Download PDF
CC BY-NC-ND 4.0 · Semin Thromb Hemost
DOI: 10.1055/s-0044-1786358
Review Article

Nonsevere Hemophilia: The Need for a Renewed Focus and Improved Outcomes

Gerard Dolan
1   Centre for Haemostasis and Thrombosis, St Thomas' Comprehensive Care Centre, London, United Kingdom
,
Karin Fijnvandraat
2   Paediatric Haematology, Emma Children's Hospital, and UMC, University of Amsterdam, Amsterdam, The Netherlands
,
Peter J. Lenting
3   Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, Le Kremlin-Bicêtre, France
,
Cristina Catarino
4   Immunochemotherapy Department, Congenital Coagulopathies Comprehensive Care Centre, Santa Maria University Hospital, Lisbon University, Lisbon, Portugal
,
Michelle Lavin
5   Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
6   National Coagulation Centre, St. James' Hospital, Dublin, Ireland
,
on behalf of the Factor Think Tank › Author Affiliations Funding The Factor Think Tank is funded by Sobi. Medical writing and editorial support for this manuscript was funded by Sobi, who also funded support with manuscript submission.
› Further Information
   Permissions and Reprints

Abstract

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a “nonsevere” phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition.

Keywords

disease management - factor VIII - factor IX - hemophilia A - hemophilia B

Authors' Contributions

All the authors developed the initial concept for this manuscript. G.D. and M.L. drafted a version that all the other authors critically revised for intellectual content. All the authors reviewed and approved the final document.


* All the members of the Factor Think Tank group are listed at factorthinktank.com.




