Depletion of CD4+/CD25high regulatory T cells may enhance or uncover factor VIII-specific T-cell responses in healthy individuals.
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Cell Proliferation↗
Biomedical subjects
H M van den Berg
Publications and source records attributed to H M van den Berg.
Measuring patients' perceptions on their functional abilities: validation of the Haemophilia Activities List.
Recently, the Haemophilia Activities List (HAL), a haemophilia-specific self-assessment questionnaire to assess a patient's self-perceived functional ability, was introduced and a limited pilot study warranted its further development. The present study finalizes the HAL and assesses the convergent and construct validity, as well as the internal consistency of its definitive version. Three questionnaires (HAL, Dutch-Arthritis Impact Measurement Scales 2 and the Impact on Participation and Autonomy questionnaire) were completed by 127 patients with severe haemophilia (<1% clotting activity), as well as four performance tests (button test, 50 metre walking test, timed-up-and-go test and figure-8 walking test). After removal of 15 non-informative items from the provisional HAL, three components within the questionnaire were identified (upper extremity activities, basic lower extremity activities and complex lower extremity activities). The internal consistency of these components was high (Cronbach's alpha = 0.93-0.95), as was internal consistency for the seven domains of the HAL (alpha = 0.61-0.96). The convergent validity of the HAL when compared to the other two questionnaires was good (r = 0.47-0.84). The construct validity of the HAL when compared to the four performance tests was generally lower (r = 0.23-0.77). The final version of the HAL has good internal consistency and convergent validity and gives the clinician insight into a patient's self-perceived ability to perform activities of daily life. It is likely that self-assessment instruments (questionnaires) and performance tests consider different concepts of functional health status and it is therefore recommended that both types are included when clinicians assess a patient's functional abilities.
Activities of Daily Living↗
Pain and functional limitations in patients with severe haemophilia.
Patients with severe haemophilia often experience pain caused by haemophilic arthropathy, and it is known that pain acts as a predictor of disability. The role of pain in functional limitations in these patients, however, has not been systematically investigated. The aim of this study was to describe pain as experienced by patients with haemophilia and to address the role of pain in subsequent functional limitations. Seventy-eight adult patients (18-70 years) with severe haemophilia completed one questionnaire on pain and one on self-perceived functional abilities. Two-thirds of the patients suffered from more than one painful joint, the ankle being mentioned most frequently (n=43). Analgesics were used by 36% of the patients indicating having pain. Six of 10 most frequently mentioned pain descriptors were of evaluative nature. Evaluative qualities of pain were associated with pain intensity, which in turn was associated with the impact of pain on daily life. Pain outcomes, after adjusting for age and treatment modality, explained 3-22% of the variance in self-perceived functional abilities. Data on radiological joint damage (Pettersson scores) were retrieved for a subgroup of 28 younger patients on prophylaxis and no significant correlations with pain parameters were found. Over two-thirds of the patients with severe haemophilia had one or more painful joints. Pain plays a small, but significant role in functional limitations. In the identified subgroup, arthropathy, as measured by the Pettersson score, seemed to have no role in pain experience. Promoting analgesic use might decrease the impact of pain on functional limitations.
Activities of Daily Living↗
Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors.
The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.
Adult↗
Can long-term prophylaxis for severe haemophilia be stopped in adulthood? Results from Denmark and the Netherlands.
Prophylaxis is the treatment of choice for children with severe haemophilia. As prophylaxis is especially important during the period of growth, the need for continued prophylaxis in adulthood should be considered. The aim of this study was to describe the incidence and outcome of stopping prophylaxis in patients with severe haemophilia who were offered prophylaxis during childhood. All patients with severe haemophilia (factor VIII/IX <0.01 IU/ml), born 1970-80, treated in two Danish and one Dutch treatment centre were studied. Data on discontinuation of prophylaxis, treatment, joint bleed frequency, clinical scores and radiological scores were collected. Eighty patients were studied. Median follow-up was 19 years (range 7-29). A total of 35% of patients discontinued prophylaxis at a median age of 21.5 years [interquartile range (IQR) 18.4-24.4], experiencing only three joint bleeds per year (IQR 1.4-8.7). Median clinical scores were similar in patients who discontinued prophylaxis [4 points (IQR 0-6)] and those who continued [3 points (IQR 1-6)], as were median Pettersson scores at 13 (IQR 1-24) vs. 13 points (IQR 5-23) respectively. In conclusion one-third of young adults with severe haemophilia on a prophylactic regimen discontinued prophylaxis in early adulthood, while maintaining a low joint bleed frequency and similar arthropathy after 4 years.
