Karin Fijnvandraat

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report.

Summary.  The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non‐genetic factors – perceived by the immune system as danger signals – which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non‐genetic risk factors on inhibitor development, and an urgent need for prospective, well‐conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy‐related issues, breast feeding and treatment‐related factors (e.g. route of administration, or use of blood components) and inhibitor development.

The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial

BACKGROUND No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sβ(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING NHS Blood and Transplant.

Intensive peri‐operative use of factor VIII and the Arg593→Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A

Summary.  Background: A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. Objectives: In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. Patients/methods: Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. Results: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty‐three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10‐fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9–119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri‐operative use of FVIII concentrate (RR 186; 95% CI, 25–1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9–86). Conclusion: The Arg593Cys genotype and intensive peri‐operative use of FVIII, especially when administered by continuous infusion, are associated with an increased risk for inhibitor development in mild/moderate hemophilia A.

Inter‐individual variation in half‐life of infused recombinant factor VIII is related to pre‐infusion von Willebrand factor antigen levels

Summary. In an attempt to explain the substantial inter‐individual variability in half‐life of infused factor VIII (FVIII) among haemophilia A patients, we studied the correlation of pre‐infusion von Willebrand factor antigen (vWFAg) levels and the half‐life of a recombinant‐DNA‐derived FVIII (r‐VIII SQ, Pharmacia, Sweden). Intra‐individual variation in half‐life was small (range of variation 0.2‐1 h) in 12 severely affected haemophiliacs who received two doses of FVIII concentrate. In contrast, inter‐individual variation in half‐life was large (range of half‐lives 6‐28.8 h). A strong correlation between half‐life and pre‐infusion vWFAg levels was present (r= 0.87, P= 0.0003). We conclude that the half‐life of infused recombinant FVIII is related to pre‐infusion vWFAg levels in severely affected haemophilia A patients.

Obesity: a new disaster for haemophilic patients? A nationwide survey

Summary.  The prevalence of obesity, an important risk factor for both cardiovascular disease and arthropathy, is strongly increasing in the general population, but data for the haemophilia population are scarce. Obesity may have a more profound effect on arthropathy and on cardiovascular disease in patients with haemophilia. To assess the prevalence of obesity in haemophilia patients and install adequate measures, if necessary. We performed a nationwide postal survey to measure the prevalence of overweight and obesity in Dutch haemophilia patients in 1992 (n = 980) and 2001 (n = 1066). A random sample of the Dutch male population served as the control group. In adult haemophiliacs, the prevalence of overweight (BMI 25–30 kg m−2) increased from 27% to 35% (95% CI 31.1–38.0) and the prevalence of obesity (BMI ≥30 kg m−2) doubled from 4% to 8% (95% CI 6.0–10.1), which was comparable with the general population. The increased prevalence of obesity in boys with haemophiliacs, which tripled in 10 years, is alarming. The increased prevalence of overweight and obesity in patients with haemophilia may have a profound effect on morbidity and quality of life of haemophilia patients by aggravating pre‐existing arthropathy and predisposing aged patients to cardiovascular disease. Measures to prevent overweight in haemophiliacs are therefore urgently needed.

Quality of life of female caregivers of children with sickle cell disease: a survey

