M.-C. Poon

Home management of haemophilia.

Summary.  The demonstrated benefits of home care for haemophilia include improved quality of life, less pain and disability, fewer hospitalizations, and less time lost from work or school. Although reduced mortality has not been demonstrated, the substantial increase in longevity since the early 1980s correlates with the introduction of home treatment and prophylaxis programmes. These programmes must be designed and monitored by haemophilia treatment centres (HTC), which are staffed with professionals with broad and complementary expertise in the disease and its complications. In return, patients and their families must be willing to accept the reciprocal responsibilities that come from administering blood products or their recombinant equivalents at home. Patients with inhibitors to factors VIII or IX pose special challenges, but these complications do not obviate participation in home care programmes. Home care was an essential prerequisite to the introduction of effective prophylactic factor replacement therapy. Prophylaxis offers significant improvements in quality of life, but requires a substantial commitment. The use of implantable venous access devices can eliminate some of the difficulty and discomfort of peripheral venous access in small children, but brings additional risks. The future holds the promise of factor concentrates for home use that have longer half‐lives, or can be administered by alternate routes. Knowledge of patient genotypes may allow treatments tailored to avoid complications such as inhibitor development. Gene therapy trials, which are currently ongoing, will ultimately lead to gene‐based treatments as a complement to traditional protein‐based therapy.

Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

Summary.  When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti‐CD20 monoclonal antibody, which has shown promise in the treatment of B‐cell‐mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m−2 of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half‐life). Patients are concurrently placed on recombinant FVIII (100 U kg−1 day−1). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non‐responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.

Low dose secondary prophylaxis reduces joint bleeding in severe and moderate haemophilic children: a pilot study in China

Summary.  The most common bleeding in haemophilic patients is in joints, and joint disability is the most common complications in these patients receiving inadequate treatment. Limited by economy and inadequate treatment, developing countries face huge challenge to reduce disability and improve quality of life (QoL) of haemophilic children. The aim of this study was to investigate the effect of low dose secondary prophylaxis in China. Children with moderate and severe haemophilia from the Beijing Children Hospital, Beijing, China, and with established joint disease, were followed for a 12‐week observation period followed by a 12‐week low dose secondary prophylaxis‐study period (for haemophilia A, factor VIII concentrate 10 IU kg−1 twice weekly; for haemophilia B, factor IX concentrate 20 IU kg−1 weekly). The reduction of joint bleeding, improvement of joint function and QoL during prophylaxis were analysed. In total 34 children (median age 7.8 years) were analyzable. The number of joint bleeds decreased from a total of 337 (individual range 3–24, mean 9.9) during the observation period to 57 (range 0–6, mean 1.7) during the study period with an overall of reduction 83%. Joint function improved in 66.7% of disease joints, with 23.2% of which were considered good to moderate. School attendance improved in all subjects, sports participation and daily activity improved moderately. Low dose secondary prophylaxis significantly reduces frequency of joint bleeding; with moderate improvement in joint function, school attendance, sport participation and daily activities. Low dose secondary prophylaxis is therefore, cost‐effective as applied to developing countries such as China, although there are still unresolved issues.

Canadian multi-institutional survey of immune tolerance therapy (ITT) – experience with the use of recombinant factor VIII for ITT

Summary.  Immune tolerance therapy (ITT) is currently the most effective approach to eradicate inhibitors in patients with haemophilia A. Limited evidence suggests that the use of plasma‐derived factor VIII (pdFVIII) for ITT may be associated with a greater success rate than recombinant factor VIII (rFVIII). Analysis of ITT cases in Canada offered the opportunity to examine the success rate of using rFVIII for ITT, as rFVIII has been used almost exclusively for Canadian haemophilia A patients since 1994. The results of 32 patients from five haemophilia treatment centres were collated. Three patients continue on ITT. Of the 29 patients who completed ITT, 25 (86.2%) used rFVIII exclusively, and four used pdFVIII exclusively or pdFVIII followed by rFVIII. The initial FVIII dosing frequency was once per day in 72.4% of patients at an average dose of 98 U kg−1 (range 50–200). Eight patients (25%) received one or more adjuvant therapies. The median duration of ITT was 1.1 years (mean 1.5 years, range 9 days to 6 years). The overall success rate of the 29 patients who completed ITT was 79.3% (23/29), which is comparable with the results of immune tolerance registries. Our results suggest that the success rate of ITT using rFVIII is not inferior to the results with pdFVIII.