Adolescent↗
Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed.
To quantify variation in clinical phenotype of severe haemophilia we performed a single centre cohort study among 171 severe haemophilia patients. Age at first joint bleed, treatment requirement (i.e. annual clotting factor use), annual bleeding frequency and arthropathy were documented. Because treatment strategies intensified during follow-up, patients were stratified in two age groups: patients born 1968-1985 (n = 91), or 1985-2002 (n = 80). A total of 2166 patient-years of follow-up were available (median 12.0 years per patient). Age at first joint bleed ranged from 0.2 to 5.8 years. Patients who had their first joint bleed later needed less treatment and developed less arthropathy. In patients born 1968-1985 during both on-demand and prophylactic treatment, the 75th percentile of annual joint bleed frequency was consistently four times as high as the 25th percentile. In both age groups variation in annual clotting factor use between 25th and 75th percentiles was 1.4-1.5 times for prophylaxis and 3.8 times for on-demand treatment. To conclude, the onset of joint bleeding is inversely related with treatment requirement and arthropathy and may serve as an indicator of clinical phenotype. Thus, providing a starting point for aetiological research and individualization of treatment.
Adolescent↗
The use of a disability model in haemophilia research.
Most haemophilia research is medically orientated. However, assessment of the impact of disease on the individual is different when viewed from a rehabilitation perspective. Several models are available to explore functioning and health from this perspective. The disablement process (DP) is such a model, and the aim of this study was to introduce this process in haemophilia research to see whether this type of research could lead to meaningful data. Forty-three adult patients with severe haemophilia participated in this study in which the three 'main pathway' domains of the DP (impairments, functional limitations and disability) and two additional factors (intra-individual and risk factors) were addressed. Three questionnaires (HAL, Dutch-AIMS2 and IPA) were incorporated, and Pettersson scores for 21 patients were retrieved. Step-wise and hierarchical regression analysis was used to assess relationship between the various domains. Arthropathy explained 48% of the variance in functional limitations and nearly 25% of the variance in disability. Functional limitations explained 54% of the variance in disability. Patients identified pain as an important aspect of health which addressed 22% and 13% of the variance in functional limitations and disability respectively. Age was correlated with arthropathy (r = 0.85; P < 0.001), whereas psychological health correlated with pain (r = 0.67; P < 0.001). Both variables were also correlated with functional limitations and disability. Analyses adjusting for the effects of age and psychological health were subsequently performed resulting in more insight in the associations within the DP. The use of the DP in haemophilia research proved to be useful.
Activities of Daily Living↗
Functional consequences of haemophilia in adults: the development of the Haemophilia Activities List.
Several instruments can be used to evaluate the functional status of patients with haemophilia, but none of these instruments is specific for haemophilia. We developed a haemophilia-specific self-assessment questionnaire to evaluate and monitor a patient's perceived functional health status: the Haemophilia Activities List (HAL). In three separate but interlinked substudies, the questionnaire was constructed and tested for face, expert, and convergent validity, as well as internal consistency and patient-evaluated relevance. Items for the questionnaire were collected by interviewing 162 patients, using the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). The items were combined to generate the first version of the questionnaire [HAL(1)]. This version was evaluated and commented on by two focus groups (patients and caregivers), and then the questionnaire was adapted on the basis of these comments, forming the final version, HAL(2). This version was then validated in a pilot study with 50 consecutive patients using the Dutch Arthritis Impact Measurements Scales 2 (Dutch-AIMS2) and the Impact on Participation and Autonomy (IPA) questionnaires. The HAL(2) showed good convergent validity (Pearson correlation 0.80-0.91; P < 0.01), and the internal consistency was good for six of the eight domains (Cronbach's alpha 0.83-0.95). Patients considered the content of the HAL to be more relevant to their situation than the content of the other questionnaires (P < 0.01). Three major factors (upper extremity function, lower extremity function, key activities/major problem activities) were identified by factor analysis. The questionnaire seems to be a useful tool to identify problematic activities as part of the functional health status of patients with haemophilia. The construct validity, test-retest reliability, and responsiveness of the HAL will be established in the future.
