H. M. Van Den Berg

Serum vitamin D concentrations among elderly people in Europe

Vitamin D status decreases with age, mainly as a result of restricted sunlight exposure, reduced capacity of the skin to produce vitamin D, and reduced dietary vitamin D intake. We measured wintertime serum 25-hydroxyvitamin D [25(OH)D] concentrations in 824 elderly people from 11 European countries. 36% of men and 47% of women had 25(OH)D concentrations below 30 nmol/L. Users of vitamin D supplements and/or sunlamps had higher 25(OH)D (median 54 nmol/L) than non users (median 31 nmol/L). Surprisingly, lowest mean 25(OH)D concentrations were seen in southern European countries. Low 25(OH)D concentrations could largely be explained by attitudes towards sunlight exposure and factors of physical health status, after exclusion of users of vitamin D supplements or sunlamps. Problems with daily living activities and wearing clothes with long sleeves during periods of sunshine were strong predictors of low wintertime serum 25(OH)D concentrations. These findings show that free-living elderly Europeans, regardless of geographical location, are at substantial risk of inadequate vitamin D status during winter and that dietary enrichment or supplementation with vitamin D should be seriously considered during this season.

Consensus perspectives on prophylactic therapy for haemophilia: summary statement

Summary.  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.

Sexual transmission of hepatitis C virus

We tested 50 heterosexual partners of hepatitis C viraemic (HCV) individuals, using second generation HCV antibody assays and a validated polymerase chain reaction assay. In none of them were HCV antibodies or HCV-RNA detected. The median duration of the sexual relationship was 13 years. This study, with the most sensitive techniques for detection of HCV, indicates that the risk of sexual transmission of HCV is absent or very low.

Prophylactic versus on‐demand treatment strategies for severe haemophilia: a comparison of costs and long‐term outcome

Summary.  A multicentre study was performed to compare clotting factor use and outcome between on‐demand and prophylactic treatment strategies for patients with severe haemophilia. Data on treatment and outcome of 49 Dutch patients with severe haemophilia, born 1970–80, primarily treated with prophylaxis, were compared with those of 106 French patients, who were primarily treated on demand. Dutch patients received intermediate dose prophylaxis, for a median duration of 12.7 years. Patients primarily treated with prophylaxis had fewer joint bleeds per year (median 2.8 vs. 11.5), a higher proportion of patients without joint bleeds (29% vs. 9%), lower clinical scores (median 2.0 vs. 8.0), and less arthropathy as measured by the Pettersson score (median 7 points vs. 16 points). Mean annual clotting factor use was equal at 1488 ± 783 IU kg−1 year−1 (mean ± standard deviation) for patients primarily treated with prophylaxis and 1612 ± 1442 IU kg−1 year−1 for patients primarily treated on demand. These findings suggest that, compared with a primarily on‐demand treatment strategy, a primarily prophylactic treatment strategy leads to better outcome at equal treatment costs in young adults with severe haemophilia.

Long-term outcome of individualized prophylactic treatment of children with severe haemophilia.

The development of arthropathy is a serious complication of severe haemophilia. With the use of prophylaxis, bleeds can be prevented and arthropathy delayed. We investigated whether an individually tailored prophylactic regimen can prevent arthropathy and whether it had a similar effect on orthopaedic outcome compared with that of a high‐dose regimen. Efficacy was determined clinically and by radiographs of six major joints. Prophylaxis was started in 70 patients at a mean age of 4·1 years. Mean follow‐up was 15·6 years (range 8–24·5 years). The mean factor VIII consumption was 2319 IU/kg/year. The mean number of joint bleeds was 3·5/year and the mean clinical score (maximum score 90) was 1·0, with a mean Pettersson joint score (maximum score 78) of 3·0 at a mean age of 13·5 years. In conclusion, long‐term, early‐onset, individualized prophylaxis in haemophilia is feasible and prevents arthropathy.