Short‐term low‐dose secondary prophylaxis for severe/moderate haemophilia A children is beneficial to reduce bleed and improve daily activity, but there are obstacle in its execution: a multi‐centre pilot study in China

We recently showed in a single centre trial that low‐dose secondary prophylaxis in severe/moderate haemophilia patients with arthropathy is feasible and beneficial. However, this regimen has not been validated in a multicentre setting and what obstacles are there to prophylaxis remain unclear. (i) Benefit study: to confirm the benefits of similar prophylaxis protocol in severe/moderate haemophilia A (HA) in a multicentre setting in China. (ii) Follow‐up obstacle study: to investigate obstacles in compliance to prophylaxis treatment. (i) Benefit study: severe/moderate HA children with arthropathy from 15 centres were enrolled to undergo an 8‐week on‐demand treatment, followed by 6 to 12‐week low‐dose secondary prophylaxis. Outcomes compared in the two periods include joint and severe bleeding, daily activities and factor consumption. (ii) Obstacle study: questionnaires to investigators to collect data on patient and centre factors contributing to inability to comply with prophylaxis. We enrolled 191 patients from 15 centres. Sixty‐six (34.6%) from three centres completed the prophylaxis protocol, and they had significantly decreased bleeding (78.8% haemarthrosis and 68.9% severe bleedings) and improved daily activities with no increase in factor consumption over that in the on‐demand therapy period. The remaining 125 patients from 12 centres were not compliant to the prophylaxis protocol; questionnaire data indicated that the major obstacles were inability of patients/parents to accept (41.7%) or to adhere (33.3%) to the prophylaxis protocol, mostly because of failure to understand the benefits and to accept the frequent injections. Non‐availability of a centre comprehensive care team was another important determinant. Short‐term low‐dose secondary prophylactic therapy is beneficial without increasing factors consumption for severe/moderate HA with arthropathy in a multi‐centre setting in China. Obstacles to overcome must include improvement in comprehensive care and in education to patient/parents and healthcare personnel.

Can activated recombinant factor VII be used to postpone the exposure of infants to factor VIII until after 2 years of age

Summary.  Two retrospective studies have suggested that exposure to factor VIII (FVIII) in early infancy is associated with an increased risk of FVIII inhibitor development. We prospectively studied 11 infants who needed replacement therapy for bleeding episodes before the age of 2 years. They received activated recombinant factor VII (rFVIIa) concentrate on demand, with the intention of postponing their first exposure to FVIII after 2 years of age. Thirty‐three bleeding episodes were treated with 154 doses of rFVIIa with no evidence of adverse effect. Bleeding was controlled in 27 of 33 episodes. Mouth bleeds were most difficult to treat. The use of rFVIIa allowed postponement of the use of FVIII for a mean of 5.5 months (median 4, range 0–12) but in only three of 11 children could be the first exposure to factor postponed after the age of 2 years. With this modest effect of rFVIIa in postponing the first exposure to FVIII, more convincing evidence for the benefit of such a postponement will have to be demonstrated before rFVIIa could be recommended for this indication.

Chinese Hemophilia Joint Health Score 2.1 reliability study.