This Dutch survey demonstrates a lower quality of life in female caregivers of children with sickle cell disease than in the healthy female population and caregivers of healthy children with the same socioeconomic status. Therefore, better support is needed to improve the quality of life of both children with sickle cell disease and their caregivers. Caring for a child with sickle cell disease poses extra demands on parents, both practically and psychologically, which may influence their quality of life. Since families of children with sickle cell disease in the Netherlands usually belong to immigrant communities with a low socio-economic status, there may be an additional strain on caregivers. The aim of the present study was to evaluate the quality of life of caregivers of children with sickle cell disease. The quality of life of female caregivers of sickle cell disease patients, measured with the TNO-AZL Adult Quality of Life questionnaire, was compared to the norm data of healthy Dutch females (n=700) and female caregivers of healthy children with the same socio-economic status and ethnic background (socio-economic status control group). Groups were compared by the Mann-Whitney U test. Point estimates and 95% confidence intervals of the median difference are presented. The results of questionnaires of 54 caregivers of children with sickle cell disease and 28 caregivers of a control group of the same socio-economic status were analyzed. Caregivers of patients with sickle cell disease had a significantly lower quality of life on all subscales compared to the Dutch norm population. Compared to the control group of the same socio-economic status, the quality of life of caregivers of patients with sickle cell disease was significantly lower on the subscales depressive moods, daily activities and vitality. In this first study reporting on the quality of life of caregivers of children with sickle cell disease, we demonstrate a reduced quality of life in these caregivers compared to the healthy Dutch female population and caregivers of healthy children with the same socio-economic status.

Surgery and inhibitor development in hemophilia A: A systematic review

Summary.  Background: Although the association between intensive treatment and the formation of inhibiting antibodies towards factor VIII (FVIII) in hemophilia A has been demonstrated, the contributing effect of surgery is presently unclear. The release of immunological danger signals resulting from tissue damage during surgery in the presence of a high FVIII antigen load may elicit the formation of FVIII antibodies. The aim of this systematic review was to investigate the role of surgery in the inhibitor risk associated with intensive treatment as compared with treatment for bleeding and prophylactic administration of FVIII. Methods: A comprehensive literature search was performed that identified four cohort studies and three case control studies, comprising 342 inhibitor patients among a total of 957 hemophilia A patients. Results: Intensive treatment increased the inhibitor risk, most pronounced with intensive treatment of ≥ 5 exposure days (EDs) compared with < 3 EDs (OR, 4.1; 95% confidence interval, 2.6–6.5). Pooled odds ratio for inhibitor development in severe hemophilia patients that received intensive treatment for surgery at first exposure was 4.1 (95% confidence interval, 2.0–8.4) compared with treatment for bleeding or prophylaxis. Information on continuous infusion, previously treated patients and non‐severe hemophilia A was insufficient for valid meta‐analyses. Conclusions: Intensive FVIII treatment for surgery at first exposure leads to a higher inhibitor risk in hemophilia A patients compared with intensive treatment for bleeding.

Reduced prevalence of arterial thrombosis in von Willebrand disease

High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies.

Growth and nutritional status of children with homozygous sickle cell disease.

Abstract Background: Poor growth and under-nutrition are common in children with sickle cell disease (SCD). This review summarises evidence of nutritional status in children with SCD in relation to anthropometric status, disease severity, body composition, energy metabolism, micronutrient deficiency and endocrine dysfunction. Methods: A literature search was conducted on the Medline/PUBMED, SCOPUS, SciELO and LILACS databases to July 2007 using the keywords sickle cell combined with nutrition, anthropometry, growth, height and weight, body mass index, and specific named micronutrients. Results: Forty-six studies (26 cross-sectional and 20 longitudinal) were included in the final anthropometric analysis. Fourteen of the longitudinal studies were conducted in North America, the Caribbean or Europe, representing 78.8% (2086/2645) of patients. Most studies were observational with wide variations in sample size and selection of reference growth data, which limited comparability. There was a paucity of studies from Africa and the Arabian Peninsula, highlighting a large knowledge gap for low-resource settings. There was a consistent pattern of growth failure among affected children from all geographic areas, with good evidence linking growth failure to endocrine dysfunction, metabolic derangement and specific nutrient deficiencies. Conclusions: The monitoring of growth and nutritional status in children with SCD is an essential requirement for comprehensive care, facilitating early diagnosis of growth failure and nutritional intervention. Randomised controlled trials are necessary to assess the potential benefits of nutritional interventions in relation to growth, nutritional status and the pathophysiology of the disease.