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Objective: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care., Study Design: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurologic examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills., Results: Five hundred and fifty-one males with hemophilia A (n = 433) or B (n = 101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n = 64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population., Conclusions: In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlight the importance of screening and intervention for challenges with cognitive and adaptive skills in this population., Clinical Trial Registration: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK); NCT03660774; https://clinicaltrials.gov/ct2/show/NCT03660774., Competing Interests: Declaration of Competing Interest CM is a consultant for Novo Nordisk, coauthor of the eTHINK and paradigm study protocols, and site co-PI of the eTHINK study and has served as a speaker for Otsuka Pharmaceutical. KSW is a consultant for Novo Nordisk, coauthor of the eTHINK and paradigm study protocols, a site PI of the eTHINK study, and a consultant for AstraZeneca, Alexion, SpringWorks, and DayOne Biopharmaceuticals. CBB was a site PI of the eTHINK study and has received consultant fees from Novo Nordisk. SEC is a site PI of the eTHINK study and a consultant for Bayer, CSL Behring, Genentech, Octapharma, and Shire and has received research funding from Genentech, Pfizer, Novo Nordisk, Spark Therapeutics, and ATHN/Hemophilia of Georgia Research. AM and MG are full-time employees of Novo Nordisk. CH is a consultant for Novo Nordisk and participated in the eTHINK study. MR has received research grants from Pfizer, Bristol-Myers Squibb, and Novo Nordisk (for clinical studies) and is a consultant for Novo Nordisk. KAS has received fees as a consultant for Novo Nordisk. GNW has received fees as a consultant for Novo Nordisk. PV is a full-time employee of Cogstate. DLC was an employee of Novo Nordisk at the time of the conception of the eTHINK study and data collections. The eTHINK study was funded by Novo Nordisk A/S, Bagsværd, Denmark., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Case: A 29-year-old man with hemophilia B presented with advanced arthropathy of the right knee, resulting in poor knee functional scores and difficulties in his livelihood. The patient underwent total knee replacement while receiving nonacog beta pegol factor IX by a multidisciplinary approach., Conclusion: Hemophilias commonly result in end-stage hemophilic arthropathy of the joints at a young age that may warrant joint replacement surgeries. This case report illustrates the surgical protocol of total knee arthroplasty in a patient who received a long-acting factor IX preparation., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C405)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Congenital hemophilia B is a rare X-linked recessive bleeding disorder caused by factor IX deficiency. Acquired hemophilia A is a rare, acquired bleeding disorder that presents with new-onset bleeding, especially in older adults, due to the development of auto-antibodies against factor VIII (FVIII). This case report presents the medical management of a patient with congenital hemophilia B and acquired hemophilia A. We highlight the limitations of maintaining factor levels with factor replacement therapy alone, particularly in hemophilia patients who have developed factor inhibitors. In addition, we draw attention to the need for dose escalation, the cost, and the need for immune-tolerance induction therapy. This case illustrates that when the current diagnosis does not explain the full clinical picture and laboratory data are inadequate, it is important to continue to seek alternative diagnoses and cost-effective treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Predicting the bleeding risk in hemophilia A and B carriers (HAC, HBC) is challenging., Objective: The objectives of this study were to describe the bleeding phenotype in HAC and HBC using the standardized Tosetto bleeding score (BS); to determine whether the BS correlates better with factor levels measured with a chromogenic assay than with factor levels measured with chronometric and thrombin generation assays; and to compare the results in HAC and HBC., Methods: This ambispective, noninterventional study included obligate and sporadic HAC and HBC followed at a hemophilia treatment center between 1995 and 2019., Results and Conclusion: The median BS (3, range 0-21 vs. 3.5, range 0-15, P  = ns, respectively) and the abnormal BS rate (35.6% vs. 38.2%, P  = ns) were not significantly different in 104 HAC and 34 HBC (mean age: 38 years, 6-80 years). However, some differences were identified. The risk of factor deficiency was higher in HBC than HAC. Specifically, Factor VIII activity (FVIII):C/Factor IX activity (FIX):C level was low (<40 IU/dl) in 18.3% (chronometric assay) and 17.5% (chromogenic assay) of HAC and in 47% and 72.2% of HBC ( P  < 0.001). Moreover, the FIX:C level thresholds of 39.5 IU/dl (chronometric assay) and of 33.5 IU/dl (chromogenic assay) were associated with very good sensitivity (92% and 100%, respectively) and specificity (80% for both) for bleeding risk prediction in HBC. Conversely, no FVIII:C level threshold could be identified for HAC, probably due to FVIII:C level variations throughout life., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients' quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Abstract: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level., Aim: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency., Methods: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT)., Results: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR., Conclusion: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objectives: To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective., Study Design: Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019., Methods: Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group., Results: There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs., Conclusions: This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

