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Journal ArticleDOI

Effects of primary and secondary prophylaxis on the clinical expression of joint damage in children with severe haemophilia A. Results of a multicenter non-concurrent cohort study.

13 Dec 2007-Thrombosis and Haemostasis (Schattauer Publishers)-Vol. 99, Iss: 1, pp 71-76
TL;DR: In this article, the role of primary versus secondary prophylaxis in haemophilia A (HA) children was investigated, and the outcome variable was imaging-proven hahemophilic joint damage.
Abstract: Patients with severe haemophilia A (HA) can either be treated by regular FVIII infusions twice or three times per week (prophylaxis), or only in case of bleeding episodes (on-demand). Whereas prophylaxis reduces the number of bleeding episodes and may therefore prevent the development of haemophilic arthropathy, there is still a lot of controversy surrounding recommendations on age and dose at start of prophylactic regimens. The present database study was performed to investigate the role of primary versus secondary prophylaxis in HA children. The outcome variable was imaging-proven haemophilic joint damage. Forty-two children were initially treated with primary prophylaxis following the first bleeding episode, and were frequency-matched (year of birth, catchment area) to 67 patients receiving "on-demand" therapy with an early switch to "secondary prophylaxis". In multivariate analysis adjusted for the HA mutation type and the presence or absence of thrombophilia, the Pettersson score investigated at a median age of 12.5 years in joints with at least one documented bleeding episode was not significantly different between the two patient groups (p = 0.944), and no statistically significant differences were found in patients with target joints (p = 0.3), nor in children in whom synovitis had occurred (p = 0.77). No conclusion can be drawn from the data presented herein whether primary prophylaxis or an early start of secondary prophylaxis is superior with respect to joint outcome in children with severe HA.

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Citations
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Journal ArticleDOI
TL;DR: Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.

397 citations

Journal ArticleDOI
TL;DR: There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children with hemophilia as compared to on-demand treatment and well-designed randomisedcontrolled trials and prospective observational controlled studies are needed to establish the best proPHylactic regimen.
Abstract: Background The hallmark of severe hemophilia is recurrent bleeding into joints and soft tissues with progressive joint damage, notwithstanding on-demand treatment. Prophylaxis has long been used but not universally adopted because of medical, psychosocial, and cost controversies. Objectives To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register. In addition, we searched major electronic databases (MEDLINE, EMBASE, CENTRAL), handsearched relevant journals and abstract books and reference lists of relevant articles. Last search of Group's Coagulopathies Trials Register: 07 April 2011. Selection criteria Randomised controlled trials and quasi-randomised controlled trials evaluating people with severe hemophilia A or hemophilia B receiving prophylactic clotting factor concentrates. Data collection and analysis Two authors independently reviewed studies for eligibility, assessed risk of bias and extracted data. Main results Six studies (including 142 participants) were eligible for inclusion. Two compared three-times-a-week prophylactic administration with on-demand treatment in children with hemophilia. Pooled results from these two studies showed a rate ratio of 0.30 (95% confidence interval; 0.12 to 0.76) for all bleedings and 0.22 (95% confidence interval 0.08 to 0.63) for joint bleedings favouring prophylaxis. Results on the number of patients with preserved joints after three to seven years of follow-up were not pooled due to significant heterogeneity. Three of the remaining four studies evaluated hemophilia A; one showed a statistically significant decrease in frequency of joint bleeds with prophylaxis compared to placebo, with a rate difference of -10.73 (95% confidence interval -16.55 to -4.91) bleeds per year. Two studies compared two prophylaxis regimens, failing to demonstrate an advantage of one regimen over the other in terms of bleeding frequency. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, rate difference -3.30 (95% confidence interval -5.50 to -1.10) bleeds per year. Non-significant increases in both inhibitor and infectious complications were observed in patients on prophylaxis, which occurred more often when using long-term venous access. Authors' conclusions There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children with hemophilia as compared to on-demand treatment. There is insufficient evidence from randomised controlled trials to confirm the observational evidence that prophylaxis decreases bleeding and related complications in patients with existing joint damage. Well-designed randomised controlled trials and prospective observational controlled studies are needed to establish the best prophylactic regimen and to assess the effectiveness of prophylactic clotting factor concentrates in adult patients.

142 citations

Journal ArticleDOI
TL;DR: This meta-analysis confirms the association between severe haemophilia and low BMD and future studies should investigate fracture rates and interventions to prevent bone loss in persons with haemophile.
Abstract: Osteoporosis is caused by bone mineral density (BMD) reduction. Haemophilia patients are at increased risk of osteoporosis because of decreased physical activity and blood-borne virus infections. This systematic review of the literature aims at evaluating BMD reduction in severe haemophilia patients and its correlation with patients’ characteristics. Seven case-control studies evaluating lumbar BMD values [g/cm2] (all studies), BMI (5/7 studies), and hepatitis C virus (HCV) seropositivity (6/7 studies) in severe haemophilia patients and controls were meta-analysed. Standardised mean difference (SMD) of BMD was used to compare cases and controls. The effect of body mass index (BMI) and HCV infection was investigated by meta-regression. One hundred one adult cases (age 33 ± 8.9) with 101 controls and 111 paediatric cases (age 8 ± 3.6) with 307 controls were available for analysis. Lumbar BMD was significantly lower in severe haemophilia patients than in controls, both in adult (pooled SMD –1.379, 95% confidence interval [CI] –2.355 to –0.403, p=0.006) and children (pooled SMD –0.438, 95% CI –0.686 to –0.189, p=0.001). The reduction in BMD in patients versus controls was not significantly correlated with the reduction in BMI or with the percentage of HCV-infected patients. This meta-analysis confirms the association between severe haemophilia and low BMD. Future studies should investigate fracture rates and interventions to prevent bone loss in persons with haemophilia

