acquila, M., Caprino, D., Bicocchi, P., Mori, P. G. & Tagliaferri, A. R. A skewed lyonization phenomenon as cause of hemophilia A in a female patient. Blood 85, 599–600 (1995).

    CAS  PubMed  Google Scholar 

  26. Makris, M. et al. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J. Thromb. Haemost. 16, 2530–2533 (2018).

    CAS  PubMed  Google Scholar 

  27. Graw, J., B. H., Oldenburg, J., Schramm, W. & Schwaab, R. in 30th Hemophilia Symposium (eds Schramm, W. & Scharrer, I.) (Springer, 2001).

  28. Oldenburg, J. et al. De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism. Blood 96, 2905–2906 (2000).

    CAS  PubMed  Google Scholar 

  29. Collins, P. W. et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood 124, 3389–3397 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Peyvandi, F. et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N. Engl. J. Med. 374, 2054–2064 (2016).

    CAS  PubMed  Google Scholar 

  31. Astermark, J. et al. The polygenic nature of inhibitors in hemophilia a: results from the Hemophilia Inhibitor Genetics Study (HIGS) combined cohort. Blood 121, 1446–1454 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Astermark, J. et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 108, 3739–3745 (2006).

    CAS  PubMed  Google Scholar 

  33. Pavlova, A. et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J. Thromb. Haemost. 7, 2006–2015 (2009).

    CAS  PubMed  Google Scholar 

  34. Hart, D. P. et al. Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A. Haematologica 104, 599–608 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Eckhardt, C. L. et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 122, 1954–1962 (2013).

    CAS  PubMed  Google Scholar 

  36. Kannicht, C. et al. Characterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIII. Thromb. Res. 131, 78–88 (2013).

    CAS  PubMed  Google Scholar 

  37. Hansson, K. & Stenflo, J. Post-translational modifications in proteins involved in blood coagulation. J. Thromb. Haemost. 3, 2633–2648 (2005).

    CAS  PubMed  Google Scholar 

  38. Everett, L. A., Cleuren, A. C., Khoriaty, R. N. & Ginsburg, D. Murine coagulation factor VIII is synthesized in endothelial cells. Blood 123, 3697–3705 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fahs, S. A., Hille, M. T., Shi, Q., Weiler, H. & Montgomery, R. R. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123, 3706–3713 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shahani, T. et al. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J. Thromb. Haemost. 12, 36–42 (2014).

    CAS  PubMed  Google Scholar 

  41. Fay, P. J., Haidaris, P. J. & Smudzin, T. M. Human factor VIIIa subunit structure. Reconstruction of factor VIIIa from the isolated A1/A3-C1-C2 dimer and A2 subunit. J. Biol. Chem. 266, 8957–8962 (1991).

    CAS  PubMed  Google Scholar 

  42. Newell, J. L. & Fay, P. J. Proteolysis at Arg740 facilitates subsequent bond cleavages during thrombin-catalyzed activation of factor VIII. J. Biol. Chem. 282, 25367–25375 (2007).

    CAS  PubMed  Google Scholar 

  43. Gilbert, G. E., Furie, B. C. & Furie, B. Binding of human factor VIII to phospholipid vesicles. J. Biol. Chem. 265, 815–822 (1990).

    CAS  PubMed  Google Scholar 

  44. Gilbert, G. E., Novakovic, V. A., Shi, J., Rasmussen, J. & Pipe, S. W. Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine. Blood 126, 1237–1244 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mann, K. G., Jenny, R. J. & Krishnaswamy, S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu. Rev. Biochem. 57, 915–956 (1988).

    CAS  PubMed  Google Scholar 

  46. Khan, A. R. & James, M. N. Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Protein Sci. 7, 815–836 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mertens, K., Cupers, R., Van Wijngaarden, A. & Bertina, R. M. Binding of human blood-coagulation Factors IXa and X to phospholipid membranes. Biochem. J. 223, 599–605 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Spaargaren, J. et al. Binding of blood coagulation factor VIII and its light chain to phosphatidylserine/phosphatidylcholine bilayers as measured by ellipsometry. Biochem. J. 310, 539–545 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Choo, K. H., Gould, K. G., Rees, D. J. & Brownlee, G. G. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 299, 178–180 (1982).

    CAS  PubMed  Google Scholar 

  50. Male, C. et al. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica 106, 123–129 (2021).

    PubMed  Google Scholar 

  51. Crossley, M. et al. Recovery from hemophilia B Leyden: an androgen-responsive element in the factor IX promoter. Science 257, 377–379 (1992).

    CAS  PubMed  Google Scholar 

  52. Morgan, G. E. et al. Further evidence for the importance of an androgen response element in the factor IX promoter. Br. J. Haematol. 98, 79–85 (1997).

    CAS  PubMed  Google Scholar 

  53. Simioni, P. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N. Engl. J. Med. 361, 1671–1675 (2009).

    CAS  PubMed  Google Scholar 

  54. Samelson-Jones, B. J., Finn, J. D., George, L. A., Camire, R. M. & Arruda, V. R. Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity. JCI Insight 5, e128683 (2019).

    Google Scholar 

  55. Cooley, B. et al. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice. Blood 128, 286–292 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Vadivel, K. & Bajaj, S. P. Structural biology of factor VIIa/tissue factor initiated coagulation. Front. Biosci. 17, 2476–2494 (2012).

    PubMed Central  Google Scholar 

  57. Geng, Y. et al. A sequential mechanism for exosite-mediated factor IX activation by factor XIa. J. Biol. Chem. 287, 38200–38209 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Geng, Y. et al. Analysis of the factor XI variant Arg184Gly suggests a structural basis for factor IX binding to factor XIa. JTH 11, 1374–1384 (2013).