Background: Venous thromboembolism (VTE) is a well-recognized complication after total joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies, and administering pharmacologic thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk., Objectives: To analyze best available evidences of VTE rates in persons with hemophilia A or B undergoing lower limb TJR and the use of postoperative pharmacologic thromboprophylaxis., Methods: We systematically screened 4 online biomedical databases to identify studies reporting VTE rates in patients with hemophilia after TJR. Case reports and case series with less than 10 patients were excluded., Results: Twenty-six observational studies were included in this systematic review, reporting 1181 TJRs in patients with hemophilia A or B. Eight studies had VTE rates as the primary outcome. Five studies reported screen-detected VTE, while 21 reported symptomatic VTE events. Overall, 17 VTE events were reported (1.4%; 95% CI, 0.9%-2.3%), including 10 (6.6%) after 151 surgeries with postoperative VTE screening and 7 (0.7%) after 1080 surgeries without postoperative screening. Thromboprophylaxis protocols were specified in 21 studies; postoperative thromboprophylaxis was used in 15 (1.3%) surgeries. This information was not available for 29.0% of the analyzed population., Conclusion: Despite the low thromboprophylaxis use in patients with hemophilia, rates of symptomatic VTE after TJR appeared to be low. We also highlighted the need to better report the thrombotic outcome in persons with hemophilia to face the ongoing changes in the hemophilia landscape., Competing Interests: Declaration of competing interests D.S., A.A., and M.P. have no competing interests to disclose. I.P. reports honoraria for lectures and/or advisory board meetings from Bayer, CSL Behring, Roche, Sobi, and Takeda, and unrestricted Grants to the Medical University of Vienna from Biotest, CSL Behring, Sobi, and Roche Diagnostics. F.D. received grants and personal fees for lectures and consultancy from Bayer, Pfizer, Astra Zeneca, Sanofi, and Boehringer. A.S. reports honoraria for lectures, manuscript writing, and/or advisory board from Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Boehringer-Ingelheim, Sanofi, Werfen, Alexion, Roche, and Viatris. A.T. received grants and personal fees for lectures and consultancy from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. W.A. received research support from Bayer and serves on advisory boards for Astra Zeneca, Bayer, BMS-Pfizer, Norgine, Sanofi, Techdow, and Viatris. C.A. received honoraria for lectures and/or participation in advisory boards from CSL Behring, Sobi, LFP, Roche, Biotest, BioMarin, Bayer, Pfizer, Novo Nordisk, and Takeda., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: Haemophilia is one of the commonest inherited bleeding disorders which may lead to long term disabilities if not treated properly. Our aim of study is to understand the clinical characteristic, treatment and complications of adult haemophilia patients in our centre., Materials and Methods: A retrospective cross-sectional review of all adult haemophilia A (HA) or haemophilia B (HB) patients who received treatment in Hospital Pulau Pinang from January 2021 to December 2022 was conducted. Data was retrieved from patients' medical records., Results: A total of 75 haemophilia patients (64 HA and 11 HB) were included in this study with median age of 37 years (range 19 70). 42 of them had severe haemophilia (50% of HA, 91% of HB). All HB and 93.8% of severe HA patients were on prophylaxis. Six severe and one mild HA patients developed inhibitor with four of them currently on non-factor prophylaxis. 24 patients (32%) had prior hepatitis C infection and all of them have been successfully treated. The mean annual bleeding rate for severe haemophilia patients were 1.77 (SD ±3.6). Target joints were observed in 9.3% of patients with ankle joint (71.4%) being the most affected joint. More than one quarter (26.7%) of our patients have comorbidities with majority of them having hypertension (17/20), followed by diabetes mellitus (5/20) and ischemic heart disease (5/20)., Conclusion: Our study showed that a significant number of adult patients with haemophilia have comorbidities. Apart from optimising factor replacement therapy, future planning should include improvement in screening, risk modification and prevention of cardiovascular disease.