Publication History

Article published online:
11 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Lewandowska M, Nasr S, Shapiro AD. Therapeutic and technological advancements in haemophilia care: quantum leaps forward. Haemophilia 2022; 28 (Suppl. 04) 77-92
    Google Scholar
  • 2 Srivastava A, Santagostino E, Dougall A. et al. WFH Guidelines for the Management of Hemophilia, 3rd ed. Haemophilia 2020; 26 (Suppl. 06) 1-158
    Google Scholar
  • 3 d'Oiron R, O'Brien S, James AH. Women and girls with haemophilia: lessons learned. Haemophilia 2021; 27 (Suppl. 03) 75-81
    Google Scholar
  • 4 Castaman G, Peyvandi F, De Cristofaro R, Pollio B, Di Minno DMN. Mild and moderate hemophilia A: neglected conditions, still with unmet needs. J Clin Med 2023; 12 (04) 1368
    Google Scholar
  • 5 Boeriu E, Arghirescu TS, Serban M. et al. Challenges in the diagnosis and management of non-severe hemophilia. J Clin Med 2022; 11 (12) 3322
    Google Scholar
  • 6 Benson G, Auerswald G, Dolan G. et al. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management. Blood Transfus 2018; 16 (06) 535-544
    Google Scholar
  • 7 MacLean PE, Fijnvandraat K, Beijlevelt M, Peters M. The impact of unaware carriership on the clinical presentation of haemophilia. Haemophilia 2004; 10 (05) 560-564
    Google Scholar
  • 8 Peerlinck K, Jacquemin M. Mild haemophilia: a disease with many faces and many unexpected pitfalls. Haemophilia 2010; 16 (Suppl. 05) 100-106
    Google Scholar
  • 9 Mingot-Castellano ME. Clinical pattern of hemophilia and causes of variability. Blood Coagul Fibrinolysis 2019; 30 (1S Suppl 1) S4-S6
    Google Scholar
  • 10 Kloosterman FR, Zwagemaker AF, Bagot CN. et al. The bleeding phenotype in people with nonsevere hemophilia. Blood Adv 2022; 6 (14) 4256-4265
    Google Scholar
  • 11 Rodeghiero F, Tosetto A, Castaman G. How to estimate bleeding risk in mild bleeding disorders. J Thromb Haemost 2007; 5 (Suppl. 01) 157-166
    Google Scholar
  • 12 Tosetto A, Castaman G, Rodeghiero F. Bleeding scores in inherited bleeding disorders: clinical or research tools?. Haemophilia 2008; 14 (03) 415-422
    Google Scholar
  • 13 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC Joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    Google Scholar
  • 14 Borhany M, Fatima N, Abid M, Shamsi T, Othman M. Application of the ISTH bleeding score in hemophilia. Transfus Apheresis Sci 2018; 57 (04) 556-560
    Google Scholar
  • 15 Kloosterman FR, Zwagemaker AF, Bagot CN. et al. Assessing the bleeding phenotype in non-severe hemophilia by use of the ISTH Bleeding Assessment Tool (BAT). Res Pract Thromb Haemost 2020;4 (S01):Abstract PB0897
    Google Scholar
  • 16 Rejtő J, Kraemmer D, Grilz E. et al. Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status. Res Pract Thromb Haemost 2023; 7 (02) 100047
    Google Scholar
  • 17 James PD, Mahlangu J, Bidlingmaier C. et al; Global Emerging HEmostasis Experts Panel (GEHEP). Evaluation of the utility of the ISTH-BAT in haemophilia carriers: a multinational study. Haemophilia 2016; 22 (06) 912-918
    Google Scholar
  • 18 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 (03) 815-825
    Google Scholar
  • 19 Loomans JI, Eckhardt CL, Reitter-Pfoertner SE. et al. Mortality caused by intracranial bleeding in non-severe hemophilia A patients. J Thromb Haemost 2017; 15 (06) 1115-1122
    Google Scholar
  • 20 Zanon E, Pasca S, Demartis F. et al; REC Registry. Intracranial haemorrhage in haemophilia patients is still an open issue: the final results of the Italian EMO.REC Registry. J Clin Med 2022; 11 (07) 1969
    Google Scholar
  • 21 Knobe K, Berntorp E. Haemophilia and joint disease: pathophysiology, evaluation, and management. J Comorb 2011; 1: 51-59
    Google Scholar
  • 22 Collins PW, Obaji SG, Roberts H, Gorsani D, Rayment R. Clinical phenotype of severe and moderate haemophilia: Who should receive prophylaxis and what is the target trough level?. Haemophilia 2021; 27 (02) 192-198
    Google Scholar
  • 23 Chai-Adisaksopha C, Noone D, Curtis R. et al. Non-severe haemophilia: Is it benign? - Insights from the PROBE study. Haemophilia 2021; 27 (Suppl. 01) 17-24
    Google Scholar
  • 24 Witkop M, Wang M, Hernandez G, Recht M, Baumann K, Cooper DL. Impact of haemophilia on patients with mild-to-moderate disease: results from the P-FiQ and B-HERO-S studies. Haemophilia 2021; 27 (Suppl. 01) 8-16
    Google Scholar
  • 25 den Uijl I, Biesma D, Grobbee D, Fischer K. Outcome in moderate haemophilia. Blood Transfus 2014; 12 (Suppl 1) s330-s336
    Google Scholar
  • 26 Álvarez Román MT, de la Corte Rodríguez H, Bonanad Boix S, Mingot-Castellano ME, Fernández Mosteirín N. ARTIHA Spanish Study Group. The factor VIII treatment history of non-severe hemophilia A: COMMENT. Joint damage in adult patients with mild or moderate hemophilia A evaluated with the HEAD-US system. J Thromb Haemost 2021; 19 (10) 2638-2641
    Google Scholar
  • 27 Abdi A, Kloosterman FR, Eckhardt CL. et al; INSIGHT Study Group. The factor VIII treatment history of non-severe hemophilia A. J Thromb Haemost 2020; 18 (12) 3203-3210
