REVIEWProphylactic therapy in haemophilia
Section snippets
Introduction and definitions
Haemophilia A and B are hereditary, X-chromosomal recessive disorders caused by deficiency or absence of coagulation factors VIII (FVIII) or IX (FIX) in the blood. Depending on the concentration of FVIII or FIX coagulant activity in blood, the disorders may be classified as severe (<1% of normal activity), moderate (1–4%) or mild (5–25%). Haemophilic arthropathy due to repeated joint bleeds is the major cause of morbidity in individuals with haemophilia. In patients with the severe form of the
Experience and evidence for prophylactic treatment
Prophylaxis was pioneered for haemophilia A in the late 1950s and in haemophilia B in the early 70s in Sweden by Nilsson and colleagues.[7], [8], [9] At the time, factor VIII (FVIII) was not always available in sufficient amounts and the doses given were small compared with today’s norms. Moreover, many patients who received prophylaxis had already developed arthropathy prior to prophylaxis initiation. Despite these limitations, Nilsson et al.7 reported the most comprehensive experience of
Prophylaxis vs. on-demand treatment
The studies during the first decades of prophylactic treatment were cohort studies followed longitudinally for many years. These long-term experiences of prophylactic treatment from Sweden and The Netherlands did not compare prophylaxis with on-demand treatment. A few larger studies have had the aim to compare prophylactic regimens with on-demand studies. In 1994, Aledort et al. published results of a 6-year uncontrolled, longitudinal study of various dosage regimens in patients with severe
Different models for prophylactic treatment
The focus of discussion has switched from prophylactic treatment vs. on demand treatment to the optimal mode of the prophylactic regimen. However, the optimal mode depends on the aim of the prophylactic treatment (Fig. 1). The optimal mode differs if the objective is to keep an acceptable joint function for a sedentary daily life or the objective is to achieve nearly normal hemostasis that allows an active leisure life including sport activities. Opinions vary widely between countries and
Prophylaxis and life-threatening bleeds
The outcome of prophylactic treatment has usually been focused on joint outcome. The early experiences with prophylaxis showed that the large improvement of joint function came when patients were given FVIII or FIX on a regular basis, despite that at the time it was given at long intervals.7 Further refinement can then be achieved by more frequent dosing and higher doses. When discussing the optimal prophylactic regimen one has to include an estimation of the risk of other serious or
How to measure the outcome of prophylactic treatment?
Prophylactic treatment of haemophilia is expensive and it is important to optimise it in the individual patient using different outcome measurers. Evaluation of the number of total and joint haemorrhages is probably the easiest measure but is dependent on reliable co-operation of the patient or parents. As commented above, subclinical joint bleeds may cause significant osteochondral changes on MRI and there is an obvious need of objective outcome measurers.
The most widely used methods for
Prophylaxis and inhibitors
Another aspect of early treatment being currently discussed, is whether the mode of administration, regular prophylactic treatment or on demand has an impact on inhibitor development. In 2005, Morado66 analysed the inhibitor incidence in 50 children with hemophilia and its relationship with mutations, type of clotting factor used and treatment modality. Thirty-eight out of 50 were treated with rFVIII and the remaining 12 with pdFVIII. Twenty children had mutations associated with high risk for
Stopping or starting prophylaxis in adults?
The WHO and WFH have recommended that prophylactic treatment should be life-long. However, opinions vary also on this topic as can illustrated by a survey of the treatment regimens at 21 European centres treating 5000 patients.73 The survey concluded that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, but that aggregate outcome data suggest a significant proportion of patients in the 18–22 years age
Prophylaxis and economy
The cost of concentrates usually account for more than 90% of the costs of hemophilia treatment. Since prophylactic treatment will consume more concentrate than on demand it will be more expensive not at least in short time follow-up. However, comparison of economics between the treatment modalities is very difficult since it has to be based on long(life)-time follow-up and include parameters such as QoL. Attempts have been made to assess the economics of prophylaxis in Germany and Europe[80],
Conflicts of interest
The author has obtained research grants or fees for consultancy/presentations from Bayer, Baxter, NovoNordisk and Octapharma.
Acknowledgement
The author is supported by grants (ALF) from Lund University and Region of Skåne, Sweden.
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Cited by (51)
Long-term impact of primary prophylaxis on joint status in patients with severe hemophilia A
2023, Research and Practice in Thrombosis and HaemostasisRadiosynovectomy in haemophilia
2019, Blood ReviewsCitation Excerpt :Haemophilic arthropathy takes place due to repeated haemorrhages into articulations leading to swelling, destruction of cartilage and bone, and development of osteoarthritis [1]. Although prophylactic replacement therapy helps in precluding arthropathy, it is not at all times appropriate (due to patient's lack of adherence) or affordable [2–8]. Early primary prophylaxis is the only approach for precluding arthropathy in haemophilia patients without inhibitors, admitting that it is not invariably totally effective in eluding joint complications [2–5].
Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: A randomized first human dose trial
2015, Journal of Thrombosis and HaemostasisExpression and characterization of a novel human recombinant factor IX molecule with enhanced in vitro and in vivo clotting activity
2015, Thrombosis ResearchCitation Excerpt :Patients with hemophilia B are commonly treated with protein replacement therapy, using recombinant or plasma derived-FIX concentrates [1]. Prophylactic therapy beginning at an early age should be considered the evidence-based treatment of choice for children with severe hemophilia, enabling normal physical, psychologic, and social development [2,3]. Prophylaxis protocols are, however, demanding on peripheral veins and very expensive [4].
Bicycle ergometer versus treadmill on balance and gait parameters in children with hemophilia
2015, Egyptian Journal of Medical Human GeneticsCitation Excerpt :The incidence of hemophilia in Egypt is 1:10,000 live births [2]. Depending on the concentration of factor VIII or IX coagulant activity in blood, the disorders may be classified as severe (<1% of normal activity), moderate (1–4%) or mild (5–25%) [3]. Patients may bleed for a long time after an injury.
Use of clinical practice guidelines on long-term prophylaxis in severe hemophilia in France: A retrospective audit
2013, Journal of PediatricsCitation Excerpt :In Malmö, it was shown that the prevention of arthropathy correlated with the intensity and earliness of treatment (full-dose regimen).7 These authors defined as primary prophylaxis a long-term continuous treatment started before the age of 2 years and before any clinically evident joint bleeding.8,9 This prophylaxis regimen usually required 20-40 IU/kg factor VIII, for example, several times per week.10,11