Introduction: Prophylactic treatment of hemophilia B with recombinant factor IX (rFIX) molecules with enhanced pharmacokinetics including rIX-FP (albutrepenonacog alfa; Idelvion © ) and rFIXFc (eftrenonacog alfa; Alprolix © ) have commonly been used in the clinic. In the absence of head-to-head comparative trials, the aim of this study was to estimate the efficacy of rIX-FP versus rFIXFc using matching-adjusted indirect comparisons (MAICs)., Methods: MAIC analyses leveraged individual patient data from the PROLONG-9FP trial and published summary-level data from the B-LONG trial for subjects who received weekly prophylaxis regimens. Individual patient data were used to assign weights and balance subjects from PROLONG-9FP with subjects from B-LONG on baseline disease severity, age, prior FIX regimen, and body mass index (BMI). Six efficacy outcomes were analyzed including annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR), and the proportion of subjects without bleeding events (for total, spontaneous, and joint bleeding events)., Results: After adjustment for baseline disease severity, age, prior FIX regimen, and BMI, rIX-FP was associated with a statistically significant decrease in AsBR (rate ratio [RR] 0.42; 95% confidence interval [CI] 0.22, 0.82; P = 0.0107), and the proportion of patients without bleeding events (odds ratio [OR] 3.24; 95% CI 1.41, 7.45; P = 0.0057), spontaneous bleeding events (OR 3.47; 95% CI 1.56, 7.73; P = 0.0023), and joint bleeding events (OR 2.41; 95% CI 1.10, 5.26; P = 0.0274) compared with rFIXFc. Prophylactic treatment with rIX-FP was also associated with a numerically lower ABR (RR 0.75; 95% CI 0.32, 1.75; P = 0.5095) and AjBR (RR 0.82; 95% CI 0.37, 1.82; P = 0.6178)., Conclusion: The MAICs demonstrated that weekly prophylaxis treatment of severe hemophilia B with rIX-FP resulted in favorable efficacy outcomes as compared to rFIXFc. These findings suggest rIX-FP may offer improved clinical benefits over rFIXFc., (© 2024. The Author(s).)

Background: Regular prophylaxis with activated prothrombin complex concentrates (aPCCs) is effective in adult patients with hemophilia with inhibitors; however, data in children are scarce., Methods: This was a single-center retrospective study at Saitama Children's Medical Center. Patients with severe and moderate hemophilia with inhibitors aged <15 years at the start of aPCCs prophylaxis were included. Medical records were retrospectively reviewed., Results: We treated nine pediatric patients with hemophilia with inhibitors (median age, 1.9 years; age range, 1.3-12.9 years; inhibitor titers before treatment with aPCCs, 5.9-69 BU/mL) using prophylactic aPCCs (doses, 50-100 U/kg; 2-3 times/week). The median prophylactic period was 13 months (range: 5-31 months). The median annualized bleeding rate (ABR) during prophylactic treatment with aPCCs was 2 (range, 0-17). In four patients, ABR was reduced by 19%-100% with prophylactic aPCCs compared to on-demand aPCCs. An adverse effect of treatment was that a patient with hemophilia B developed nephrotic syndrome 34 months after starting regular prophylaxis with aPCCs., Conclusions: Regular prophylactic aPCCs reduced the ABR even in younger children with hemophilia A and B. Serious adverse events include nephrotic syndrome, which requires caution., (© 2024 Japan Pediatric Society.)