    Google Scholar
  • 28 Zwagemaker AF, Kloosterman FR, Hemke R. et al. Joint status of patients with nonsevere hemophilia A. J Thromb Haemost 2022; 20 (05) 1126-1137
    Google Scholar
  • 29 Måseide RJ, Berntorp E, Astermark J. et al. Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study). Haemophilia 2024; 30 (01) 98-105
    Google Scholar
  • 30 De la Corte-Rodriguez H, Rodriguez-Merchan EC, Alvarez-Roman MT, Martin-Salces M, Rivas-Pollmar I, Jimenez-Yuste V. Arthropathy in people with mild haemophilia: exploring risk factors. Thromb Res 2022; 211: 19-26
    Google Scholar
  • 31 Fischer K, Poonnoose P, Dunn AL. et al; participants of the International Symposium on Outcome Measures in Hemophilic Arthropathy. Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective. Haemophilia 2017; 23 (01) 11-24
    Google Scholar
  • 32 Hassan S, Monahan RC, Mauser-Bunschoten EP. et al. Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018. J Thromb Haemost 2021; 19 (03) 645-653
    Google Scholar
  • 33 White II GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Factor VIII and Factor IX Subcommittee. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85 (03) 560
    Google Scholar
  • 34 Bowyer AE, Gosselin RC. Factor VIII and Factor IX activity measurements for hemophilia diagnosis and related treatments. Semin Thromb Hemost 2023; 49 (06) 609-620
    Google Scholar
  • 35 Makris M, Oldenburg J, Mauser-Bunschoten EP, Peerlinck K, Castaman G, Fijnvandraat K. Subcommittee on Factor VIII, Factor IX and Rare Bleeding Disorders. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (12) 2530-2533
    Google Scholar
  • 36 Peyvandi F, Oldenburg J, Friedman KD. A critical appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost 2016; 14 (02) 248-261
    Google Scholar
  • 37 Zwagemaker AF, Kloosterman FR, Gouw SC. et al; DYNAMO study group. Little discrepancy between one-stage and chromogenic factor VIII (FVIII)/IX assays in a large international cohort of persons with nonsevere hemophilia A and B. J Thromb Haemost 2023; 21 (04) 850-861
    Google Scholar
  • 38 Kitchen S, Bowyer A, Makris M. Both one-stage and chromogenic factor VIII assays are required for the diagnosis of mild hemophilia A. J Thromb Haemost 2023; 21 (04) 773-775
    Google Scholar
  • 39 Kihlberg K, Strandberg K, Rosén S, Ljung R, Astermark J. Discrepancies between the one-stage clotting assay and the chromogenic assay in haemophilia B. Haemophilia 2017; 23 (04) 620-627
    Google Scholar
  • 40 Baker P, Platton S, Gibson C. et al; British Society for Haematology, Haemostasis and Thrombosis Task Force. Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Br J Haematol 2020; 191 (03) 347-362
    Google Scholar
  • 41 Zwagemaker AF, Kloosterman FR, Coppens M. et al; DYNAMO Study Group. Desmopressin for bleeding in non-severe hemophilia A: suboptimal use in a real-world setting. Res Pract Thromb Haemost 2022; 6 (06) e12777
    Google Scholar
  • 42 Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232 (01) 25-32
    Google Scholar
  • 43 Hermans C, Mancuso ME, Nolan B, Pasi KJ. Recombinant factor VIII Fc for the treatment of haemophilia A. Eur J Haematol 2021; 106 (06) 745-761
    Google Scholar
  • 44 Pitance V, Désage S, Lienhart A, Meunier S, Chamouard V. Haemophilia A patients' medication adherence to prophylaxis with efmoroctocog alfa. Haemophilia 2021; 27 (03) e368-e375
    Google Scholar
  • 45 Klamroth R, Windyga J, Radulescu V. et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood 2021; 137 (13) 1818-1827
    Google Scholar
  • 46 Malec L, Matino D. Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review. Haemophilia 2023; 29 (06) 1419-1429
    Google Scholar
  • 47 Rayment R, Chalmers E, Forsyth K. et al; British Society for Haematology. Guidelines on the use of prophylactic factor replacement for children and adults with Haemophilia A and B. Br J Haematol 2020; 190 (05) 684-695
    Google Scholar
  • 48 Iorio A, Königs C, Reding MT. et al. Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: a review of the literature. Haemophilia 2023; 29 (01) 33-44
    Google Scholar
  • 49 Négrier C, Mahlangu J, Lehle M. et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. Lancet Haematol 2023; 10 (03) e168-e177
    Google Scholar
  • 50 Weyand AC, Malec L, Pipe SW. Advancements in haemophilia A and health equity: is it time to redefine severity?. Lancet Haematol 2024; 11 (02) e90-e92
    Google Scholar
  • 51 Genentech Inc. Hemlibra® Summary of Product Characteristics. 2024 . Accessed February 2024 at: https://www.ema.europa.eu/en/documents/product-information/hemlibra-epar-product-information_en.pdf
    Google Scholar
  • 52 Walsh C, Boggio L, Brown-Jones L. et al. Identified unmet needs and proposed solutions in mild-to-moderate haemophilia: A summary of opinions from a roundtable of haemophilia experts. Haemophilia 2021; 27 (Suppl. 01) 25-32
    Google Scholar
  • 53 van Moort I, Bukkems LH, Heijdra JM. et al; OPTI-CLOT Study Group. von Willebrand factor and factor VIII clearance in perioperative hemophilia A patients. Thromb Haemost 2020; 120 (07) 1056-1065
