Hemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these... Show moreHemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these changes on current clinical outcomes is unknown.Therefore, we comprehensively assessed the changes in health status over time of patients with hemophilia using observational study data. Our results show that clinical outcomes of these patients have improved tremendously over the past decades. The annual bleeding rate and the proportion of patients with joint impairment have decreased strongly. In addition, HCV has almost been eradicated among patients with hemophilia in the Netherlands. As a result, life expectancy has increased to where it is almost equal to that of the general population.Although clinical outcomes have improved in many ways, inhibitor development continues to be a significant problem in patients treated with clotting factor products. Therefore, using three different study approaches, we also evaluated several methods to better predict the risk of inhibitor development (which is still a significant complication of treatment with FVIII). The results of these studies are promising and could be used to improve current inhibitor prediction strategies and inform future research on this topic. Show less
Hassan, S.; Ramspek, C.L.; Ferrari, B.; Diepen, M. van; Rossio, R.; Knevel, R.; ... ; COVID-19 Network Working Grp 2022
Background and objectives Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the... Show moreBackground and objectives Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population. Methods Dutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0. Results Data from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10). Conclusion Socioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced. Show less
Hassan, S.; Ferrari, B.; Rossio, R.; Mura, V. la; Artoni, A.; Gualtierotti, R.; ... ; COVID-19 Network Working Grp 2022
Background The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating... Show moreBackground The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources. Aims The primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality. Methods This was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell's C-index and model calibration was assessed using a calibration plot. Results Out of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot. Conclusion The predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance. Show less
Introduction: Persons with hemophilia and hepatitis C virus (HCV) infection have a lower health-related quality of life (HRQoL) than those never HCV infected. However, it is unknown whether HRQoL... Show moreIntroduction: Persons with hemophilia and hepatitis C virus (HCV) infection have a lower health-related quality of life (HRQoL) than those never HCV infected. However, it is unknown whether HRQoL after HCV eradication is comparable to individuals never HCV infected. We aimed to compare HRQol. between HCV-cured and never chronically HCV-infected persons with hemophilia.Methods: All persons with hemophilia in the Netherlands were invited for a nationwide study conducted in 2018-2019. For the current analysis, participants born before 1992 with data on HRQoL and HCV status were included. HCV status was collected from medical records. HRQoL was measured by RAND-36 questionnaire, with a minimally important difference set at 4.0 points. Multivariable linear regression was used to adjust for age, hemophilia severity, HIV status, and self-reported joint impairment.Results: In total, 486 persons were eligible; 180 were HCV cured and 306 never chronically HCV infected. Compared with those never HCV infected, HCV-cured individuals were older (57 vs. 53 years), more often had severe hemophilia (67% vs. 21%), and reported more impaired joints (median 3 vs. 0). Compared with those never HCV infected, adjusted RAND-36 domain scores of HCV-cured individuals cured were lower on all RAND-36 domains except Pain, ranging from a difference of 4.5 (95% CI, -8.8 to -0.3) for Physical functioning to 11.3 (95% CI, -19.4 to -3.1) for Role limitations due to physical problems.Conclusion: Despite effective HCV treatment, HRQoL of HCV-cured persons with hemophilia is still lower than HRQoL of those never chronically HCV-infected on all RAND-36 domains. This implies that careful psychosocial follow-up and support are indicated. Show less
Background The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in... Show moreBackground The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in persons with hemophilia. Objective To validate the Dutch-Flemish version of the PROMIS-29 Profile v2.01 in adults with hemophilia. Methods Dutch males with hemophilia (all severities) completed questionnaires that contained sociodemographic and clinical characteristics, the PROMIS-29, RAND-36, and the Hemophilia Activities List (HAL). Structural validity of each subscale was assessed with confirmatory factor analysis (CFA). Internal consistency was calculated for each subscale with sufficient model fit in CFA. Construct validity was assessed by testing hypotheses about (1) correlations of each PROMIS-29 subscale with corresponding scales of RAND-36 and domains of HAL, and (2) mean differences in T-scores between subgroups with different hemophilia severities, self-reported joint impairment, and HIV infection status. We considered >= 75% of data in accordance with the hypotheses evidence for construct validity. Results In total, 770 persons with hemophilia participated in this cross-sectional study. CFA revealed sufficient structural validity for five subscales: Physical Function, Depression, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Internal consistency was high and Cronbach's alpha ranged from 0.79 for Sleep Disturbance to 0.96 for Pain Interference. Differences between clinical subgroups were in the expected direction. Construct validity was confirmed for Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Intensity. Conclusion This study revealed sufficient evidence for structural validity, internal consistency, and construct validity for most PROMIS Profile-29 subscales among people with hemophilia in the Netherlands. Show less
Introduction Although sports participation is advocated in people with haemophilia (PWH), detailed data concerning sports participation in Dutch PWH is lacking.Aim to assess sports participation in... Show moreIntroduction Although sports participation is advocated in people with haemophilia (PWH), detailed data concerning sports participation in Dutch PWH is lacking.Aim to assess sports participation in Dutch PWH (6-65 years) compared to the Dutch general population (GP).Methods Data from a nationwide, cross-sectional study in PWH were analysed. Sports participation (type, duration, frequency) was assessed by the Modifiable Activities Questionnaire (MAQ), limitations in activities using the (Paediatric) Haemophilia Activities List ((Ped)HAL). Sports in the two highest categories according to the National Hemophilia Foundation classification were considered high-risk sports. Groups were compared using Chi-square testing.Results A total of 524 Adult PWH (median age: 45 (IQR: 30-55); 37% severe) and 126 paediatric PWH (median age: 11 (IQR: 8-14); 52% severe) were included. Sports participation was higher in adults (70%) than the GP (58%) and similar to the GP in children (PWH: 68%, GP: 72%). High-risk sports participation decreased with age in PWH: from 65% (6-12 years) to 17% (50-65 years), which was also observed in the GP. Sports participation in children was independent of severity (non-severe: 67% vs. severe: 65%; P = 0.97), but not in adults (non-severe: 75%, severe: 62%; P < 0.01). Non-severe PWH played more high-risk sports than severe PWH: children at 65% vs. 48% (P = 0.05), adults at 25% vs. 15% (P = 0.07).Discussion These results suggest that sports participation in PWH was comparable to the GP. Sports participation was dependent of haemophilia severity in adults. Children were more involved in high-risk sports than adults. More studies on sports-related injury-risk are needed for adequate counselling. Show less
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... Show moreObjectives: 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. Show less
Hassan, S.; Palla, R.; Valsecchi, C.; Garagiola, I.; El-Beshlawy, A.; Elalfy, M.; ... ; Peyvandi, F. 2019