Standard FIX prophylaxis for PWHB require frequent injections, which has led to the development of extended half-life products like rIX-FP (albutrepenonacog alfa) that has shown good efficacy in clinical studies. This ambispective study aims to report a real-world experience with rIX-FP in a Spanish centre with PWHB who switched from SHL-FIX or began prophylaxis with rIX-FP. Five PWHB were included in this study, Four PTP switched to rIX-FP with prophylaxis every 7 days whilst one PUP started with an every-14-days regimen. 3 PTPs extended their dosing intervals to every 14 days or every 21 days. In all PTPs, median annualized spontaneous and joint bleeding rates were maintained at 0.00 and median (range) of ABR was 0.92 (0.00-2.77) after switch to rIX-FP. Mean trough level with previous product was 3.68% ( SD  = 2.06), while it was 7.08% ( SD  = 3) with all rIX-FP dosing intervals. After switching to rIX-FP, all PTP reduced their annual infusion rate between 50 and 84% and their annual FIX consumption by 61% (59-67%). This is the first reported real-world experience with albutrepenonacog alfa in a small cohort in Spain and demonstrates good bleeding control together with a reduction of the infusion rate, factor consumption and higher through factor level than previous treatment.

Background: Arthropathy is a common complication in patients with hemophilia. We examined the prevalence of this skeletal complication in patients with hemophilia who were registered at a Comprehensive Hemophilia Center in Shiraz, Southern Iran., Materials and Methods: In this cross-sectional study, an orthopedic specialist visited 448 patients and conducted screenings for skeletal complications. The assessment included evaluating the type of hemophilia, disease severity, treatment modality, the presence of inhibitors, and the identification of skeletal complications., Results: Ninety patients with hemophilia A, with a mean age (SD) of 31.6 (14.4) years, and 10 patients with hemophilia B, with a mean age of 30.5 (20.6) years, were assessed. The most frequently affected joints were the knee and ankle joints. In the univariate analysis, patients with severe disease were more likely to exhibit synovitis, a target joint, and bone disease compared to patients with non-severe disease. Additionally, a history of treated or active hepatitis and an annual bleeding rate showed significant associations with the target joint. In the multivariable logistic regression analysis, disease severity (OR 14.43, 95% CI 1.6-129.6) and a higher age at diagnosis (OR 1.06, 95% CI 1.00-1.13) increased the likelihood of developing osteoporosis. A history of hepatitis (OR 3.67, 95% CI 1.28-10.48) was identified as an independent risk factor for the target joint., Conclusion: Skeletal complications are a common occurrence in hemophilia. Regular consultations with orthopedic specialists, focusing on bleeding control and hepatitis prevention, are essential for reducing the impact of this debilitating complication., (© 2023. The Author(s).)

