Prophylaxis entails long-term continuous intravenous administration of concentrates of the deficient factor with a view to preventing spontaneous bleeds and the development of haemophilic arthropathy. Factor concentrates are administered once, twice or thrice a week .
Prophylactic treatment regimens include primary prophylaxis (regular infusion of the deficient factor for over 45 weeks/year, before the onset of joint damage) and secondary prophylaxis (similar to primary prophylaxis but in the presence of joint damage) .
The PEDNET group (1998–2006) analysed two parameters, age and time to onset of hemarthrosis, to categorize the different kinds of prophylaxis. They classified prophylaxis into primary prophylaxis A (regular and continuous treatment after the first joint bleed and before the second year of age); primary prophylaxis B (regular and continuous treatment before the second year of age, without prior hemarthrosis); secondary prophylaxis A (regular and continuous treatment after the second year of age and two or more hemarthroses); and secondary prophylaxis B (regular yet intermittent treatment following frequent bleeding events). Finally, tertiary prophylaxis was added, which is applicable to adults with significant intermittent joint pain (for periods shorter than 45 weeks/year).
Prophylaxis has widely been considered a gold standard in the treatment of patients with haemophilia. Indeed, although on-demand treatment has not been shown to stop the progression of arthropathy, only prophylaxis can contribute to preventing its appearance. Prophylaxis also prevents life-threatening bleeding events such as intracranial haemorrhages.
Initiation of prophylaxis at an early age and continuous uninterrupted factor administration in patients with haemophilia have been hailed as essential by organizations such as the WHO, the World Federation of Hemophilia (WFH), the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation of the United States and the Scientific Committee of the Royal Victoria Eugenia Foundation.
Despite its many advantages, implementation of prophylaxis is not widespread given the need for central venous access; the high patient/year cost (150 000 euros, which is three times higher than on-demand treatment); the uncertainly as to when and how to begin and how long to administer the therapy; and the problems of adherence.
Prophylactic therapeutic regimens
Administration of treatment 52 weeks a year is aimed at achieving trough factor levels above 1%, changing the patient's bleeding phenotype from severe to moderate. Factors to be considered include level of physical activity, development of target joints, pharmacokinetic profile, overall haemostatic effect and adherence to treatment. Prophylaxis has been shown to result in a reduction in the number of bleeds in excess of 15%. Among other pharmacokinetic parameters, it is essential to evaluate the area under the curve (AUC), the clearance rate (C1) and the half-life (T ½). In addition, monitoring should include a thromboelastogram (TEG) and a thrombin generation test (TGT).
The most widely used prophylaxis regimens include the Swedish (Malmö), the Dutch and the Canadian protocols. The Swedish model involves administration of high doses of the deficient factor (25–40 IU/kg) three days a week starting at 1–2 years of age, or before the first joint bleed. Under this protocol, prophylaxis is administered throughout the patient's lifetime. The Dutch protocol employs intermediate doses (15–25 IU/kg) two or three times a week starting after the appearance of at least one hemarthrosis. Finally, the Canadian protocol consists in the administration of incremental doses (50 IU/kg weekly at first, then increasing the dose to 30 IU/kg twice a week and subsequently to 25 IU/kg every other day depending on the patient's response). All three protocols require careful monitoring (every 3 months) as well as following up the reduction in inhibitor titres (65%).
In the 1960s and 1970s, small retrospective noncontrolled series were published in Sweden, the Netherlands, Canada and the USA with short follow-up periods and nonuniform doses. These studies demonstrated that prophylaxis was effective for the prevention of bleeding. Nilsson  observed that 1–2 year-old children who received prophylaxis two or three times a week showed a reduction in hemarthrosis as well as radiographic articular improvement as compared with patients treated on demand. Aledort et al. studied a group of patients treated for over 45 weeks a year and followed them up for 6 years. They observed a greater decrease in the number of hemarthroses and a greater orthopaedic and radiographic improvement than in patients treated on demand. Nonetheless, they found no improvement of the clinical and radiographic signs observed before the beginning of prophylaxis.
