M. Richards

Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Summary.u2002 Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6u2003months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty‐eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1u2003month nine of 35 (26%), 1–6u2003months 13 of 51 (25%), 6–12u2003months 27 of 130 (21%), 12–18u2003months 13 of 66 (20%) and >18u2003months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (Pu2003=u20030.018), no significant difference was observed in children treated at different time points during the first year of life (Pu2003=u20030.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma‐derived FVIII (Pu2003= 0.006) and in those with a major molecular defect (Pu2003=u20030.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.

A survey of adherence to haemophilia therapy in six European countries: results and recommendations

Summary.u2002 Very few studies have addressed the question of adherence of haemophiliacs to their treatment. The aim of our study was to compare their levels of adherence to therapy and also to provide recommendations. Professionals of an international research company performed individual interviews with 30 patients in each of six European countries (France, Germany, Italy, Spain, Sweden and UK) resulting in a total of 180 patients. Twenty‐eight interviews with haemophilia physicians and specialist nurses were also undertaken. Overall adherence to treatment was high (80–87% in each country). There was a positive correlation between greater adherence and younger age, prophylactic treatment, time spent with a haemophilia treatment centre (HTC) and the quality of the relationship with the haematologist and nurse. The four leading reasons for not using the prescribed amount of clotting factor or skipping the administration interval were reduction, fluctuation or disappearance of symptoms, forgetfulness, lack of time for treatment and convenience. These reasons differed according to the country and the age of the patient. The main suggestions made by patients to improve adherence related to HTC, environment and factor concentrates. Patients considered also that internet and electronic patient diaries were likely to improve adherence. In this selected group of European haemophilia patients, adherence to treatment appears higher than for most patients with other chronic diseases. However, it remains important to be aware of the possibility of non‐adherence given the serious implications, particularly when considering a differently selected group of patients.

A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A

Consensus‐based guidelines supported by the literature are presented on the role of prophylactic administration of factor VIII concentrate in children and adults with severe haemophilia A. The timing of initiation of prophylaxis, the choice of prophylactic regimen, monitoring, management of breakthrough bleeding and education of the patient and family are discussed.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Summary.u2002 Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14u2003days; for liver biopsy, 70–100%, 1–7u2003days; tonsillectomy: 90–100%, 5–11u2003days; indwelling venous access device insertion: 100%, 3–10u2003days; circumcision: 50–60%, 2–4u2003days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better‐designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.

Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data

Summary.u2002 A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16–24u2003years and adults aged over 50u2003years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16–20u2003years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50u2003years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18–22u2003years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis.

Guideline on the management of haemophilia in the fetus and neonate

Evidence‐based guidelines are presented for the management of haemophilia in the fetus and neonate. This includes information regarding the management of pregnancy and delivery as well as aspects of management during the early neonatal period. Specific issues regarding the mode of delivery and the risk of intra‐cranial and extra‐cranial haemorrhage are discussed.

Treatment related factors and inhibitor development in children with severe haemophilia A

Summary.u2002 With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982‐2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non‐caucasian ethnicity were each responsible for approximately 5‐fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta‐cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment‐related factors as important risks for inhibitor development in Haemophilia A.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations

Summary.u2002 Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra‐articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti‐inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB).

Management of neonates with inherited bleeding disorders – a survey of current UK practice

E. A. CHALMERS,* M. D. WILLIAMS, M. RICHARDS, S. A. BROWN,§ R. LIESNER,– A. THOMAS,** V. VIDLER, K. J. PASI, and F. G. H. HILL, ON BEHALF OF THE PAEDIATRIC WORKING PARTY OF UKHCDO *Royal Hospital for Sick Children, Glasgow, Birmingham Children’s Hospital, Birmingham, St. James’s University Hospital, Leeds, §Royal Free Hospital, London, –Great Ormond Street Hospital, London, **Royal Hospital for Sick Children, Edinburgh, Sheffield Children’s Hospital, Sheffield, Royal London Hospital, London

Outcome measures in European patients with haemophilia: Survey of implementation in routine clinical practice, perception of relevance and recommendations by European treaters in the EHTSB.

This study was conducted to evaluate the current implementation of outcome measures in routine clinical haemophilia practice and to explore and appreciate the perception of the relevance of such measures by treaters.