    CAS  PubMed  Google Scholar 

  59. Monahan, P. E. Velander, W. H. & Bajaj, S. P. in Handbook of Proteolytic Enzymes 3rd edn Ch. 640 (eds Rawlings, S. D. & Salvesen, G.) 2898–2905 (Academic Press, 2013).

  60. Hooiveld, M. et al. Blood-induced joint damage: longterm effects in vitro and in vivo. J. Rheumatol. 30, 339–344 (2003).

    PubMed  Google Scholar 

  61. van Vulpen, L. F. et al. IL-1beta, in contrast to TNFalpha, is pivotal in blood-induced cartilage damage and is a potential target for therapy. Blood 126, 2239–2246 (2015).

    PubMed  Google Scholar 

  62. Hooiveld, M. J. et al. Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: a possible mechanism of hemophilic arthropathy. Arthritis Rheum. 50, 2024–2031 (2004).

    PubMed  Google Scholar 

  63. Roosendaal, G. et al. Blood-induced joint damage: a human in vitro study. Arthritis Rheum. 42, 1025–1032 (1999).

    CAS  PubMed  Google Scholar 

  64. Dunn, A. Pathophysiology, diagnosis and prevention of arthropathy in patients with haemophilia. Haemophilia 17, 571–578 (2011).

    CAS  PubMed  Google Scholar 

  65. Rodriguez-Merchan, E. C. Musculo-skeletal manifestations of haemophilia. Blood Rev. 30, 401–409 (2016). This is a comprehensive paper on the main musculo-skeletal sequelae of haemophilic bleedings.

    PubMed  Google Scholar 

  66. Stephensen, D. et al. Changing patterns of bleeding in patients with severe haemophilia A. Haemophilia 15, 1210–1214 (2009).

    CAS  PubMed  Google Scholar 

  67. Scott, M. J. et al. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study. Haemophilia 25, 205–212 (2019).

    CAS  PubMed  Google Scholar 

  68. Drake, T. A., Morrissey, J. H. & Edgington, T. S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134, 1087–1097 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cooke, E. J. et al. Vascular permeability and remodelling coincide with inflammatory and reparative processes after joint bleeding in factor VIII-deficient mice. Thromb. Haemost. 118, 1036–1047 (2018).

    PubMed  PubMed Central  Google Scholar 

  70. Hakobyan, N., Kazarian, T., Jabbar, A. A., Jabbar, K. J. & Valentino, L. A. Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene. Blood 104, 2060–2064 (2004).

    CAS  PubMed  Google Scholar 

  71. Hooiveld, M. et al. Short-term exposure of cartilage to blood results in chondrocyte apoptosis. Am. J. Pathol. 162, 943–951 (2003).

    PubMed  PubMed Central  Google Scholar 

  72. Pulles, A. E. et al. Proteoglycan synthesis rate as a novel method to measure blood-induced cartilage degeneration in non-haemophilic and haemophilic rats. Haemophilia https://doi.org/10.1111/hae.13969 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Christensen, K. R. et al. Rapid inflammation and early degeneration of bone and cartilage revealed in a time-course study of induced haemarthrosis in haemophilic rats. Rheumatology 58, 588–599 (2019).

    CAS  PubMed  Google Scholar 

  74. Jansen, N. W., Roosendaal, G., Bijlsma, J. W., Degroot, J. & Lafeber, F. P. Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study. Arthritis Rheum. 56, 199–207 (2007).

    PubMed  Google Scholar 

  75. Ovlisen, K., Kristensen, A. T., Jensen, A. L. & Tranholm, M. IL-1 beta, IL-6, KC and MCP-1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis. Haemophilia 15, 802–810 (2009).

    CAS  PubMed  Google Scholar 

  76. Roosendaal, G. et al. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J. Bone Jt. Surg. Br. 80, 540–545 (1998).

    CAS  Google Scholar 

  77. Hooiveld, M. J., Roosendaal, G., van den Berg, H. M., Bijlsma, J. W. & Lafeber, F. P. Haemoglobin-derived iron-dependent hydroxyl radical formation in blood-induced joint damage: an in vitro study. Rheumatology 42, 784–790 (2003).

    CAS  PubMed  Google Scholar 

  78. Roosendaal, G. et al. Blood-induced joint damage: a canine in vivo study. Arthritis Rheum. 42, 1033–1039 (1999).

    CAS  PubMed  Google Scholar 

  79. Mannucci, P. M., Coppola, R., Lombardi, R., Papa, M. & de Biasi, R. Direct proof of extreme lyonization as a cause of low factor VIII levels in females. Thromb. Haemost. 39, 544–545 (1978).

    CAS  PubMed  Google Scholar 

  80. Renault, N. K. et al. Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. Eur. J. Hum. Genet. 15, 628–637 (2007).

    CAS  PubMed  Google Scholar 

  81. Antonarakis, S. E. et al. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N. Engl. J. Med. 313, 842–848 (1985).

    CAS  PubMed  Google Scholar 

  82. Den Uijl, I. E. et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia 17, 849–853 (2011).

    Google Scholar 

  83. Srivastava, A. et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia https://doi.org/10.1111/hae.14046 (2020). These are newly issued haemophilia guidelines authored by a number of international experts.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ljung, R. C. Intracranial haemorrhage in haemophilia A and B. Br. J. Haematol. 140, 378–384 (2008).

    PubMed  Google Scholar 

  85. Davies, J. & Kadir, R. A. Mode of delivery and cranial bleeding in newborns with haemophilia: a systematic review and meta-analysis of the literature. Haemophilia 22, 32–38 (2016).

