Intracranial haemorrhage in haemophilia A and B

In countries with a good standard of health care, intracranial haemorrhage (ICH) during the neonatal period affects 3·5–4·0% of all haemophilia boys, which is considerably (40–80 times) higher than expected in the normal population. ICHs are also frequent after the neonatal period, affecting 3–10% of the haemophilia population who are mainly treated on demand. The risk is higher in inhibitor patients. Spontaneous haemorrhage is reported more frequently than trauma-induced haemorrhage in most studies. The prevalence of ICH in patients treated with a prophylactic regimen is not known. Although more frequent in younger patients, a substantial proportion of ICH occur in adults, suggesting that general risk factors because of age, such as hypertension, are increasingly important as the haemophiliac gets older. Some studies have reported a substantial proportion of ICH affecting patients with milder forms of haemophilia. The risk of ICH has to be considered when discussing treatment strategies for haemophilia patients.     

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.

In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.     

The current status of prophylactic replacement therapy in children and adults with haemophilia

Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on‐demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer‐acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels.     

A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P < 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P < 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25–40 IU kg⁻¹ of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg⁻¹ of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full-dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long-term factor concentrate needs for persons with haemophilia living in North America.     

Paediatric care of the child with haemophilia

The paediatric care of children with haemophilia in developed countries should focus on the health of the child, not on the disorder. Gene therapy offers the hope of an ultimate 'cure' for the disorder, but until this is a viable proposition, patients should be given more control over their treatment, and the focus should be on 'self-monitored and self-adjusted' prophylaxis. New instruments for measuring joint function and radiographic changes, and quality of life are valuable tools in improving the treatment of paediatric care for children with haemophilia.     

The risk associated with indwelling catheters in children with haemophilia

Infections are the most frequent complications associated with the use of central venous lines (CVLs) in children with haemophilia. Several retrospective studies that include data from a substantial number of patients have reported approximately 0.2-0.3 infections per 1000 catheter-days (mainly Port-A-Cath). Some studies have shown a much higher frequency of infections, 1-2/1000 catheter-days. The most plausible explanations, for the difference seen in frequency of infections with Port-A-Caths, are probably related to the protocol used for the device care and the quality of education and the compliance of the users, whether these are parents or health-care professionals. The figures are low for clinically apparent thrombosis in the larger series on record, but routine venograms were not performed in most of these series. In studies, where this has been performed, a high frequency of abnormalities (>50%) on venograms have been seen in some series but not in others. Despite obvious potential risks with CVLs, they are useful in many cases and facilitate the treatment of a serious disorder. With careful guidelines and surveillance protocols, the risk of complications should be reduced in the future.     

MRI scores of ankle joints in children with haemophilia – comparison with clinical data

Fifty-six ankle joints in 38 haemophilic boys were investigated by magnetic resonance imaging (MRI) and the findings were classified according to both the Denver- and the European scoring schemes. The different MRI scores were compared with each other and with clinical data on number of joint bleeds and the orthopaedic joint score. MRI changes that were more advanced than a small effusion were found in 33 (59%) of the ankles and osteochondral changes were observed in 20 (36%). The total number of bleeds in individual ankles ranged from 0 to 80 (mean: 11). The orthopaedic joint score was 0 for 49 ankles and ranged from one to four for seven ankles. There was a significant and strong correlation between the assessment results obtained with the two MRI scoring methods (correlation coefficients ranged from 0.80 to 0.95, P < 0.001), and both types of MRI scores were weakly but significantly correlated with the clinical data on the number of joint bleeds and the orthopaedic joint score (correlation coefficients: 0.32-0.39, P < 0.01 or P < 0.05). MRI is useful for evaluating early joint changes in patients with haemophilia. The European scoring method differentiates the arthropathic changes further than the Denver scale does, but the two different scoring methods have similar correlation to the number of joint bleeds and the orthopaedic joint score.     