Introduction: Hemophilia A and B are disorders associated with the deficit of coagulation factors VIII and IX., Objective: Was to determine the incidence of complications in a cohort of patients diagnosed with moderate and severe hemophilia A or B under treatment in a specialized institution., Methods: A retrospective study of a cohort of patients with replacement therapy for hemophilia A or B, evaluating treatment and complications between January/2012 and July/2019. Sociodemographic, clinical and disease management-related variables were extracted from the medical records. Time to inhibitor development and rate associated with bleeding and hospitalizations were evaluated., Results: A total of 159 male patients were identified with hemophilia A (n = 140; 88.1%) and B (n = 19; 11.9%) with a mean follow-up of 5.9±2.3 years. The mean age was 23.6±16.1 years, hemophilia was reported as severe in 125 patients in hemophilia A (89.3%) and 13 patients in hemophilia B (68.4%). Primary prophylaxis was registered in 17.0% of patients, 44.7% secondary, and 38.3% tertiary, with recombinant factors (n = 84; 52.8%) followed by plasma derived factors (n = 75; 47.2%). The incidence of inhibitor development was 0.3 per 100 patients/year, with mean time to event of 509 days. The incidence of bleeding was 192 per 100 patients/year, especially at the joint (n = 99; 62.3%) and muscle (n = 25; 15.7%) level. The incidence of hospitalization was 3.7 per 100 patients/year., Conclusions: The most common complication was joint bleeding which was expected in this type of patients. Low proportion of patients developed factor inhibitors during the follow up., Competing Interests: yes: Reyes JM, Lourdes M and Castano N are paid employees of Pfizer Colombia. Juan David Wilches-Gutierrez, Diana Rocio Arias-Osorio are paid employees of IPS-Especializada. Andres Gaviria-Mendoza, Natalia Castaño-Gamboa, Luis Fernando Valladales-Restrepo, Manuel E. Machado-Duque and Jorge Machado-Alba are paid employees of Audifarma SA. Harrison David Ospina-Arzuaga do not have any conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Machado Alba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Haemophilia B is a rare inherited bleeding disorder in which patients have impaired coagulation. This study describes a patient with Haemophilia B and paroxysmal supraventricular tachycardia (PSVT) who underwent radio frequency catheter ablation (RFCA). The perioperative replacement therapy with coagulation factor IX (FIX) was agreed upon after an interdisciplinary consultation involving a team of specialists in haematology, cardiovascular medicine and cardiothoracic surgery. There were no obvious bleeding points or complications during the perioperative period following the treatment, nor recurrence of PSVT within a three-year follow-up period. In summary, RFCA can be performed safely in patients with haemophilia B on the premise of developing an individualized perioperative exogenous coagulation factor supplementation regimen based upon an adequate preoperative evaluation and clinical monitoring and management by an interdisciplinary team., Competing Interests: Declaration of conflicting interestsThe authors declare that there are no conflicts of interest.

Introduction: Extended half-life (EHL) factor VIII and IX concentrates as prophylaxis against bleeds have been available to selected persons with haemophilia (PWH) in Australia since March 2018. Preliminary analysis of switching to EHL demonstrated increased treatment adherence, fewer injections and improved bleeding outcomes., Aims: To characterise clinical practices regarding the use of EHL in Australia, to further evaluate treatment regimens and bleeding outcomes, and to analyse the influence of EHL product pharmacokinetics on clinical decision-making., Methods: A national, retrospective study was conducted using the Australian Bleeding Disorders Registry (ABDR). Patients on EHL products during the entire 2019 calendar year were included for analysis., Results: A complete and validated dataset of 174 PWH was analysed, 115 Haemophilia A (HA) and 59 Haemophilia B (HB). Adherence to EHL therapy was 85.7% in HA and 87.2% in HB. About 63.5% of HA and 64.4% of HB PWH reported zero spontaneous bleeds over 12months. Ankles were the most frequent spontaneous bleed site. Approximately one-third patients underwent dose adjustments, with most frequent reasons being pharmacokinetics, body weight change and breakthrough bleeds. About 19.5% of PWH had target joint history, with spontaneous bleeds reported in 58% of that cohort on EHL. Multivariate regression showed significant impact of non-adherence, target joint history and short half-life on spontaneous bleeds in the HA cohort; however only short half-life had significant impact in the HB cohort., Conclusion: EHL usage in Australia shows excellent treatment adherence and bleeding outcomes. This study affirms the use and value of widely available population-based pharmacokinetics as a clinical tool., (© 2023 John Wiley & Sons Ltd.)

Objective: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes., Methods: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period., Results: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study., Conclusion: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors., Aims: To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage., Methods: A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS., Results: 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs., Conclusion: This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed., (© 2023 John Wiley & Sons Ltd.)