    CAS  PubMed  Google Scholar 

  86. Marlar, R. A., Strandberg, K., Shima, M. & Adcock, D. M. Clinical utility and impact of the use of the chromogenic vs one-stage factor activity assays in haemophilia A and B. Eur. J. Haematol. 104, 3–14 (2020).

    CAS  PubMed  Google Scholar 

  87. Kitchen, S. et al. A computer-based model to assess costs associated with the use of factor VIII and factor IX one-stage and chromogenic activity assays. J. Thromb. Haemost. 14, 757–764 (2016).

    CAS  PubMed  Google Scholar 

  88. Pavlova, A., Delev, D., Pezeshkpoor, B., Muller, J. & Oldenburg, J. Haemophilia A mutations in patients with non-severe phenotype associated with a discrepancy between one-stage and chromogenic factor VIII activity assays. Thromb. Haemost. 111, 851–861 (2014).

    CAS  PubMed  Google Scholar 

  89. Cid, A. R. et al. One-stage and chromogenic FVIII:C assay discrepancy in mild haemophilia A and the relationship with the mutation and bleeding phenotype. Haemophilia 14, 1049–1054 (2008).

    CAS  PubMed  Google Scholar 

  90. Trossaert, M. et al. Prevalence, biological phenotype and genotype in moderate/mild hemophilia A with discrepancy between one-stage and chromogenic factor VIII activity. J. Thromb. Haemost. 9, 524–530 (2011).

    CAS  PubMed  Google Scholar 

  91. Laurie, A. D. et al. Preimplantation genetic diagnosis for hemophilia A using indirect linkage analysis and direct genotyping approaches. J. Thromb. Haemost. 8, 783–789 (2010).

    CAS  PubMed  Google Scholar 

  92. Ljung, R. C. Prenatal diagnosis of haemophilia. Haemophilia 5, 84–87 (1999).

    CAS  PubMed  Google Scholar 

  93. Cutler, J., Chappell, L. C., Kyle, P. & Madan, B. Third trimester amniocentesis for diagnosis of inherited bleeding disorders prior to delivery. Haemophilia 19, 904–907 (2013).

    CAS  PubMed  Google Scholar 

  94. Tabor, A. & Alfirevic, Z. Update on procedure-related risks for prenatal diagnosis techniques. Fetal Diagn. Ther. 27, 1–7 (2010).

    PubMed  Google Scholar 

  95. Bustamante-Aragones, A. et al. Foetal sex determination in maternal blood from the seventh week of gestation and its role in diagnosing haemophilia in the foetuses of female carriers. Haemophilia 14, 593–598 (2008).

    CAS  PubMed  Google Scholar 

  96. Ljung, R. C. & Sjorin, E. Origin of mutation in sporadic cases of haemophilia A. Br. J. Haematol. 106, 870–874 (1999).

    CAS  PubMed  Google Scholar 

  97. Leuer, M. et al. Somatic mosaicism in hemophilia A: a fairly common event. Am. J. Hum. Genet. 69, 75–87 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Edwards, J. H. Familiarity, recessivity and germline mosaicism. Ann. Hum. Genet. 53, 33–47 (1989).

    CAS  PubMed  Google Scholar 

  99. Gupta, S. & Shapiro, A. D. Optimizing bleed prevention throughout the lifespan: womb to tomb. Haemophilia 24 (Suppl. 6), 76–86 (2018).

    PubMed  Google Scholar 

  100. Shapiro, A. D., Mitchell, I. S. & Nasr, S. The future of bypassing agents for hemophilia with inhibitors in the era of novel agents. J. Thromb. Haemost. 16, 2362–2374 (2018).

    CAS  PubMed  Google Scholar 

  101. Hoots, W. K. & Shapiro, A. D. Treatment of bleeding and perioperative management in hemophilia A and B. UpToDate, https://www.uptodate.com/contents/treatment-of-bleeding-and-perioperative-management-in-hemophilia-a-and-b (2021).

  102. Pai, M. et al. NHF-McMaster guideline on care models for haemophilia management. Haemophilia 22 (Suppl. 3), 6–16 (2016).

    PubMed  Google Scholar 

  103. Pipe, S. W. & Kessler, C. M. Evidence-based guidelines support integrated disease management as the optimal model of haemophilia care. Haemophilia 22 (Suppl. 3), 3–5 (2016).

    PubMed  Google Scholar 

  104. Soucie, J. M. et al. Mortality among males with hemophilia: relations with source of medical care. Blood 96, 437–442 (2000).

    CAS  PubMed  Google Scholar 

  105. Soucie, J. M. et al. Home-based factor infusion therapy and hospitalization for bleeding complications among males with haemophilia. Haemophilia 7, 198–206 (2001).

    CAS  PubMed  Google Scholar 

  106. Schutgens, R. E. G., Voskuil, M. & Mauser-Bunschoten, E. P. Management of cardiovascular disease in aging persons with haemophilia. Hamostaseologie 37, 196–201 (2017).

    PubMed  Google Scholar 

  107. Mannucci, P. M. & Iacobelli, M. Progress in the contemporary management of hemophilia: the new issue of patient aging. Eur. J. Intern. Med. 43, 16–21 (2017).

    PubMed  Google Scholar 

  108. Hollingdrake, O. et al. Haemophilia and age-related comorbidities: do men with haemophilia consult a general practitioner for men’s preventative health checks. Haemophilia 22, e335–e337 (2016).

    CAS  PubMed  Google Scholar 

  109. Boccalandro, E. et al. Ageing successfully with haemophilia: a multidisciplinary programme. Haemophilia 24, 57–62 (2018).

    CAS  PubMed  Google Scholar 

  110. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. https://www1.wfh.org/publication/files/pdf-1472.pdf (2012).