Activities of Daily Living↗
Hepatitis C infection in children with haemophilia: a pilot study.
Many haemophilia patients were infected with hepatitis C virus (HCV) in childhood after transfusion with inadequately or non-virus inactivated clotting factor products. Limited information is available on the clinical course of HCV infection in children. To assess the clinical consequences of hepatitis C in these young patients we performed a pilot study of 31 patients with haemophilia, infected with HCV before the age of 13. Current median age was 20 years. Nineteen (61%) patients had chronic hepatitis C, whereas the remaining 12 patients spontaneously cleared HCV. The median duration of infection was 17 years. Among patients chronically infected with HCV, an enlarged liver and/or spleen on ultrasound was present in 59%, whereas 63% had abnormal aminotransferases and/or gamma-GT values. In conclusion, 39% of the patients infected in childhood cleared HCV spontaneously. The majority of the patients with chronic hepatitis C had ultrasound and/or laboratory abnormalities and these findings may be associated with the presence of chronic liver disease.
Adolescent↗
Haemoglobin-derived iron-dependent hydroxyl radical formation in blood-induced joint damage: an in vitro study.
OBJECTIVE: It has been reported that joint bleeds cause cartilage damage and that the combination of red blood cells (RBC) plus mononuclear cells (MNC) causes the adverse effects. The present study is to elucidate the mechanism by which blood, as present in whole blood, may cause this cartilage damage. METHODS: Human cartilage samples were cultured for 4 days in the presence of 50% whole blood, isolated MNC plus RBC, CD14+ cells (monocytes/macrophages) plus RBC, or lysed RBC with interleukin 1beta (IL-1beta; a major catabolic product of activated monocytes/macrophages). Antioxidants were used to investigate the involvement of oxidative stress. A subsequent 12-day culture period in the absence of additions is referred to as the recovery period. Changes in cartilage proteoglycan synthesis were determined at days 4 and 16. RESULTS: Cartilage cultured in the presence of whole blood, MNC plus RBC, or monocytes/macrophages plus RBC resulted in a prolonged inhibition of proteoglycan synthesis (>90% inhibition at day 16; all three P<0.05). Lysed RBC together with IL-1beta also induced prolonged inhibition of proteoglycan synthesis (>56% of controls, P<0.05). Dimethylsulphoxide (DMSO), scavenging hydroxyl radicals, could reverse the inhibition of cartilage proteoglycan synthesis. CONCLUSIONS: Based on these results we hypothesize that IL-1beta produced by activated monocytes/macrophages increases the production of hydrogen peroxide by chondrocytes. This in combination with haemoglobin-derived iron from the RBC will result in the formation of hydroxyl radicals in the vicinity of chondrocytes. This mechanism may result in chondrocyte damage and as such be involved in blood-induced cartilage damage.
Adult↗
An unconscious girl with sickle-cell disease.
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Cerebral Ventriculography↗
Meta-analysis on the effectiveness of B-domain deleted factor VIII for prophylaxis.
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Factor VIII↗
Comparing outcomes of different treatment regimens for severe haemophilia.
Published retrospective reports from France, the Netherlands and Sweden were analysed for data relating to the long-term outcomes (primarily the development of arthropathy) of three regimens for the management of severe haemophilia: on-demand treatment, intermediate-dose prophylaxis and high-dose prophylaxis. The mean annual consumption of factor concentrate was also compared. These data indicate that both prophylaxis regimens resulted in significantly improved long-term outcomes, as assessed by pain, clinical and radiological assessment scores. At the same time, the most recently reported annual factor consumption levels of these young adult patients are comparable in the on-demand and intermediate-dose prophylaxis cohorts, suggesting that the improvement in long-term clinical outcomes and reduced risk of arthropathy may lead to reduced factor consumption in adult patients who received early prophylactic therapy.