DDAVP (desmopressin; 1-deamino-cys-8-D-arginine-vasopressin) treatment in children with haemophilia B

We tested the response to desmopressin (1-deamino-cys-8-D-arginine-vasopressin; DDAVP) in four patients with haemophilia B [factor IX (F IX) at diagnosis 1.4-5%]. The activated partial thromboplastin time (aPTT) was significantly shortened in all patients. Although there was an up to 1.4-fold increase in F IX levels in three patients, maximal F IX activity remained below 10%. Much more prominent were the increases in F VIII (three- to fourfold), in von Willebrand factor antigen (VWF:Ag; 2.5-fold) and particularly in VWF collagen-binding activity (VWF:CBA; fivefold). These changes were reflected by the prophylactic efficacy of DDAVP for dental surgery. After pretesting, DDAVP could be a useful drug for reducing the need for plasma products for prevention of minor surgical bleeding in patients with mild to moderate haemophilia B.     

Aspects of haemophilia prophylaxis in Sweden

Summary.  Prophylactic treatment of haemophilia has been gaining acceptance as the optimal therapeutic option in an increasing number of haemophilia centres in the developed world in recent years. This paper focus on three aspects of prophylactic therapy: when to start treatment, venous access and the dose/dose interval. Evidence is in favour of prophylactic treatment to be started at an early age using either a peripheral vein with 1–2 injections per week and a successive increase in the frequency depending on the child and the veins, or, using a Port-A-Cath which allows a better prophylactic coverage by infusions preferably every second day in haemophilia A and every third day in haemophilia B.     

Prophylactic treatment in Sweden — overtreatment or optimal model?

Summary. At the haemophilia centre in Malmö, Sweden, regular prophylactic treatment is begun at 1–1½ years of age, before the onset of joint bleeds. The dose and dose interval are optimised by means of pharmacokinetic studies to determine the individual patient's FVIII or IX metabolism, the goal of maintaining a level <1% of normal being taken as a guideline which experience has shown to yield satisfactory control of bleeding diathesis. An optimal model for prophylactic treatment needs to be applicable to haemophiliacs and acceptable to health authorities in a majority of the countries in the world. To fulfill these criteria, the Swedish model, which has been shown to yield most satisfactory outcome, can hopefully be further refined in the future. Were continuous infusion, using a recombinate concentrate with a prolonged half-life, technically feasible and socially acceptable to the child, we would probably have attained the optimal model of prophylactic treatment.     

The impact of prenatal diagnosis on the incidence of haemophilia in Sweden

Summary A demographic survey was made of all children (n= 137) born with severe or moderate haemophilia in Sweden during the period 1970-92. Bn addition, all prenatal diagnoses (n= 86) performing during the period were evaluated. The annual incidence of severe and moderate haemophilia, having remained constant for decades, increased from 0.78/10,000 males in the 1970s to 1.34 in the 1980s, levelling off at 1.31 in the 1990s. Although prenatal diagnosis did not affect the incidence of haemophilia in the 1970s and 1980s, it did so in the 1990s, because the incidence would have been 40% higher (1.83) had not prental diagnosis been available and 16 affected fetuses been aborted. The average proportion of sporadic cases, 62%, remained almost unchanged during the study period, suggesting mutation rates to be constant. There were fewere children in families with known haemophilia than in sporadic families, but no evidence was found to suggest that the frequency of female offspring (i.e. potential carriers) born in haemophilia families had increased since the option of prenatal diagnosis was introduced.     

How to manage invasive procedures in children with haemophilia

Invasive procedures can be performed safely in children with haemophilia due to the availability of factor VIII/IX for patients without inhibitors. Most guidelines are based on the experiences in adults, but still there is no established consensus on the optimal factor levels or duration of replacement therapy for adults undergoing surgery. Few publications have focused on surgery in children with haemophilia. Children who have developed inhibitors to factor VIII/IX have to be treated with bypassing agents and constitute a group at higher risk for bleeding complications during surgery. The aim of this review is to summarize the experiences and opinions in the literature on replacement treatment of children with haemophilia, with and without inhibitors, during and after surgery, with a focus on the most prevalent clinical situations.     