  111. Manco-Johnson, M. J. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N. Engl. J. Med. 357, 535–544 (2007).

    CAS  PubMed  Google Scholar 

  112. Manco-Johnson, M. J., Soucie, J. M. & Gill, J. C. Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood 129, 2368–2374 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Collins, P. W. et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J. Thromb. Haemost. 7, 413–420 (2009).

    CAS  PubMed  Google Scholar 

  114. Skinner, M. W. WFH: closing the global gap–achieving optimal care. Haemophilia 18 (Suppl. 4), 1–12 (2012).

    PubMed  Google Scholar 

  115. Fischer, K. et al. Prophylactic treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen. Haemophilia 8, 753–760 (2002).

    CAS  PubMed  Google Scholar 

  116. Oldenburg, J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 125, 2038–2044 (2015).

    CAS  PubMed  Google Scholar 

  117. Krämer, L. Retrospektive Studie zu den Auswirkungen der Langzeitprophylaxe mit Faktor VIII-Konzentrat bei Patienten mit schwerer Hämophilie A auf den Gelänkstatus von Kniegelenk, oberen Sprunggelenk un Ellenbogengelenk (Universität Bonn, 2013).

  118. den Uijl, I. E. et al. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 17, 41–44 (2011).

    Google Scholar 

  119. Fischer, K. Optimizing efficacy of factor VIII prophylaxis for severe haemophilia A. Haemophilia 17, 9–15 (2011).

    CAS  Google Scholar 

  120. Lundin, B., Ljung, R. & Pettersson, H., European Paediatric Network for Haemophilia Management (PEDNET). MRI scores of ankle joints in children with haemophilia-comparison with clinical data. Haemophilia 11, 116–122 (2005).

    CAS  PubMed  Google Scholar 

  121. De la Corte-Rodriguez, H., Rodriguez-Merchan, E. C. & Jimenez-Yuste, V. Point-of-care ultrasonography in orthopedic management of hemophilia: multiple uses of an effective tool. HSS J. 14, 307–313 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. National Hemophilia Foundation. MASAC Recommendations Regarding Doses of Clotting Factor Concentrate in the Home. Document #242. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Regarding-Doses-of-Clotting-Factor-Concentrate-in-the-Home (2016).

  123. Kitchen, S., Kershaw, G. & Tiefenbacher, S. Recombinant to modified factor VIII and factor IX - chromogenic and one-stage assays issues. Haemophilia 22 (Suppl. 5), 72–77 (2016).

    CAS  PubMed  Google Scholar 

  124. Rodriguez-Merchan, E. C. Serological biomarkers in hemophilic arthropathy: can they be used to monitor bleeding and ongoing progression of blood-induced joint disease in patients with hemophilia? Blood Rev. 41, 100642 (2020).

    PubMed  Google Scholar 

  125. Mancuso, M. E. & Santagostino, E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J. Clin. Med. 6, 39 (2017).

    PubMed Central  Google Scholar 

  126. Ar, M. C., Balkan, C. & Kavakli, K. Extended half-life coagulation factors: a new era in the management of hemophilia patients. Turk. J. Haematol. 36, 141–154 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bjorkman, S. Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A. Haemophilia 16, 597–605 (2010).

    CAS  PubMed  Google Scholar 

  128. Meeks, S. L. & Batsuli, G. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches. Hematol. Am. Soc. Hematol. Educ. Program. 2016, 657–662 (2016).

    Google Scholar 

  129. Miller, C. H. et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia 18, 375–382 (2012).

    CAS  PubMed  Google Scholar 

  130. European Medicines Agency. Factor VIII medicines: no clear and consistent evidence of difference in risk of inhibitor development between classes. EMA/603417/2017. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/09/WC500234822.pdf (2017).

  131. Miller, C. H. et al. Comparison of clot-based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study. J. Thromb. Haemost. 11, 1300–1309 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. van den Berg, H. M. Different impact of factor VIII products on inhibitor development? Thromb. J. 14, 31 (2016).

    PubMed  PubMed Central  Google Scholar 

  133. Soucie, J. M. et al. A study of prospective surveillance for inhibitors among persons with haemophilia in the United States. Haemophilia 20, 230–237 (2014).

    CAS  PubMed  Google Scholar 

  134. Hay, C. R. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 4, 558–563 (1998).

    CAS  PubMed  Google Scholar 

  135. Giuffrida, A. C. et al. Inhibitors in mild/moderate haemophilia A: two case reports and a literature review. Blood Transfus. 6, 163–168 (2008).

    PubMed  PubMed Central  Google Scholar 

  136. National Hemophilia Foundation. MASAC Recommendations on Standardized Testing and Surveillance for Inhibitors in Patients with Hemophilia A and B. Document #236, https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-on-Standardized-Testing-and-Surveillance-for-Inhibitors-in-Patients-with-Hemophilia-A-and-B (2015).

  137. Konkle, B. A. et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J. Thromb. Haemost. 5, 1904–1913 (2007).

    CAS  PubMed  Google Scholar 

  138. Antunes, S. V. et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 20, 65–72 (2014).

    CAS  PubMed  Google Scholar 

  139. Wang, M. et al. PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding. Haemophilia 23, 832–843 (2017).

    CAS  PubMed  Google Scholar 

  140. Nakatomi, Y. et al. Combining FVIIa and FX into a mixture which imparts a unique thrombin generation potential to hemophilic plasma: an in vitro assessment of FVIIa/FX mixture as an alternative bypassing agent. Thromb. Res. 125, 457–463 (2010).

    CAS  PubMed  Google Scholar 

  141. Rocino, A., Franchini, M. & Coppola, A. Treatment and prevention of bleeds in haemophilia patients with inhibitors to factor VIII/IX. J. Clin. Med. 6, 46 (2017).