Introduction: Bypassing agents (BPAs) are used to treat acute bleeding episodes, manage bleeding during perioperative care, and prophylactically minimize bleed occurrence in persons with hemophilia A or B with inhibitors (PwHABI). However, the effectiveness of BPAs that have been prescribed for the last several decades can be variable, motivating the development of a new recombinant activated factor VII, eptacog beta., Areas Covered: This review covers key eptacog beta findings from phase 1b and phase 3 (PERSEPT) clinical trials, which formed the basis for its regulatory approval to treat PwHABI ages 12 and older. Descriptions of eptacog beta structure and glycosylation profile, mechanism of action, preclinical study results, and cost analyses are also presented., Expert Opinion: PwHABI have had only two options for bleed treatment for the past several decades. With its distinct glycosylation profile, eptacog beta offers a novel therapy aiming to improve upon BPAs currently in use, providing an option with more than one dosing regimen and a rapid response that allows most bleeds to be treated with just one dose. This has become particularly important given the use of subcutaneous medications (e.g., emicizumab) for prophylaxis of bleeding. Clinicians should consider eptacog beta as a BPA for all PwHABI.

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.)

Background: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia., Objectives: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors., Methods: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment., Results: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037)., Conclusion: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

The purpose of prophylaxis in hemophilic patients is to prevent bleeding. The latest guidelines of the World Hemophilia Federation recommend that all patients with a severe hemorrhagic phenotype should receive prophylactic treatment, defined as the regular administration of therapeutic products (either factor concentrates or nonfactor replacement treatments). These products are aimed at preserving hemostasis and preventing bleeding, especially into joints. The guidelines also stipulate that prophylaxis should allow patients with hemophilia to lead healthy and active lives, participating in most physical and social activities, similar to the nonhemophilic population., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.

