(MED-WE-01.2) Describe the burden of non-severe hemophilia

Conventionally, the ISTH SSC classified haemophilia severity by residual plasma activity as severe ( <1%), moderate (1–5%), and mild (>5–40%), with these definitions generally correlating with bleeding symptoms and mortality.1 However, advances in therapies for severe haemophilia (SH) have reduced mortality, morbidity of polyarthropathy and treatment burden.
Non-severe haemophilia (NSH)—defined by the absence of severe disease—encompasses a complex clinical spectrum that demands a reassessment of disease and treatment burden. NSH includes not only men with moderate (MoH) and mild haemophilia (MiH) but also an increasing number of severe haemophilia patients on non-replacement therapies, as well as carrier women with low factor levels or symptomatic bleeding.2 Although they generally experience less polyarthropathy than SH cases, joint disease remains a significant concern affecting mobility and quality of life in both MoH and MiH, potentially secondary to recurrent or inadequately treated bleeds.3-5
The management of non-severe patients brings several new clinical challenges, in addition to the lack of recognition of the severity of joint disease. Clinical management is often complicated by delayed symptom recognition and suboptimal self-management; patients often seek care late due to limited disease understanding. Moreover, slow but progressive bleeding can culminate in large muscle haematomas, with noticeable symptoms arising only after considerable tissue inflammation and increased tissue pressure. Moreover, the ability to self-treat is restricted, posing significant logistical considerations in the event of requiring treatment. Treatment is also complicated by the development of inhibitors, which can arise during the lifetime due to the low treatment frequency.6
An inconsistent approach to prophylaxis and treatment further complicates the management.7 For instance, children with haemophilia A who have factor levels below 3% are now increasingly considered for primary prophylaxis to prevent joint damage. Similarly, haemophilia B patients with factor levels between 1% and 2% have long been managed with prophylaxis and have been included in multiple clinical trials. Although there have been increasing suggestions for the need for prophylaxis, current evidence has not yet translated into treatment guidelines.8,9
Currently, well‐established multidisciplinary care pathways exist for severe haemophilia, but there remains no consensus regarding optimal treatment thresholds, monitoring strategies, or patient education for NSH. These complexities indicate that defining NSH solely by the absence of severe haemophilia fails to capture the multifaceted needs of the patients, including women. Future research should establish evidence-based guidelines addressing bleeding risk, joint health, equity of care and self-management to optimise care for this diverse patient group.
References
1. White GC, 2nd, Rosendaal F, Aledort LM, et al. 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(3):560.
2. 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. Journal of thrombosis and haemostasis: JTH. 2021;19(8):1883-1887.
3. Zwagemaker AF, Kloosterman FR, Hemke R, et al. Joint status of patients with nonsevere hemophilia A. Journal of thrombosis and haemostasis: JTH. 2022;20(5):1126-1137.
4. Scott MJ, Xiang H, Hart DP, et al. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study. Haemophilia. 2019;25(2):205-212.
5. Wang M, Recht M, Iyer NN, Cooper DL, Soucie JM. Hemophilia without prophylaxis: Assessment of joint range of motion and factor activity. Res Pract Thromb Haemost. 2020;4(6):1035-1045.
6. Fischer K, Iorio A, Lassila R, et al. Inhibitor development in non-severe haemophilia across Europe. Thromb Haemost. 2015;114(4):670-675.
7. 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(1):33-44.
8. Thachil J, Connors JM, Mahlangu J, Sholzberg M. Reclassifying hemophilia to include the definition of outcomes and phenotype as new targets. Journal of thrombosis and haemostasis: JTH. 2023;21(7):1737-1740.
9. Weyand AC, Malec L, Pipe SW. Advancements in haemophilia A and health equity: is it time to redefine severity? The Lancet Haematology. 2024;11(2):e90-e92.