    PubMed Central  Google Scholar 

  142. Tagariello, G. et al. High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance. J. Hematol. Oncol. 6, 63 (2013).

    PubMed  PubMed Central  Google Scholar 

  143. Earnshaw, S. R., Graham, C. N., McDade, C. L., Spears, J. B. & Kessler, C. M. Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. Haemophilia 21, 310–319 (2015).

    CAS  PubMed  Google Scholar 

  144. Holstein, K. et al. Current view and outcome of ITI therapy - a change over time? Thromb. Res. 148, 38–44 (2016).

    CAS  PubMed  Google Scholar 

  145. Benson, G. et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. Eur. J. Haematol. 88, 371–379 (2012).

    CAS  PubMed  Google Scholar 

  146. Valentino, L. A. et al. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 21, 559–567 (2015).

    CAS  PubMed  Google Scholar 

  147. Nakar, C. et al. Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two U.S. centres. Haemophilia 21, 365–373 (2015).

    CAS  PubMed  Google Scholar 

  148. Tengborn, L. et al. Anaphylactoid reactions and nephrotic syndrome–a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers. Haemophilia 4, 854–859 (1998).

    CAS  PubMed  Google Scholar 

  149. Franchini, M. & Mannucci, P. M. Inhibitor eradication with rituximab in haemophilia: where do we stand? Br. J. Haematol. 165, 600–608 (2014).

    CAS  PubMed  Google Scholar 

  150. Ragni, M. V. Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy. Hematology 2017, 605–609 (2017).

    PubMed  PubMed Central  Google Scholar 

  151. Pasi, K. J. et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N. Engl. J. Med. 377, 819–828 (2017).

    CAS  PubMed  Google Scholar 

  152. Bhat, V., von Drygalski, A., Gale, A. J., Griffin, J. H. & Mosnier, L. O. Improved coagulation and hemostasis in hemophilia with inhibitors by combinations of (super)factor Va and factor VIIa. Thromb. Haemost. 115, 551–561 (2016).

    PubMed  Google Scholar 

  153. Arkin, S. et al. Escalating single doses of PF-05230907 (recombinant factor Xa variant FXaI16L) are safe and demonstrate hemostatic pharmacology in healthy volunteers [abstract]. Blood 128, 3781–3781 (2016).

    Google Scholar 

  154. Polderdijk, S. G. I., Baglin, T. P. & Huntington, J. A. Targeting activated protein C to treat hemophilia. Curr. Opin. Hematol. 24, 446–452 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Peterson, J. A., Maroney, S. A. & Mast, A. E. Targeting TFPI for hemophilia treatment. Thromb. Res. 141, S28–S30 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Rodriguez-Merchan, E. C. & Valentino, L. A. Emicizumab: review of the literature and critical appraisal. Haemophilia 25, 11–20 (2019).

    PubMed  Google Scholar 

  157. U.S. Food and Drug Administration. FDA approves emicizumab-kxwh for prevention and reduction of bleeding in patients with hemophilia A with factor VIII inhibitors. fda.gov https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm585650.htm (2017)

  158. Genentech. Hemlibra [Package Insert], https://www.gene.com/download/pdf/hemlibra_prescribing.pdf (2018).

  159. Oldenburg, J. et al. Emicizumab prophylaxis in hemophilia a with inhibitors. N. Engl. J. Med. 377, 809–818 (2017).

    CAS  PubMed  Google Scholar 

  160. Hartmann, R., Feenstra, T., Valentino, L., Dockal, M. & Scheiflinger, F. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J. Thromb. Haemost. 16, 1580–1591 (2018).

    Google Scholar 

  161. National Hemophilia Foundation. Recommendation on the Use and Management of Emicizumab-KXWH (Hemlibra®) for Hemophilia A with and without Inhibitors. MASAC document 258, https://www.hemophilia.org/sites/default/files/document/files/258_emicizumab.pdf (2020).

  162. Young, G. Implementing emicizumab in hemophilia inhibitor management: emicizumab should be prescribed after tolerance. Blood Adv. 2, 2780–2782 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Le Quellec, S. & Negrier, C. Emicizumab should be prescribed independent of immune tolerance induction. Blood Adv. 2, 2783–2786 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. Santagostino, E., Young, G., Escuriola Ettingshausen, C., Jimenez-Yuste, V. & Carcao, M. Inhibitors: a need for eradication? Acta Haematol. 141, 151–155 (2019).

    CAS  PubMed  Google Scholar 

  165. Ljung, R. et al. Inhibitors in haemophilia A and B: management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur. J. Haematol. 102, 111–122 (2019).

    PubMed  Google Scholar 

  166. Batsuli, G., Zimowski, K. L., Tickle, K., Meeks, S. L. & Sidonio, R. F. Jr Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia 25, 789–796 (2019).

    CAS  PubMed  Google Scholar 

  167. George, L. A. Hemophilia gene therapy comes of age. Blood Adv. 1, 2591–2599 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. George, L. A. et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N. Engl. J. Med. 377, 2215–2227 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Pasi, K. J. et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N. Engl. J. Med. 382, 29–40 (2020).

    CAS  PubMed  Google Scholar 

  170. George, L. et al. Phase I/II trial of SPK-8011: stable and durable FVIII expression for >2 years with significant ABR improvements in initial dose cohorts following AAV-mediated FVIII gene transfer for hemophilia A [abstract]. Res. Pract. Thromb. Haemost. 4, OC 03.5 (2020).

  171. Samelson-Jones, B. J. et al. Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants. Blood Adv. 5, 1324–1332 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Nathwani, A. C. R. U., Tuddenham, E., Chowdary, P., McIntosh, J. & Riddell, A. et al. Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing “empty viral particles” on safety and efficacy of gene transfer. Blood 132, 491 (2018).