86 citations

Journal ArticleDOI
TL;DR: Evidence from literature and current clinical strategies for prophylactic treatment in patients with severe haemophilia is summarized, focusing on challenges and open issues (optimal regimen and implementation, duration of treatment, long-term adherence and outcomes, cost-benefit ratios) in this setting.
Abstract: A four-decade clinical experience and recent evidence from randomised controlled studies definitively recognised primary prophylaxis, i.e. the regular infusion of factor concentrates started after the first haemarthrosis and/or before the age of two years, as the first-choice treatment in children with severe haemophilia. The available data clearly show that preventing bleeding since an early age enables to avoid or reduce the clinical impact of muscle-skeletal impairment from haemophilic arthropathy and the related consequences in psycho-social development and quality of life of these patients. In this respect, the aim of secondary prophylaxis, defined as regular long-term treatment started after the age of two years or after two or more joint bleeds, is to avoid (or delay) the progression of arthropathy. The clinical benefits of secondary prophylaxis have been less extensively studied, especially in adolescents and adults; also in the latter better outcomes and quality of life for earlier treatment have been reported. This review summarises evidence from literature and current clinical strategies for prophylactic treatment in patients with severe haemophilia, also focusing on challenges and open issues (optimal regimen and implementation, duration of treatment, long-term adherence and outcomes, cost-benefit ratios) in this setting.

67 citations

Journal ArticleDOI
Amy L. Dunn1
TL;DR: Recurrent haemarthroses in patients with severe and moderate haemophilia can result in the development of one or more target joints and subsequent degenerative joint disease, which is characterized by physical and physiological changes in articular cartilage, synovium and bone.
Abstract: Recurrent haemarthroses in patients with severe and moderate haemophilia can result in the development of one or more target joints and subsequent degenerative joint disease. This debilitating process is characterized by physical and physiological changes in articular cartilage, synovium and bone. Models of degenerative joint disease have been examined after the addition of whole blood or blood components to cell cultures or animal joints, or by monitoring biomarkers in individuals with and without haemophilia. Inhibition of cartilage-based proteoglycan synthesis and induction of proliferative synovitis are commonly observed in these models of degenerative joint disease. Clinical evaluation of joint disease includes use of specially designed physical examination and radiographic tools. Efforts to prevent or limit arthropathy include the use of prophylactic factor infusion regimens, surgical joint intervention or both.

60 citations

References
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Journal ArticleDOI
TL;DR: Haemophilia terms were successfully defined using the Delphi approach, and five of the seven terms were highly endorsed with greater than 90% agreement.
Abstract: Summary. The creation of acceptable standard definitions for terms used in the care and assessment of haemophilia patients has become increasingly important, as a growing number of international clinical studies have been initiated. The Delphi approach has been used in health research to reach consensus in large groups and can be used to develop definitions by using several iterations of surveys eliciting opinions from specialists in the field. Three consecutive surveys were designed based on the Delphi approach and distributed to specialist physicians, nurses and physiotherapists in order to develop definitions for seven haemophilia terms: ‘primary prophylaxis’, ‘secondary prophylaxis’, ‘target joint’, ‘joint bleed’, ‘significant soft-tissue bleed’, ‘superficial soft-tissue bleed’ and ‘mucosal bleed’. Suggestions were solicited, compiled into a subsequent survey and fed back to the group to rank-order the importance of each suggested component of the definition. Final definitions were created using the top-ranked suggestions and sent back to the experts for approval. Five of the seven terms were highly endorsed with greater than 90% agreement. Some differences in agreement were found when analysed by profession. Haemophilia terms were successfully defined using the Delphi approach. Further refinement from members of the international haemophilia community will ensure that comprehensive standard definitions can be used in multicentre studies in the future.

52 citations

Journal ArticleDOI
TL;DR: The asymptotic efficiencies of dependent sample designs relative to independent sample designs with adjustment were found to vary with the strengths of the relationships of disease with exposure and potential confounder: as the relationship with exposure increases, dependent samples lose efficiency; as the relationships with confoundinger increases,dependent samples gain efficiency.

49 citations

Journal ArticleDOI
TL;DR: The aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion.
Abstract: Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 males worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.

44 citations

Journal ArticleDOI
TL;DR: This study identified substantial increased costs of care associated with target joint development and provides further support for more aggressive treatment aimed at reducing target joints-either moreaggressive treatment of joint bleeds or institution of primary prophylactic therapy at an early age.

39 citations

Journal ArticleDOI
Rolf Ljung1
TL;DR: Patients with haemophilia should be given more control over their treatment, and the focus should be on `self‐monitored and self‐adjusted' prophylaxis.
Abstract: 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.

30 citations

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