Transcription factor NF-κB as a potential biomarker for oxidative stress

There is increasing interest in the involvement of transcription factors, such as of the transcription factor NF-κB (nuclear factor-κB), in the pathogenesis of various diseases. NF-κB is involved in the control of the transcription of a variety of cellular genes that regulate the inflammatory response by the production of cytokines, chemokines, cell adhesion molecules and acute phase proteins. The involvement of NF-κB is especially of interest as it is activated by oxidative stress and its activation can be modulated by antioxidant compounds. The activation of NF-κB can be determined by the electromobility shift assay (EMSA) with a NF-κB binding-site-specific probe. EMSA can also be used on human mononuclear cells isolated from peripheral blood, which could make the assay applicable for clinical trials. The critical steps of the EMSA are discussed, addressing some pitfalls of the assay. The procedure that can be used to express NF-κB activity in human subjects is evaluated. This offers the possibility to use NF-κB as a functional biomarker of oxidative stress as illustrated by several examples of in vitro and in vivo studies. Chemicals/CAS: Biological Markers; NF-kappa B

Definitions in hemophilia: communication from the SSC of the ISTH

V. S . BLANCHETTE ,* N . S . KEY ,† L . R . L JUNG,‡ M. J . MANCOJOHNSON,§ H. M. VAN DEN BERG ¶ and A . SR IVASTAVA,** FOR THE SUBCOMMITTEE ON FACTOR VI I I , FACTOR IX AND RARE COAGULAT ION DISORDERS *Pediatric Thrombosis and Hemostasis Program, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, ON, Canada; †Departments of Medicine and Pathology, UNC Hemophilia and Thrombosis Center Chapel Hill, Hill, NC, USA; ‡Department of Paediatrics and Malmo Centre for Thrombosis and Haemostasis, Lund University, Skanes Universitetssjukhus, Malmo, Sweden; §Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, USA; ¶Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, the Netherlands; and **Department of Hematology, Christian Medical College, Vellore, India

Prophylactic treatment for severe haemophilia: comparison of an intermediate‐dose to a high‐dose regimen

Summary.  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.

Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A

Context: The development of inhibitory antibodies against infused factor (F) VIII is a major complication of treatment of patients with severe hemophilia A.Objective: This study was set up to examine the effects of treatment‐related factors on inhibitor development among previously untreated patients with severe hemophilia A.Design, setting and patients: In this multicenter cohort study, we combined individual patient data obtained from four recombinant FVIII product registration studies (Kogenate®, Kogenate Bayer®, Recombinate®, ReFacto®) that were performed between 1989 and 2001. From the databases we selected all 236 previously untreated patients with severe hemophilia A who were subsequently treated with FVIII on at least 50 days.Main outcome measures: Clinically relevant inhibitor development, defined as the occurrence of at least two positive inhibitor titers and a decreased recovery.Results: 67 patients (28%) developed clinically relevant inhibitors (44 high‐titer) at a median of ten exposure days. Age at first exposure was not associated with inhibitor development. Peak treatment moments and surgical procedures were related to an increased inhibitor risk [adjusted relative risk 1.6 (95% confidence interval 1.0–2.6) and 2.7 (95% confidence interval 1.3–5.7), respectively]. A shorter duration between exposure days was associated with an increased risk of inhibitor development. There was a possible association between dosing of FVIII and inhibitor development, which largely disappeared after adjustment for confounding factors.Interpretation: These findings show that intensive treatment periods are associated with an increased risk of inhibitor development in previously untreated patients with severe hemophilia A. Our results do not support the notion that age at first exposure is associated with the risk of developing inhibitors.

Changes in treatment strategies for severe haemophilia over the last 3 decades: effects on clotting factor consumption and arthropathy

A cohort study was performed among 214 patients with severe haemophilia, born 1944–1994, to describe changes in treatment over the last 3 decades and its effects on clotting factor consumption and haemophilic arthropathy. Data on treatment strategy, clotting factor consumption, and outcome were collected for 3567 patient years (from 1972 to 1998), and 493 Pettersson scores were analysed. Median follow up was 17 years (range 6–27 years), and median age in 1998 was 27.6 years. Since 1965, replacement therapy, prophylaxis, and home treatment have been used and treatment intensified. Over the last 3 decades, annual clotting factor consumption increased by 260%, for both prophylactic and on‐demand treatment. Annual clotting factor consumption kg–1 increased during childhood and appeared to stabilize in early adulthood for patients born 1965–79, who were treated with early replacement therapy or early prophylaxis. In contrast, clotting factor consumption increased continuously for patients born before 1965, who had had no access to replacement therapy during the early years of their life. The annual number of joint bleeds decreased over the years. Arthropathy as measured by the Pettersson score generally became apparent around the age of 15 years and was lowest in patients treated with primary prophylaxis. In conclusion, clotting factor consumption has increased and haemophilic arthropathy has decreased due to the intensification of treatment for severe haemophilia over the last 3 decades. Annual clotting factor consumption stabilizes in adulthood for patients who receive early intensive treatment.