    Google Scholar 

  173. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006).

    CAS  PubMed  Google Scholar 

  174. Mingozzi, F. et al. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13, 419–422 (2007).

    CAS  PubMed  Google Scholar 

  175. Hoots, W. K. Emergency Care Issues in Hemophilia. Treatment of Hemophilia series 43, http://www1.wfh.org/publication/files/pdf-1196.pdf (2007).

  176. Donaldson, J. & Goddard, N. Compartment syndrome in patients with haemophilia. J. Orthop. 12, 237–241 (2015).

    PubMed  PubMed Central  Google Scholar 

  177. Caviglia, H., Landro, M., Galatro, G., Candela, M. & Neme, D. Pseudotumors of the limbs in patients with hemophilia. J. Blood Disord. 2, 1026 (2015).

    Google Scholar 

  178. van Vulpen, L. F. D., Mastbergen, S. C., Lafeber, F. & Schutgens, R. E. G. Differential effects of bleeds on the development of arthropathy - basic and applied issues. Haemophilia 23, 521–527 (2017).

    PubMed  Google Scholar 

  179. Simpson, M. L. & Valentino, L. A. Management of joint bleeding in hemophilia. Expert. Rev. Hematol. 5, 459–468 (2012).

    CAS  PubMed  Google Scholar 

  180. Rodriguez-Merchan, E. C. Radiosynovectomy in haemophilia. Blood Rev. 35, 1–6 (2019).

    PubMed  Google Scholar 

  181. Rodriguez-Merchan, E. C. & Valentino, L. A. Safety of radiation exposure after radiosynovectomy in paediatric patients with haemophilia. Haemophilia 21, 411–418 (2015).

    CAS  PubMed  Google Scholar 

  182. Rodriguez-Merchan, E. C. The role of orthopaedic surgery in haemophilia: current rationale, indications and results. EFORT Open. Rev. 4, 165–173 (2019).

    PubMed  PubMed Central  Google Scholar 

  183. Manners, P. J. et al. Joint aspiration for acute hemarthrosis in children receiving factor VIII prophylaxis for severe hemophilia: 11-year safety data. J. Rheumatol. 42, 885–890 (2015).

    PubMed  Google Scholar 

  184. De la Corte-Rodriguez, H. et al. Accelerating recovery from acute hemarthrosis in patients with hemophilia: the role of joint aspiration. Blood Coagul. Fibrinolysis 30, 111–119 (2019).

    PubMed  Google Scholar 

  185. Lewandowska, M. et al. Management of people with haemophilia A undergoing surgery while receiving emicizumab prophylaxis: Real-world experience from a large comprehensive treatment centre in the US. Haemophilia 27, 90–99 (2021).

    PubMed  Google Scholar 

  186. Muller, J. et al. Laboratory monitoring in emicizumab-treated persons with hemophilia A. Thromb. Haemost. 119, 1384–1393 (2019).

    PubMed  Google Scholar 

  187. Auerswald, G. et al. Pain and pain management in haemophilia. Blood Coagul. Fibrinolysis 27, 845–854 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Humphries, T. J. & Kessler, C. M. Managing chronic pain in adults with haemophilia: current status and call to action. Haemophilia 21, 41–51 (2015).

    CAS  PubMed  Google Scholar 

  189. Rodriguez-Merchan, E. C. Treatment of musculo-skeletal pain in haemophilia. Blood Rev. 32, 116–121 (2018).

    CAS  PubMed  Google Scholar 

  190. Holstein, K. et al. Pain management in patients with haemophilia: a European survey. Haemophilia 18, 743–752 (2012).

    CAS  PubMed  Google Scholar 

  191. Witkop, M. et al. Assessment of acute and persistent pain management in patients with haemophilia. Haemophilia 17, 612–619 (2011).

    CAS  PubMed  Google Scholar 

  192. Wallny, T. et al. Pain status of patients with severe haemophilic arthropathy. Haemophilia 7, 453–458 (2001).

    CAS  PubMed  Google Scholar 

  193. No Authors listed. Study protocol for the World Health Organization project to develop a Quality of Life assessment instrument (WHOQOL). Qual. Life Res. 2, 153–159 (1993).

    Google Scholar 

  194. Limperg, P. F. et al. Health-related quality of life questionnaires in individuals with haemophilia: a systematic review of their measurement properties. Haemophilia 23, 497–510 (2017).

    CAS  PubMed  Google Scholar 

  195. van Balen, E. et al. Patient-relevant health outcomes for hemophilia care: development of an international standard outcomes set. Res. Pract. Thromb. Haemost. 5, e12488 (2021). Patient-relevant outcomes are important in follow-up of haemophilia treatment. This paper describes a set of important outcomes including QoL, based on a systematic literature review.

    PubMed  PubMed Central  Google Scholar 

  196. van den Berg, H. M. et al. Assessments of outcome in haemophilia - what is the added value of QoL tools? Haemophilia 21, 430–435 (2015).

    PubMed  Google Scholar 

  197. Carcao, M. et al. Measuring the impact of changing from standard half-life (SHL) to extended half-life (EHL) FVIII prophylaxis on health-related quality of life (HRQoL) in boys with moderate/severe haemophilia A: lessons learned with the CHO-KLAT tool. Haemophilia 26, 73–78 (2020).

    CAS  PubMed  Google Scholar 

  198. Price, V. E. et al. Updating the Canadian Hemophilia Outcomes-Kids’ Life Assessment Tool (CHO-KLAT) in the era of extended half-life clotting factor concentrates. Res. Pract. Thromb. Haemost. 5, 403–411 (2021).