Central venous lines in haemophilia

Summary.  Infections and technical problems are the most frequent complications when using implantable central venous access devices in patients with haemophilia. There are two major experiences reported concerning infections in noninhibitor patients: one is approximately 0.2 infections per 1000 days and the other approximately 1.0 (0.7–1.6) per 1000 days. Infections are more frequent in inhibitor patients and approximately one infection per 6–12 months of use can be expected. The figures are low for clinically apparent thrombosis in the larger series on record, but routine venograms were not carried out in most of these series. In studies where this has been done, a high frequency of abnormalities on venograms has been seen in some but not in others. The final decision to use a central line has to take into account the medical goal, the patient's bleeding tendency, the social situation and the expected risk of complications at the particular haemophilia centre. Some of the complications may be reduced by adequate aseptic measures both during implantation and in subsequent use, and by clear basic routines for surveillance of the systems and repeated education of the users.     

Treatment of children with haemophilia in Europe: a survey of 20 centres in 16 countries.

A survey was made of the current status of treatment of haemophilic boys at 20 centres in 16 European countries and includes approximately 1500 of the estimated 6500 haemophiliacs in the participating countries. Many mild haemophiliacs are not seen, or seen infrequently, at haemophilia centres and this requires study. Nine of 18 centres provide continuous prophylaxis to 80-100% of their patients, five centres provide it to 55-80% and the remaining four centres to 15-40% of the boys. The median dose given was 6240 U kg-1 year-1 (range 3120-7800). Four centres administered only recombinant concentrates to children with severe haemophilia A, while seven centres administered recombinant concentrates to 75-90% and the remaining centres to less than 50% of the boys (two centres < 10%). When asked for the choice of concentrate for a newly diagnosed boy with severe haemophilia A, all but one centre preferred recombinant concentrate. Most boys below 6 years received concentrates via a peripheral vein but three centres preferred a central venous line for 80-100% of the boys. Thirteen of 18 centres applied home treatment to 84-100% of the boys and the remaining five centres to 57-77% of the boys.     

The use of prophylaxis in 2663 children and adults with haemophilia: results of the 2006 Canadian national haemophilia prophylaxis survey

Summary. Prophylaxis is standard of care for boys with severe haemophilia A. Indications for prophylaxis in adulthood, non‐severe haemophilia A, haemophilia B and haemophilia with inhibitors are less well defined. This survey, conducted in 2006, aimed to describe prophylaxis use in patients of all ages and severities with haemophilia A or haemophilia B in Canada. Data on 2663 individuals (2161 haemophilia A; 502 haemophilia B), including 78 inhibitor‐positive patients, were returned by 22/25 Canadian haemophilia treatment centres. This represented 98% of the Canadian haemophilia population. Frequency of prophylaxis use, defined as infusion of factor VIII/IX concentrate at least once weekly for ≥45 weeks of the year, was highest in individuals with severe haemophilia A (69%). It was lower in individuals with severe haemophilia B (32%), moderate haemophilia A (18%) or B (5%) and mild haemophilia A (1%) or B (1%). Among individuals with severe haemophilia A, the frequency of prophylaxis use was 84% in children (≤18 years) and 55% in adults (>18 years). Thirteen per cent of inhibitor‐positive individuals were receiving prophylaxis with bypassing agents. Comparison with data obtained from a 2002 Canadian survey showed a greater use of prophylaxis in children ≤5 years of age with severe haemophilia A (73% vs. 49%). Prophylaxis is no longer confined to children with severe haemophilia A, but is used in a significant proportion of adults with severe haemophilia A and individuals with severe haemophilia B or moderate haemophilia A. Prophylaxis is being started earlier in boys with severe haemophilia A.     

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

Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months 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: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). 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 (P = 0.006) and in those with a major molecular defect (P = 0.009). 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.