Adolescent↗
Health-related quality of life as outcome parameter in haemophilia treatment.
Health-related quality of life (HRQoL) is increasingly used as an outcome parameter in haemophilia treatment. Currently, only generic HRQoL instruments are used, as disease-specific instruments for haemophilia are not available. The most widely used generic instruments are the descriptive SF-36 questionnaire and the EQ-5D questionnaire for assessment of utilities, ie preference-based HRQoL. Results of both instruments show significant correlation. All haemophilia prophylaxis studies using HRQoL as an outcome report a decreased HRQoL compared with the general population, a positive effect of prophylactic treatment and a negative effect of age. Generic instruments for measuring HRQoL are able to pick up differences between groups of patients with haemophilia and enable us to make comparisons across diseases. However, in order to establish the optimal treatment strategy for severe haemophilia, further information is needed on the long-term effects of different strategies on HRQoL. In addition, haemophilia-specific HRQoL instruments should be developed in order to provide detailed information for adjustment and evaluation of treatment in individual patients.
HIV Infections↗
Consensus perspectives on prophylactic therapy for haemophilia: summary statement.
Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.
Consensus Statements as Topic↗
[Oral surgery in hemophilia patients].
Oral surgery in hemophilia patients requires special arrangements in close collaboration with a hemotologist. Minor oral surgeries in not complicated cases can be done by a dentist or an oral surgeon with aid and assistance of a hemotologist. All major oral surgeries in hemophilia patients with antibodies counteracting coagulation agents should occur in a hemophilia treatment centre.
Adult↗
Effects of prophylactic treatment regimens in children with severe haemophilia: a comparison of different strategies.
Both Sweden and the Netherlands have a long experience with primary prophylaxis in children with severe haemophilia. In these countries it has been offered to all children for the last 3-4 decades. In Sweden prophylaxis is generally started at an earlier age with a higher dosage and frequency than in the Netherlands. Patients in the Netherlands receive a more individually tailored regimen, with prophylaxis now started after the first one or two joint bleeds and dosages are increased when breakthrough bleeds occur. The current study evaluated the effect prophylaxis on long-term outcomes and the consumption of clotting factor concentrates in Dutch and Swedish cohorts. Our results show that the orthopaedic outcome in the oldest groups of patients from Sweden and the Dutch cohorts were comparable, although the Swedish patients used twice as much clotting products per year. In the youngest patients, joint status is very good and further follow-up is necessary to demonstrate the benefits of either strategy. In conclusion, more individually tailored regimens aimed at preventing bleeding prevent joint damage in children with severe haemophilia, while clotting factor consumption is about half of that in previously described regimens.
Adolescent↗
Prophylactic treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen.
A multicentre study was performed in Sweden and the Netherlands, comparing effects of two prophylactic regimens in 128 patients with severe haemophilia, born 1970-90. 42 Swedish patients (high-dose prophylaxis), were compared with 86 Dutch patients (intermediate-dose prophylaxis). Patients were evaluated at the date of their last radiological score according to Pettersson. Annual clotting factor consumption and bleeding frequency were registered for a period of three years before evaluation. Patients in the high-dose group were younger at evaluation (median 15.2 vs. 17.9 years), started prophylaxis earlier (median 2 vs. 5 years), and used 2.19 times more clotting factor kg-1 year-1. Patients treated with high-dose prophylaxis had fewer joint bleeds (median 0.3 year-1 vs. 3.3 year-1) and the proportion of patients without arthropathy as measured by the Pettersson score was higher (69% vs. 32%), however, the age-adjusted difference in scores (median 0 points vs. 4 points) was small and at present not statistically significant. Clinical scores and quality of life were similar. These findings suggest that, compared with intermediate-dose prophylaxis, high-dose prophylaxis significantly increases treatment costs and reduces joint bleeds over a period of 3 years, but only slightly reduces arthropathy after 17 years of follow-up.
Adolescent↗