    PubMed  PubMed Central  Google Scholar 

  199. Dover, S. et al. Measuring the impact of hemophilia on families: development of the Hemophilia Family Impact Tool (H-FIT). Res. Pract. Thromb. Haemost. 5, e12519 (2021).

    PubMed  PubMed Central  Google Scholar 

  200. Carcao, M. et al. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia 25, 676–684 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Pierce, G. F. et al. First-year results of an expanded humanitarian aid programme for haemophilia in resource-constrained countries. Haemophilia 24, 229–235 (2018).

    CAS  PubMed  Google Scholar 

  202. Maseide, R. J. et al. Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B - the MoHem study. Haemophilia 26, 891–897 (2020).

    PubMed  Google Scholar 

  203. Olsson, A., Hellgren, M., Berntorp, E. & Baghaei, F. Association between bleeding tendency and health-related quality of life in carriers of moderate and severe haemophilia. Haemophilia 21, 742–746 (2015).

    CAS  PubMed  Google Scholar 

  204. Chambost, H. & Ljung, R. Changing pattern of care of boys with haemophilia in western European centres. Haemophilia 11, 92–99 (2005).

    CAS  PubMed  Google Scholar 

  205. Makris, M. et al. EUHASS: The European Haemophilia Safety Surveillance system. Thromb. Res. 127 (Suppl. 2), S22–S25 (2011).

    CAS  PubMed  Google Scholar 

  206. Fischer, K. et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 122, 1129–1136 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Collins, P. W. et al. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia 17, 2–10 (2011).

    CAS  PubMed  Google Scholar 

  208. Astermark, J. et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br. J. Haematol. 105, 1109–1113 (1999).

    CAS  PubMed  Google Scholar 

  209. Fischer, K. et al. When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH. J. Thromb. Haemost. 14, 1105–1109 (2016).

    CAS  PubMed  Google Scholar 

  210. Bjorkman, S. & Collins, P. Measurement of factor VIII pharmacokinetics in routine clinical practice. J. Thromb. Haemost. 11, 180–182 (2013).

    CAS  PubMed  Google Scholar 

  211. Lenting, P. J., Denis, C. V. & Christophe, O. D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 130, 2463–2468 (2017).

    CAS  PubMed  Google Scholar 

  212. Pipe, S. W. et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 6, e295–e305 (2019).

    PubMed  Google Scholar 

  213. Ferrante, F. I. S., Kunze, M. & Michaels, L. A. Anti-TFPI antibody BAY1093884: early termination of phase II dose escalation study due to thrombosis. Haemophilia 26, 77–78 (2020).

    Google Scholar 

  214. Figueiredo, M. Novo Nordisk pauses 3 clinical trials of concizumab amid safety concerns, Hemophila News Today, https://hemophilianewstoday.com/2020/03/18/novo-nordisk-pauses-three-clinical-trials-of-concizumab-due-to-safety-concerns/ (2020).

  215. Astermark, J. FVIII inhibitors: pathogenesis and avoidance. Blood 125, 2045–2051 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Young, G. et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 134, 2127–2138 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Astermark, J. et al. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 90, 924–931 (2005).

    CAS  PubMed  Google Scholar 

  218. Gouw, S. C. et al. Factor VIII products and inhibitor development in severe hemophilia A. N. Engl. J. Med. 368, 231–239 (2013).

    CAS  PubMed  Google Scholar 

  219. Gouw, S. C., van der Bom, J. G. & Marijke van den Berg, H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 109, 4648–4654 (2007).

    CAS  PubMed  Google Scholar 

  220. Brackmann, H. H. & Gormsen, J. Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder. Lancet 2, 933 (1977).

    CAS  PubMed  Google Scholar 

  221. Astermark, J. Immune tolerance induction in patients with hemophilia A. Thromb. Res. 127 (Suppl. 1), S6–S9 (2011).

    CAS  PubMed  Google Scholar 

  222. Pasi, K. J. et al. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran - results of the phase 1 inhibitor cohort. J. Thromb. Haemost. https://doi.org/10.1111/jth.15270 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Blas, Y. D. et al. Phase 1b study to evaluate safety, tolerability, and maximum tolerated dose of PF-05230907 for intracerebral hemorrhage. Stroke 52, 294–298 (2021).

    CAS  Google Scholar 

  224. Croteau, S. E., Wang, M. & Wheeler, A. P. 2021 clinical trials update: Innovations in hemophilia therapy. Am. J. Hematol. 96, 128–144 (2021).

    PubMed  Google Scholar 

  225. Chowdary, P. Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia. Int. J. Hematol. 111, 42–50 (2020).

    PubMed  Google Scholar 

  226. Lenting, P. J. Laboratory monitoring of hemophilia A treatments: new challenges. Blood Adv. 4, 2111–2118 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Martel-Pelletier, J. et al. Osteoarthritis. Nat. Rev. Dis. Prim. 2, 16072 (2016).

    PubMed  Google Scholar 

  228. WHO. Towards a Common Language for Functioning, Disability and Health: ICF The International Classification of Functioning, Disability and Health, https://cdn.who.int/media/docs/default-source/classification/icf/icfbeginnersguide.pdf?sfvrsn=eead63d3_4 (2002)

  229. Young, N. L. et al. Development of a health-related quality of life measure for boys with haemophilia: the Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT). Haemophilia 10 (Suppl. 1), 34–43 (2004).

    PubMed  Google Scholar 

  230. von Mackensen, S., Bullinger, M. & Haemo-Qo, L. G. Development and testing of an instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL). Haemophilia 10 (Suppl. 1), 17–25 (2004).