Recommendations and scientific evidence
Different international groups have hailed prophylaxis as the most effective treatment in patients with haemophilia. Between 1994 and 1996, the WHO, the World Federation of Hemophilia, the MASAC and Canadian and Dutch medical organizations recommended prophylaxis in patients with severe haemophilia [5–7]. In 2001, the MASAC extended their recommendation to patients with severe haemophilia regardless of their age . Ninety-one percent of the European hospitals that lead the way in the treatment of haemophilia recommend continuous long-term prophylactic treatment in patients started early on prophylaxis .
In the Joint Outcome Study , Manco-Johnson noted the superiority of prophylaxis over on-demand treatment in the prevention of joint damage, which was seen to reduce the frequency of bleeds into joints and other structures and to avoid the development of haemophilic arthropathy. The ESPRIT study , which compared the frequency of joint bleeds in patients on prophylaxis with those observed in individuals receiving on-demand treatment, as a function of the number of joints, showed that patients on prophylaxis experienced fewer bleeding episodes (0.2 vs. 0.52 monthly events/patient). This confirms the efficacy of prophylaxis in preventing bleeding and arthropathy in children with (particularly early-onset) haemophilia.
In a paediatric population with severe haemophilia, with a three times weekly prophylactic regimen for patients with haemophilia A and a twice-weekly prophylactic regimen for those with haemophilia B, Panicker observed a significant reduction in severe bleeding episodes (15.4/year vs. 1.86/year), with symptomatic target joint improvement and fewer hospitalizations and visits to the emergency room. The cost was three times higher for prophylactic treatment than for on-demand treatment.
Prophylaxis in adults
Although some retrospective trials confirm the benefits of prophylaxis, others point to a lack of conclusive data to support switching adult patients with established haemophilic arthropathy who always received on-demand treatment to prophylactic treatment. Several prospective trials support the implementation of prophylaxis in severe haemophilia A given that the half-life of FVIII is longer in adults and there is a weaker association between trough levels and bleeding.
Collins et al. analysed the efficacy of prophylaxis in a 13-month long multicentre prospective open-label study of twenty 30 to 45-year-old patients with severe haemophilia A. Patients were treated on demand for 6 months and then prophylactically for another 7 months (with a dose of 20–40 IU/kg three times a week), preceded by a 1-month washout period. The following parameters were measured: postinfusion FVIII levels at 48 and 72 h; bleeding rate and joint function; quality of life and socioeconomic variables; and negative effects of the therapy and inhibitor titres.
Valentino et al. compared the efficacy of two prophylactic regimens with respect to each other and to on-demand treatment. He observed similar bleeding rates between both groups on prophylaxis, without significant factor consumption differences between them and without development of inhibitors in any of the patients included in either group. Thirty-three percent of patients on prophylaxis experienced no bleeding, whereas 100% of those treated on demand suffered haemorrhages.
Prophylaxis in elderly patients
Life expectancy in patients with haemophilia is currently similar to that of the general population. The goal is to treat these patients as if they did not have haemophilia, administering longer or shorter prophylaxis regimens as appropriate. Factors such as age-related haemorrhagic morbidity; antithrombotic prophylaxis; development of neoplasms, hepatopathy and hepatocarcinoma; and evolution of HIV must be monitored. Conditions such as heart disease (atrial fibrillation, ischaemic heart disease and so on), osteoarthritis, osteoporosis and chronic pain (present in 50% of patients with haemophilic arthropathy) must be carefully considered. At the same time, the potential effects of prophylaxis on the patients’ sex lives, renal status, prostate involvement and cataract must be analysed before indicating prophylactic treatment in this group.
Prophylaxis in patients with inhibitors
Leissinger et al. noted the efficacy of prophylaxis with FEIBA in 26 patients with haemophilia and inhibitors (14 treated on demand and 12 prophylactically) over a period of 6 months. Prophylaxis was associated with a 62% reduction in bleeding episodes, a 61% reduction in hemarthroses and a 72% reduction in bleeding into target joints).
For their part, Young et al. recruited 74 patients (54 children, seven adolescents and 13 adults), of whom 36 were administered prophylactic treatment with factor rVIIa. Following the study, a 52% reduction in bleeding events was observed in all patients (except for the youngest ones). In the paediatric group, the reduction rate was 57%. The high efficacy of prophylactic treatment in patients with haemophilia and inhibitors has been widely reported in the literature in the past few years .
Conflicts of interest
There are no conflicts of interest.
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