Prevalence and Incidence of Non-neutralizing Antibodies in Congenital Hemophilia A- A Systematic Review and Meta-Analysis.

Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0-100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16-38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.

Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review.

Essentials Data on product-related immunogenicity in previously treated haemophilia A patients is scarce. A systematic review and meta-analysis of all currently available evidence was conducted. The overall incidence rate was 2.06 per 1000 person-years (95% confidence interval: 1.06-4.01). Some recombinant factor VIII products were associated with increased immunogenicity. SUMMARY: Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product-related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of < 0.02 IU mL-1 who had been treated with FVIII for at least 50 days. Pooled incidence rates of inhibitor development according to product types were calculated with a random intercept Poisson regression model. Results Forty-one independent cohorts were included; 39 patients developed de novo inhibitors during 19 157 person-years of observation. The overall incidence rate was 2.06 per 1000 person-years, with a 95% confidence interval (CI) of 1.06-4.01. According to product type, the pooled incidence rates were 0.99 (95% CI 0.37-2.70) per 1000 person-years for patients treated with Advate, 5.86 (95% CI 0.25-134.92) per 1000 person-years for those treated with Kogenate/Helixate, 1.35 (95% CI 0.66-2.77) per 1000 person-years for those treated with Kogenate FS/Helixate NexGen, 12.05 (95% CI 1.53-94.78) per 1000 person-years for those treated with Refacto, and 4.64 (95% CI 0.82-26.43) per 1000 person-years for those treated with Refacto AF. Conclusion These results suggest that some products may be associated with increased immunogenicity. However, the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk.

Measuring activities and participation in persons with haemophilia: A systematic review of commonly used instruments.

INTRODUCTION: Monitoring clinical outcome in persons with haemophilia (PWH) is essential in order to provide optimal treatment for individual patients and compare effectiveness of treatment strategies. Experience with measurement of activities and participation in haemophilia is limited and consensus on preferred tools is lacking. AIM: The aim of this study was to give a comprehensive overview of the measurement properties of a selection of commonly used tools developed to assess activities and participation in PWH. METHODS: Electronic databases were searched for articles that reported on reliability, validity or responsiveness of predetermined measurement tools (5 self-reported and 4 performance based measurement tools). Methodological quality of the studies was assessed according to the COSMIN checklist. Best evidence synthesis was used to summarize evidence on the measurement properties. RESULTS: The search resulted in 3453 unique hits. Forty-two articles were included. The self-reported Haemophilia Acitivity List (HAL), Pediatric HAL (PedHAL) and the performance based Functional Independence Score in Haemophilia (FISH) were studied most extensively. Methodological quality of the studies was limited. Measurement error, cross-cultural validity and responsiveness have been insufficiently evaluated. CONCLUSION: Albeit based on limited evidence, the measurement properties of the PedHAL, HAL and FISH are currently considered most satisfactory. Further research needs to focus on measurement error, responsiveness, interpretability and cross-cultural validity of the self-reported tools and validity of performance based tools which are able to assess limitations in sports and leisure activities.

Vaccinations are not associated with inhibitor development in boys with severe haemophilia A.

BACKGROUND: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. OBJECTIVE: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. METHODS: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. RESULTS: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. CONCLUSION: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations.

Health-related quality of life questionnaires in individuals with haemophilia: a systematic review of their measurement properties.

BACKGROUND: The evaluation of health related quality of life (HRQOL) is essential for a full assessment of the influence of an illness on patients' lives. The aim of this paper is to critically appraise and compare the measurement properties of HRQOL questionnaires studied in haemophilia. METHODS: Bibliographic databases (Embase, Medline, Cinahl and PsycInfo) were searched for articles evaluating measurement properties of HRQOL questionnaires in haemophilia. Articles were excluded that did not report HRQOL measurement properties, or when <50% of the study population had haemophilia. The methodological quality of the selected studies was evaluated using the COSMIN checklist. The measurement properties of the HRQL questionnaires were rated as 'positive', 'indeterminate' or 'negative', accompanied by levels of evidence. RESULTS: The search resulted in 1597 unique hits, of which 22 studies were included. These articles evaluated three questionnaires for children (CHO-KLAT, Haemo-QoL and one unnamed measure) and five for adults (Hemofilia-QoL, Haemophilia Well-Being Index, HAEMO-QoL-A, Haem-A-QoL, and SF-36). The CHO-KLAT was the paediatric measure that showed the strongest measurement properties in high-quality studies. The Haemophilia Well-Being Index and HAEMO-QoL-A performed best among the adult measures. None of the studies reported measurement error and responsiveness. CONCLUSION: Our findings suggest that there is no need for new disease-specific HRQOL questionnaires for haemophilia, but rather that additional research is necessary to document the measurement properties of the currently available questionnaires, specifically focusing on the structural validity, measurement error and responsiveness of these questionnaires.

Similar bleeding phenotype in young children with haemophilia A or B: a cohort study.

The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01-0.05 IU mL(-1) respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.

Prenatal diagnosis for haemophilia: a nationwide survey among female carriers in the Netherlands.