    Google Scholar 

  231. Pollak, E., Muhlan, H., Mackensen, S. V. & Bullinger, M., HAEMO-QOL Group. The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia. Haemophilia 12, 384–392 (2006).

    CAS  PubMed  Google Scholar 

  232. Manco-Johnson, M., Morrissey-Harding, G., Edelman-Lewis, B., Oster, G. & Larson, P. Development and validation of a measure of disease-specific quality of life in young children with haemophilia. Haemophilia 10, 34–41 (2004).

    CAS  PubMed  Google Scholar 

  233. Mackensen, S. & Gringeri, A. Development and pilot testing of a disease-specific quality of life questionnaire for adult patients with haemophilia (Ham-A-QoL). Blood 104, 2214 (2004).

    Google Scholar 

  234. Rentz, A. et al. Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia. Haemophilia 14, 1023–1034 (2008).

    CAS  PubMed  Google Scholar 

  235. Arranz, P. et al. Development of a new disease-specific quality-of-life questionnaire to adults living with haemophilia. Haemophilia 10, 376–382 (2004).

    CAS  PubMed  Google Scholar 

  236. Remor, E. Development and psychometric testing of the Hemophilia Well-being Index. Int. J. Behav. Med. 20, 609–617 (2013).

    PubMed  Google Scholar 

  237. Remor, E. Hemolatin-QoL Desarollo de medida especifica para la evaluacónde la calidad de vida en pacientas adultos con hemophilia en America-Latina Terapic. Rev. Interam. de. Psicol.ía/Interam. J. Psychol. 39, 211–220 (2005).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Translational Medicine, Lund University, Malmö, Sweden

    Erik Berntorp

  2. Skane University Hospital, Malmö, Sweden

    Erik Berntorp

  3. Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands

    Kathelijn Fischer

  4. The Royal London Hospital Haemophilia Centre, Barts Health NHS Trust, London, UK

    Daniel P. Hart & David Stephensen

  5. Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK

    Daniel P. Hart

  6. Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Maria Elisa Mancuso

  7. Kent Haemophilia & Thrombosis Centre, Canterbury, UK

    David Stephensen

  8. Indiana Hemophilia and Thrombosis Center, Inc., Indianapolis, IN, USA

    Amy D. Shapiro

  9. Department of Paediatrics, University of Toronto, Toronto, Canada

    Victor Blanchette

  10. Division of Haematology/Oncology, Research Institute, Hospital for Sick Children, Toronto, Canada

    Victor Blanchette

Authors
  1. Erik Berntorp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathelijn Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel P. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Elisa Mancuso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Stephensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amy D. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Victor Blanchette
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (E.B.); Epidemiology (K.F.); Mechanisms/pathophysiology (D.P.H. and D.S); Diagnosis, screening and prevention (M.E.M.); Management (A.D.S.); Quality of life (V.B.); Outlook (E.B.); Overview of Primer (E.B.). All authors provided critical evaluation of the complete manuscript.

Corresponding author

Correspondence to Erik Berntorp.

Ethics declarations

Competing interests

E.B. has received grants and/or research support from Bayer, CSL Behring, Shire and Sobi/Bioverativ and honoraria and/or consultation fees from Bayer, Octapharma and Shire/Takeda. The Van Creveldkliniek has received speaker’s fees from Bayer, Baxter/Shire, Sobi/Biogen, CSL Behring and Novo Nordisk; has performed consultancy for Bayer, Biogen, CSL Behring, Freeline, Novo Nordisk, Roche and Sobi; and has received research support from Bayer, Baxter/Shire, Novo Nordisk, Pfizer and Biogen for work done by K.F. Queen Mary University London has received research grants from Bayer, Octapharma and Takeda for work performed by D.P.H. He or his institution have received speaker or consultancy honoraria from Bayer, BioMarin, Biotest, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Sobi, Takeda and UniQure. M.E.M. has acted as paid consultant, adviser or speaker for Bayer Healthcare, BioMarin, Catalyst, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Spark Therapeutics and Takeda. D.S. is Chair of EAHAD Physiotherapy Committee, received research grant funding from the National Institute for Health Resarch (NIHR), Novo Nordisk, Pfizer, Roche, Sobi and acted as paid adviser or speaker for Bayer, Pfizer, Sobi, Roche and Takeda. V.B. is Chair of the International Prophylaxis Study Group (the IPSG), which is funded by grants from Bayer Healthcare, Bioverativ (now Sanofi/Genzyme), Novo Nordisk, Pfizer, Shire (now Takeda) and Spark Therapeutics to the Hospital for Sick Children Foundation, Toronto, Canada. He has received fees for participation in education events and advisory boards sponsored by Amgen, Bayer Healthcare, Novo Nordisk, Pfizer, Roche and Shire (now Takeda), and for participation in data safety monitoring boards for Octapharma and Takeda. He is recipient of investigator-initiated grants from Bayer Healthcare, Bioverativ (now Sanofi/Genzyme) and Shire (now Takeda). A.D.S. has served as consultant for Genentech, Roche, Novo Nordisk, BioMarin, Bioveritiv, Sanofi, ProMetic Bio Sciences, Kedrion, Sigilon and Takeda. She has received research funding from the above plus Agios, OPKO, Global Bio Therapeutics, Sangamo, Sigilon, Octapharma and Novartis.

Additional information

Peer review information

Nature Reviews Disease Primers thanks C. Hermans, K. Kavakli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

EAHAD F8 variants database: https://f8-db.eahad.org

EAHAD F9 variants database: https://f9-db.eahad.org

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Berntorp, E., Fischer, K., Hart, D.P. et al. Haemophilia. Nat Rev Dis Primers 7, 45 (2021). https://doi.org/10.1038/s41572-021-00278-x

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-021-00278-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research