Search

Introduction: Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted., Aim: To examine the association between hypermobility-related disorders, vitamin C status and BDUC., Methods: Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score ≥ 10 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high-performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed., Results: The majority of patients were female (56/60). Median ISTH BAT score was 13 (range 10-23). Beighton score was positive in 29/60 patients compared to 1/20 healthy controls (HC) (p < .001). Hyperextensive skin was observed in (18/60) patients, and none (0/20) of the HC (p = .0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4 μmol/L; p = .001). Suboptimal, or low vitamin C were identified in 19/60 compared to 1/20 HC (p = .018)., Conclusion: Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient., Aim: To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care., Methods: The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS)., Results: The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R 2 .22) and EQ VAS score (B -.37, R 2 .17)., Conclusion: Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Purpose: In the past decades, haemophilia treatment has greatly improved the health of persons with haemophilia (PWH). This study compares PWH to the general population on social conditions and health., Methods: In December 2021, all Danes with moderate or severe haemophilia A or B, or von Willebrands disease type 3 were invited to participate in an online self-report survey concerning sociodemographic factors, self-rated health, teeth status, chronic health conditions, symptoms and loneliness. This study compares responses from the 124 adult male PWH with responses from a male general population sample (N = 4849). Analyses used logistic regression, controlling for age and highest completed education., Results: Fewer PWH were in the oldest age group (65-84 years). Controlling for age, no significant differences were found regarding cohabitation status or education. Fewer PWH were employed (OR = .48, [.33-.71])-particularly in the 45-64 age group. PWH were less likely to report good health (OR = .49, [.31-.77]). The odds of joint disease was much higher (OR = 13.00, [8.37-20.28]). Also, hypertension (OR = 2.25, [1.13-5.65]) and previous stroke (OR = 2.51, [1.44-3.50]) were more frequent. PWH were more likely to report pain in the arms/hands/legs/hips (OR = 2.94, [1.92-4.52]), but less likely to report pain in the head/neck/shoulder (OR = .66, [.45-.96])., Conclusion: The disease burden of haemophilia has improved so PWH resembles the general population in areas such as marriage and education. However, even for young PWH, the disease still imposes a significant burden from hemophilia arthropathy and pain in extremities and joints. Middle-aged PWH also have poorer levels of employment than same-aged peers., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life., Aim: To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130)., Methods: PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety., Results: There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed., Conclusions: Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL)., Aim: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment., Methods: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated., Results: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile., Conclusion: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher., Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors., Methods: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded., Results: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment., Conclusion: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA)., Aim: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA., Methods: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS)., Results: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low., Conclusion: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research., Aim: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations., Methods: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing., Results: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis., Conclusion: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB., (© 2020 John Wiley & Sons Ltd.)

Background: In a previous smaller study, we found evidence of a diminished global coagulation capacity after maximal exercise in patients with severe haemophilia A (HA)., Aim: To validate these results, we repeated the study in a larger cohort. We also examined if the exercise-induced increased levels of von Willebrand factor (VWF) might prolong the effect of factor concentrate administered just before exercise., Methods: We studied individual and global coagulation parameters after maximal physical exercise in 10 persons with severe HA and 10 healthy matched control subjects. Blood samples were taken before, 10 minutes, 60 minutes and 4 hours after exercise., Results: Rotational thromboelastometry (ROTEM) and thrombin generation assay-calibrated automated thrombogram (TGA-CAT) showed significantly increased coagulation capacity after maximal exercise in healthy controls but not in patients with severe HA. VWF antigen and activity levels increased significantly in both groups, whereas FVIII:C only showed a significant increase in the control group. No statistically significant differences were seen between FVIII pharmacokinetic results obtained with and without exercise., Conclusion: Our findings do not support the presence of a FVIII-independent mechanism that increases global coagulation, but rather underscores the importance of FVIII in mediating the increased coagulation capacity seen after exercise. Our results could not support the hypothesis that exercise-induced increased levels of VWF for patients with severe HA lead to a prolonged effect of factor concentrate administered just before exercise., (© 2019 John Wiley & Sons Ltd.)