Introduction: The World Haemophilia Federation advises regular musculoskeletal assessment covering all International Classification of Functioning and Health (ICF) domains, including limitations in activities and participation in persons with haemophilia (PWH). This enables clinicians to detect changes early and enable adjustments in personalized healthcare when needed. However, data on the course of physical functioning and occurrence of decline is lacking. The aim of this study is to describe changes in perceived limitations in activities of PWH and to identify factors associated with a change., Methods: Data were collected from medical health records of regular check-up visits of adults with moderate and severe haemophilia in two time periods. Perceived limitations in activities was measured with the Haemophilia Activities List (HAL). Association between variables (e.g., age, body mass index, bleeding rate and synovitis) and change in perceived limitations was assessed using a generalized linear model., Results: A total of 104 PWH were included. At T0, the median HAL sum score was 79.5 (IQR 62.1-93.6) and at T1 the median HAL sum score was 74.2 (IQR 57.5-88.3). A functional decline was found in 35.6% of PWH, 55.8% remained stable and 8.7% improved. Among other variables, a BMI > 30 kg/m 2 appeared to be an important factor that negatively influenced the change in perceived functioning in adult PWH. With the included factors we could only explain a small part of this decline (R 2 adj : .12)., Conclusion: The majority of PWH remained stable in their perceived functional ability over mid-long term (median 3.5 years). However, about a third showed a clinical relevant decline in their functional ability., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences., Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function., Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters., Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed., Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors., Methods: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete., Findings: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported., Interpretation: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia., Funding: Sanofi., Competing Interests: Declaration of interests AS is a member of advisory boards and grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and has received research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. SR has received honoraria for consulting from Reliance Life Sciences; participated in a speakers bureau for Takeda; and has been a member of advisory boards for Pfizer, Sanofi, and Sigilon Therapeutics. KK has received honoraria from and attended speakers bureaus for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk and is on advisory committees for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk. RK has received research funding from Bayer and LEO Pharma; received honoraria from Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda; and attended speakers bureaus for Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda. GK consults for Alnylam Pharmaceuticals, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure; has received research funding from Alnylam, Bayer, Bio Products Laboratory, OPKO Biologics, Pfizer, Roche, and Takeda; has attended speakers bureaus for Bayer, Pfizer, CSL Behring, Shire Pharmaceuticals, Novo Nordisk, and Roche; and is on advisory committees for Alnylam, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure. LK has received research funding from Roche and honoraria from Sanofi, Novo Nordisk, and Roche; has participated in speakers bureaus for Roche, Sanofi, Novo Nordisk, and Takeda; and is on advisory committees for Roche, Sanofi, and Novo Nordisk. C-YC has received research funding from Bayer and Sanofi and honoraria from Bayer, Sanofi, Novo Nordisk, Takeda, Chugai Pharmaceutical, and Pfizer; and has participated in advisory boards for Sanofi, Novo Nordisk, Bayer, and Chugai Pharmaceutical. NM has received research funding for clinical research yet to be conducted and is vice-chair of St Francis Hospice, South Africa. LF has received research funding from Pfizer, Roche, Sobi, and CSL Behring. OS has received research funding and honoraria from Novo Nordisk, Shire Pharmaceuticals, CSL Behring, Sanofi, Pfizer, and LFB and has participated in speaker bureaus for Novo Nordisk, Pfizer, Shire Pharmaceuticals, Octapharma and Roche. SP, ZQ, and SA are current employees of, and equity holders in, Sanofi. BM was an employee of and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is currently an employee of Editas Medicine. SWP has received consultancy fees from ApcinteX, ASC Therapeutics, Bayer, BioMarin Pharmaceutical, CSL Behring, GeneVentiv, HEMA Biologics, Freeline Therapeutics, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; has received research funding from Siemens; and is a member of a scientific advisory committee for GeneVentiv. C-WY, WX, and CNB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors., Methods: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102., Findings: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported., Interpretation: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia., Funding: Sanofi., Competing Interests: Declaration of interests GY reports grants from Genentech/Roche, Grifols, and Takeda; and speaking and consultancy fees from Apcintex, BioMarin, Genentech/Roche, Grifols, Hema Biologics/ Laboratoire français du Fractionnement et des Biotechnologies biomedicaments, Novo Nordisk, Pfizer, Rani, Sanofi, Spark, Takeda, and UniQure. AS reports membership on advisory committees or grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and reports research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. KK reports grants and consultancy fees from Novo Nordisk, Roche, and Takeda. JSa is the president of the Malaysian Society of Patient Blood Management. HT reports grants or honorarium from Sanofi, Takeda, Roche, and CSL Behring. SP, ZQ, and SK are employees and equity holders in Sanofi. BM was an employee and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is an employee of Editas Medicine. SA is an employee and equity holder in Sanofi, and a member of the WEST advisory committee. SR reports consultancy fees from Reliance Life Sciences; grants for conference attendance from Takeda; and fees for attendance at advisory board meetings from Pfizer, Sanofi, Sigilon, and Takeda. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Haemophilia B patients with factor IX inhibitors have particularly unmet needs for conventional therapy., Aim: Phase II/III clinical trial, multicentre, open-label, prospective, self-controlled study was conducted to assess MC710 prophylaxis in haemophilia B patients with inhibitors., Methods: We enrolled haemophilia patients who had received episodic or prophylactic treatment with bypassing agents up to that time. The participants continued their conventional therapy for 24 weeks and then MC710 was prophylactically infused intravenously every 2 or 3 days at 60 to 120 μg as FVIIa per kilogram of body weight for 24 weeks. The primary endpoint was the annual bleeding rate (ABR) requiring bypassing agents, which was compared intraindividually between the conventional therapy period and the MC710 prophylaxis period., Results: A total of 11 male haemophilia B patients were enrolled. The median ABR ratio for each participant (the prophylaxis period ABR divided by the conventional therapy period ABR) was .33 (2.1/6.5), range from .00 to 3.77. ABR ratios for 9 of the 11 patients ranged from .00 to .60, and 3 of the 9 patients had zero bleeding events during the prophylaxis period. Meanwhile, ABR ratios for the remaining two patients were 2.53 and 3.77, respectively. Although a fibrinogen decrease recovered by the dose reduction was reported for only one participant as the sole adverse drug reaction in this study, no thrombotic events or other safety concerns were reported., Conclusion: MC710 prophylaxis is considered to be decrease the bleeding rate in haemophilia B patients with inhibitors without safety concerns., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement., Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×10 13 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed., Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred., Conclusions: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life., Aim: To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making., Methods: A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life., Results: Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n = 609) and 29% (n = 668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n = 599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health., Conclusion: There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood., Aim: We evaluated the association between FEL and ABR in PwHB., Methods: This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR., Results: The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05)., Conclusion: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US., (© 2022 HCD Economics. Haemophilia published by John Wiley & Sons Ltd.)