To meet the rapidly expanding need for musculoskeletal (MSK) specialists [physiotherapists (PTs), physiatrists] in haemophilia care in China, a 4‐day Train the Trainer workshop was conducted in July/August 2009 in Beijing. A key focus was to train the participants to administer the Hemophilia Joint Health Score (HJHS) version 2.1 for effectively evaluating the MSK health of boys <18 years of age with haemophilia. The aim of this study was to test the HJHS version 2.1 inter‐ and intra‐rater reliability in a group of Chinese PTs and physiatrists with limited experience in haemophilia care. Each of the trained Chinese physiatrists and PTs examined eight boys 4–17 years old with moderate and severe haemophilia on day 1 and repeated the examination on the same patients the next day using the HJHS version 2.1. The boys had a wide range of target joint involvement and arthropathy. The HJHS score sheet, work sheets and manual had been translated into simple Chinese prior to the study. The interrater (ICC 0.90) and intra‐rater (ICC 0.91) reliability was excellent. The internal consistency of the HJHS items was also excellent with Cronbachs alpha of 0.86. With basic training in the administration of the HJHS version 2.1, the tool was reliably administered by Chinese PTs and physiatrists with limited haemophilic experience.

Suspected collagen disorders in the bleeding disorder clinic: A case–control study

Disorders of collagen are associated with a mild bleeding tendency because of the potential abnormal interaction of collagen, von Willebrand factor (VWF) and platelets required during primary haemostasis and due to generalized soft tissue fragility. Abnormal collagen may contribute to bleeding in existing mucocutaneous bleeding disorders, but the prevalence in this setting is unknown. Generalized symptomatic joint hypermobility (SJH) is common in collagen disorders and may be objectively measured. To assess the association between symptomatic joint hypermobility and mucocutaneous bleeding disorders, we performed a case–control study in which case subjects were 55 consecutive individuals who had visited our bleeding disorder clinic with a diagnosis of von Willebrand disease, low von Willebrand factor levels, mild platelet function disorder or undefined bleeding disorder. Controls were 50 subjects without a bleeding disorder, and were age and gender matched to the cases. All subjects were assessed with: (i) Beighton score for joint hypermobility, (ii) revised Brighton criteria, (iii) Condensed MCMDM1‐VWD bleeding questionnaire, and (iv) haemostasis laboratory studies. The prevalence of SJH/suspected collagen disorder in the bleeding disorder clinic was 24% (13/55) compared with 2% (1/50) in the control population (OR 15, 95% CI 2–121). Seventy‐seven per cent of bleeding disorder clinic SJH subjects (10/13) had a prior personal or family history of Ehlers‐Danlos, Benign Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Symptomatic joint hypermobility was associated with increased odds of an underlying mucocutaneous bleeding disorder. These findings suggest that a collagen disorder is common and often unrecognized in the bleeding disorder clinic as a potential contributor to the bleeding symptoms.

Patterns of tertiary prophylaxis in Canadian adults with severe and moderately severe haemophilia B

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2‐year observation period from 2009 to 2011. Thirty‐four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year‐1). The severe subgroup (FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty‐one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on‐demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196 283 U year‐1 compared to 46 361 U year‐1 for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study.

What should men living with haemophilia need to know? The perspectives of Canadian men with haemophilia

Haemophilia is an inherited bleeding disorder affecting approximately 3000 Canadian men (Walker 2012). To manage their disease effectively individuals must be knowledgeable about the disease, bleed prevention strategies, treatment approaches, and complications. Data on individuals’ knowledge levels are scarce. The availability of such data could lead to better educational strategies for disease management. The aim of this study was to determine current knowledge levels, needs and gaps among Canadian individuals with haemophilia to facilitate optimal disease management. A survey was disseminated to adult males with haemophilia at three Haemophilia Treatment Centres (HTCs) in Canada. Self‐reported current knowledge levels and knowledge seeking were measured. Survey respondents reported highest levels of knowledge in the following areas: identifying and treating a bleed, haemophilia and physical activity, travel, career issues and genetics. Lower levels of knowledge were reported in the areas of sexual activity, product safety, information about factor, haemophilia and ageing, advocacy, timing of prophylactic infusions, and new or alternative therapies. Treating a bleed was the most commonly sought information, followed by information about factor, product safety, identifying a bleed and other health care issues. There was a positive correlation between knowledge seeking and severity of disease. HTC attendance was associated with knowledge seeking, and HTCs were the most frequented knowledge source, followed by the Canadian Haemophilia Society website. Canadian men were well informed; the HTCs role in knowledge sharing was recognized. Timing of infusions, sexual activity and ageing are areas which should be targeted in knowledge sharing.