Desmopressin in nonsevere hemophilia A:patient perspectives on use and efficacy

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients’ views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged &lt;12 years. Results: In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0–88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients’ self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion: Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.</p

Joint disease in haemophilia : Pathophysiology, pain and imaging

Haemarthroses cause major morbidity in patients with haemophilia. Blood has devastating effects on all joint components, resulting in synovitis, osteochondral degeneration and ultimately end-stage haemophilic arthropathy. Key players in this process are iron and inflammation. Preventing joint bleeds is of utmost importance to maintain joint health as targeted therapies directed against blood-induced inflammation and iron-mediated processes are lacking. Joint bleeds result in acute pain as well as chronic pain due to synovitis or arthropathy. Acute pain originates from nociceptors activated by tissue damage. In chronic inflammation, central and peripheral sensitization of nociceptors might occur resulting in chronic pain. This also triggers a series of brain disorders such as emotional fear, anxiety, mood depression and impairment of cognitive functions. Treatment of haemophilia-related pain not only consists of analgesics, but also of exercise, education and in selected cases antidepressants and anticonvulsants. For objective assessment of joint structural outcome and detecting earlier changes of haemophilic arthropathy, both ultrasound (US) and magnetic resonance (MR) imaging have shown valuable. Both can be considered equally able to reveal signs of disease activity. MR imaging is able to visualize haemosiderin deposition and is more comprehensive in depicting osteochondral changes. Disadvantages of MR imaging are the duration of the examination, evaluation of a single joint at a time, costs and may require sedation, and it may need intraarticular contrast injection to depict initial osteochondral changes with accuracy. As such, US is a more useful screening tool and can be used for repeated follow-up examinations

Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease

Background: Patients with moderate hemophilia express varying bleeding phenotypes. Objectives: To assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile. Methods: This sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B. Patient characteristics and information on bleeding tendency, joint status, and quality of life were obtained from electronic patient files and self-reported questionnaires. A severe bleeding phenotype was defined as an annual bleeding rate ≥5, an annual joint bleeding rate ≥3, and/or the use of secondary/tertiary prophylaxis, and a mild phenotype vice versa. TG was measured with the Nijmegen Hemostasis Assay. Results: This study included 116 patients: 21% had a severe phenotype of whom 46% used prophylaxis. Patients with a severe phenotype treated on demand reported a higher median annual bleeding rate (7), annual joint bleeding rate (3), and more frequently an impaired joint (77%) than patients with a severe phenotype on prophylaxis (2; 0; 70%) or patients with a mild phenotype (0; 0; 47%). Furthermore, patients with a severe phenotype treated on demand experienced a more decreased quality of life. Despite similar factor activity levels, patients with a severe phenotype had a lower thrombin peak height and thrombin potential (0.7%; 0.06%) than patients with a mild phenotype (21.3%; 46.8%). Conclusion: Patients with moderate hemophilia and a severe phenotype treated on demand displayed a high burden of disease as well as a low thrombin generation profile advocating them toward more intensive prophylactic treatment.</p

In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype

Background: Heterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding. Objectives: The objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia. Methods: The Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis. Results: In total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively. Conclusion: A decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity

Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands

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 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

Search for Majorana neutrinos in same-sign WW scattering events from pp collisions at s√=13 TeV

A search for Majorana neutrinos in same-sign WW scattering events is presented. The analysis uses s√=13 TeV proton–proton collision data with an integrated luminosity of 140 fb−1 recorded during 2015–2018 by the ATLAS detector at the Large Hadron Collider. The analysis targets final states including exactly two same-sign muons and at least two hadronic jets well separated in rapidity. The modelling of the main backgrounds, from Standard Model same-sign WW scattering and WZ production, is constrained with data in dedicated signal-depleted control regions. The distribution of the transverse momentum of the second-hardest muon is used to search for signals originating from a heavy Majorana neutrino with a mass between 50 GeV and 20 TeV. No significant excess is observed over the background expectation. The results are interpreted in a benchmark scenario of the Phenomenological Type-I Seesaw model. In addition, the sensitivity to the Weinberg operator is investigated. Upper limits at the 95% confidence level are placed on the squared muon-neutrino–heavy-neutrino mass-mixing matrix element |VμN|2 as a function of the heavy Majorana neutrino’s mass mN, and on the effective μμ Majorana neutrino mass |mμμ|

Measurement of inclusive jet and dijet cross sections in proton-proton collisions at 7 TeV centre-of-mass energy with the ATLAS detector

Jet cross sections have been measured for the first time in proton-proton collisions at a centre-of-mass energy of 7 TeV using the ATLAS detector. The measurement uses an integrated luminosity of 17 nb−1 recorded at the Large Hadron Collider. The anti-k t algorithm is used to identify jets, with two jet resolution parameters, R=0.4 and 0.6. The dominant uncertainty comes from the jet energy scale, which is determined to within 7% for central jets above 60 GeV transverse momentum. Inclusive single-jet differential cross sections are presented as functions of jet transverse momentum and rapidity. Dijet cross sections are presented as functions of dijet mass and the angular variable χ. The results are compared to expectations based on next-to-leading-order QCD, which agree with the data, providing a validation of the theory in a new kinematic regime