    Google Scholar
  • 54 Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18 (03) e173-e187
    Google Scholar
  • 55 DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007; 138 (03) 305-315
    Google Scholar
  • 56 Kloosterman F, Zwagemaker AF, Abdi A, Gouw S, Castaman G, Fijnvandraat K. Hemophilia management: huge impact of a tiny difference. Res Pract Thromb Haemost 2020; 4 (03) 377-385
    Google Scholar
  • 57 Eckhardt CL, van Velzen AS, Peters M. et al; INSIGHT Study Group. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 2013; 122 (11) 1954-1962
    Google Scholar
  • 58 Eckhardt CL, Loomans JI, van Velzen AS. et al; INSIGHT Study Group. Inhibitor development and mortality in non-severe hemophilia A. J Thromb Haemost 2015; 13 (07) 1217-1225
    Google Scholar
  • 59 van Velzen AS, Eckhardt CL, Peters M. et al. Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study. J Thromb Haemost 2017; 15 (07) 1422-1429
    Google Scholar
  • 60 van Velzen AS, Eckhardt CL, Streefkerk N. et al; INSIGHT study group. The incidence and treatment of bleeding episodes in non-severe haemophilia A patients with inhibitors. Thromb Haemost 2016; 115 (03) 543-550
    Google Scholar
  • 61 Lim MY, Cheng D, Recht M, Kempton CL, Key NS. Inhibitors and mortality in persons with nonsevere hemophilia A in the United States. Blood Adv 2020; 4 (19) 4739-4747
    Google Scholar
  • 62 Prezotti ANL, Frade-Guanaes JO, Yamaguti-Hayakawa GG, Ozelo MC. Immunogenicity of current and new therapies for hemophilia A. Pharmaceuticals (Basel) 2022; 15 (08) 911
    Google Scholar
  • 63 van Velzen AS, Eckhardt CL, Peters M. et al; INSIGHT consortium. Product type and the risk of inhibitor development in nonsevere haemophilia A patients: a case-control study. Br J Haematol 2020; 189 (06) 1182-1191
    Google Scholar
  • 64 van Velzen AS, Eckhardt CL, Hart DP. et al; INSIGHT study group. Inhibitors in nonsevere haemophilia A: outcome and eradication strategies. Thromb Haemost 2015; 114 (01) 46-55
    Google Scholar
  • 65 Khair K, Chalmers E, Flannery T. et al. Expert opinion on the UK standard of care for haemophilia patients with inhibitors: a modified Delphi consensus study. Ther Adv Hematol 2021; 12: 20 406207211007058
    Google Scholar
  • 66 Miller CH, Bean CJ. Genetic causes of haemophilia in women and girls. Haemophilia 2021; 27 (02) e164-e179
    Google Scholar
  • 67 van Galen KPM, d'Oiron R, James P. et al. A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH. J Thromb Haemost 2021; 19 (08) 1883-1887
    Google Scholar
  • 68 Garagiola I, Mortarino M, Siboni SM. et al. X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers. Eur J Hum Genet 2021; 29 (02) 241-249
    Google Scholar
  • 69 Puetz J, Cheng D. Descriptive analysis of bleeding symptoms in haemophilia carriers enrolled in the ATHNdataset. Haemophilia 2021; 27 (06) 1045-1050
    Google Scholar
  • 70 Rajpurkar M, Forsyth A, Manco-Johnson M. Current challenges for men and women with mild-to-moderate haemophilia. Haemophilia 2021; 27 (Suppl. 01) 5-7
    Google Scholar
  • 71 Staber J, Croteau SE, Davis J, Grabowski EF, Kouides P, Sidonio Jr RF. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia 2018; 24 (02) 180-185
    Google Scholar
  • 72 Weyand AC, Sidonio Jr RF, Sholzberg M. Health issues in women and girls affected by haemophilia with a focus on nomenclature, heavy menstrual bleeding, and musculoskeletal issues. Haemophilia 2022; 28 (Suppl. 04) 18-25
    Google Scholar
  • 73 Punt MC, Waning ML, Mauser-Bunschoten EP. et al. Maternal and neonatal bleeding complications in relation to peripartum management in hemophilia carriers: a systematic review. Blood Rev 2021; 49: 100826
    Google Scholar
  • 74 Streif W, Knöfler R. Perinatal Management of Haemophilia. Hamostaseologie 2020; 40 (02) 226-232
    Google Scholar
  • 75 van Galen K, Lavin M, Skouw-Rasmussen N. et al; European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD). European principles of care for women and girls with inherited bleeding disorders. Haemophilia 2021; 27 (05) 837-847
    Google Scholar
  • 76 European Commission Directorate-General for Research and Innovation Collaboration. Collaboration. A key to unlock the challenges of rare diseases research. Accessed February 2024 at: https://op.europa.eu/en/publication-detail/-/publication/6552d53b-abf4-11ec-83e1-01aa75ed71a1
    Google Scholar
  • 77 United Kingdom Government Department of Health & Social Care. Policy paper: England Rare Disease Action Plan. 2023 . Accessed February 2024 at: https://www.gov.uk/government/publications/england-rare-diseases-action-plan-2023/england-rare-diseases-action-plan-2023-main-report#section-2-addressing-the-priorities-of-the-uk-rare-diseases-framework-in-2023
    Google Scholar
  • 78 Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379 (9824) 1447-1456
    Google Scholar
  • 79 World Federation of Hemophilia. Report on the Annual Global Survey 2022. 2023 . Accessed February 2024 at: https://www1.wfh.org/publications/files/pdf-2399.pdf
    Google Scholar