Carriers of haemophilia face difficult choices regarding prenatal diagnosis, but little is known about the determinants that influence their decisions. The aim of this study was to assess the incidence of prenatal diagnosis and potential determinants affecting the choice for prenatal diagnosis. A nationwide survey was performed among all women who underwent carriership testing for haemophilia in the Netherlands between 1992 and 2004. Prenatal diagnosis was assessed in 207 carriers of haemophilia A or B who had been pregnant. Prenatal diagnosis was categorized into early first trimester (Y-PCR testing or chorionic villus sampling) often intended to prevent the birth of a child with haemophilia, and into late prenatal diagnosis (amniocentesis or ultrasound assessment) aimed at obstetrical management. Of 207 carriers 112 (54%) underwent prenatal diagnosis. Forty-eight women underwent early prenatal diagnosis and 64 women underwent late prenatal diagnosis. In 26 pregnancies early prenatal diagnosis was positive for haemophilia, and in 18 of these pregnancies termination was opted for. The choice for early prenatal diagnosis was associated with a liberal view towards termination of pregnancy (relative risk (RR) 12.5; 95% confidence interval (CI) 3.1-51.2), severe haemophilia in the family (RR 20.2; CI 2.7-153.6), absence of a religion (RR 1.9; CI 1.1-3.1) and older age (RR 2.0; CI 1.0-3.9). The choice for late prenatal diagnosis was associated with birth year after 1970 (RR 2.3; CI 1.5-3.5) and a previous child with haemophilia (RR 2.2; CI 1.4-3.4). More than half of all Dutch haemophilia carriers underwent prenatal diagnosis. Several determinants were strongly associated with prenatal diagnosis.

Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients.

The development of neutralizing antibodies against factor VIII (FVIII) is a major complication of treatment with FVIII in patients with severe haemophilia A. This study was designed to describe the relationship between the type and location of the factor 8 (F8) gene mutation and the development of clinically relevant inhibitors in patients with severe haemophilia A. We conducted a single centre cohort study among 318 consecutive patients (baseline FVIII activity level <0.01 IU mL(-1)) born between 1934 and 2007 who were treated with FVIII on at least 50 exposure days. The primary outcome was clinically relevant inhibitor development, defined as the occurrence of at least two positive inhibitor titres and a decreased recovery. Clinically relevant inhibitors were diagnosed in 14% (43) of patients (30 high-titre). The cumulative incidence of inhibitor development was 18% (35 of 200) in high-risk gene defects (67% in patients with large deletions, 30% in patients with nonsense mutations, 15% in patients with intron 1 or 22 inversions) and 7% (8 of 118) in low-risk gene defects (7% in patients with small deletions and insertions, 6% in patients with missense mutations, 8% in patients with splice site mutations). In patients with point mutations, the cumulative risk of developing inhibitors was highest in patients with mutations in the A3 and C2 domains (13% and 17% respectively). In conclusion, in agreement with earlier observations, the type and location of the F8 gene mutation were important determinants of inhibitor development in patients with severe haemophilia A.

Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units.

Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo-antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25-50 IU kg(-1) every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL(-1). Success rate was associated with both a pre-ITI titre and a maximum titre during ITI below 40 BU mL(-1) (P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL(-1) (P = 0.040). In low titre inhibitors (<5 BU mL(-1)) this effect was even stronger (P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre-ITI titre below 40 BU mL(-1). The time to success is predicted by a maximum ITI titre below 40 BU mL(-1), and is even shorter in low titre inhibitors (<5 BU mL(-1)). We suggest that all patients with severe haemophilia A and a pre-ITI inhibitor titre below 5 BU mL(-1), should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL(-1) may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy.

Discordant antibody response in monozygotic twins with severe haemophilia A caused by intensive treatment.

Both genetic factors and environmental factors are suggested to play a role in the aetiology of inhibitor development in patients with severe haemophilia A. Monozygotic twins are ideal candidates to study the influence of environmental factors. We describe a pair of 3-year-old monozygotic twin brothers with severe haemophilia A. Prenatal diagnosis confirmed the presence of an intron 22 inversion. Other patient-related factors such as birth weight, vaccinations and the duration of breastfeeding were similar. At the age of 7 months, one boy suffered from a spontaneous subdural haematoma, which needed complete correction of haemostasis with continuous infusion of a third-generation recombinant factor VIII. A persistent high-titre inhibitor with severe clinical symptoms developed, that could only be eradicated with high-dose immune tolerance induction (ITI) for 36 months in combination with rituximab therapy. His twin brother first received treatment at 9 months of age with the same FVIII product. After treatment on nine exposure days, he developed a low-titre inhibitor at the age of 14.5 months. Unlike his brother, he was tolerized without difficulties with low-dose ITI within 2 months. The discordant antibody responses were underlined by dissimilar IgG1 and IgG4 levels in their plasma. The discordant immune response to FVIII in this pair of monozygotic twin brothers seemed to be related to intensity of treatment and severity of bleeds. This confirms that these environmental factors play an additional role in the development of inhibitors.

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.

Implantable diagnostic and therapeutic devices in children.

Many advances have been made in the use of implantable diagnostic and therapeutic devices in adults. In children the indications for and diagnostic and therapeutic value of these devices still have to be determined. Our aim is to provide an overview of the clinical use of diagnostic and therapeutic devices in children. The role of implantable loop recorders (ILR), the feasibility and safety of transvenous pacing in neonates, the value of permanent pacing in children with recurrent syncope or reflex anoxic seizures and the role of implantable cardioverter defibrillator devices are highlighted with relevant case histories.