Background: Pregnancy, peripartum management, and outcomes of mild hemophiliacs and hemophilia carriers in the United States are not well established., Aim: To describe the management and outcomes of mild hemophiliacs and hemophilia carriers during assisted conception, pregnancy, peripartum and post-partum period at our hemophilia treatment center (HTC)., Methods: Retrospective review of electronic medical records of pregnant women with mild hemophilia A or B (Factor VIII [FVIII] or Factor IX [FIX] level <0.4 IU/mL) and hemophilia A and B carriers followed at our HTC from January 2008 to October 2020. Demographics, the reason for diagnosis, FVIII and FIX levels at baseline and third trimester, bleeding phenotype and genotype were obtained. Method of conception, factor replacement, iron supplementation, mode of delivery, type of anesthesia, peripartum complications, and offspring outcomes was recorded., Results: There was a total of 18 pregnancies in 12 women (2 with mild hemophilia A, 2 mild hemophilia B, 6 hemophilia A carriers, and 2 hemophilia B carriers). Eleven pregnancies (61%) were conceived naturally and 7 (39%) via in-vitro fertilization (IVF). Eight (44.4%) and 10 (55.6%) pregnancies were vaginal and C-section deliveries, respectively. Neuraxial anesthesia was administered in 17 (94.4%) deliveries without complications. Four pregnancies (22.2%) had bleeding complications, 2 of which were post-partum hemorrhages not requiring transfusion., Conclusion: In our case series of pregnant hemophilia carriers and mild hemophiliacs, successful outcomes were achieved with a carefully detailed multidisciplinary-driven approach.

Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure-matching strategy with a wild-type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 μg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown., Aim: We investigated the relationship between hypertension/blood pressure and inhibitors in PWH. Additional goals were to determine the relationships with haemophilia type, race, and viral status., Methods: Records were extracted retrospectively for PWH (age ≥18 years) between 2003 and 2014 from four Hemophilia Treatment Centers in North America and included demographics, weight, height, haemophilia type/severity, HCV and HIV infection status, hypertension, use of anti-hypertensive medications, and inhibitor status. We fitted semiparametric generalized additive models (GAMs) to describe adjusted curves of blood pressure (BP) against age., Results: Among 691 PWH, 534 had haemophilia A and 157 had haemophilia B, with a median age of 39 years (range 18 to 79). Forty-four PWH (6.5%) had a history of inhibitors, without evidence for a higher prevalence of hypertension or higher BP. A higher prevalence of hypertension and higher BP were noted for haemophilia A (vs. haemophilia B), coinfection with HCV/HIV (vs. uninfected), or moderate haemophilia (vs. severe haemophilia)., Conclusion: While there was no signal to suggest that a history of inhibitors is associated with hypertension, differences based on haemophilia type, severity, and viral infection status were identified, encouraging prospective investigations to better delineate haemophilia-specific risk factors for hypertension., (© 2022 John Wiley & Sons Ltd.)

Background: Haemophilia A and B are X-linked recessive bleeding disorders resulting from a deficiency of factors VIII and IX, respectively. Early diagnosis and a comprehensive approach to management is mandatory. This study aimed to describe the profile of patients with haemophilia (PWH) managed at Dr George Mukhari Academic Hospital (DGMAH) with the view to identify potential areas to improve haemophilia care., Methods: A cross-sectional, descriptive study that retrospectively reviewed clinical and laboratory records of PWH managed at DGMAH haemophilia treatment centre from 01 January 2003 to 31 December 2017., Results: Forty-four males were identified, with the majority being adults (~61%). Haemophilia A patients (~82%) outnumbered those with haemophilia B (~18%). Spontaneous mucocutaneous bleeding was the most frequent presenting feature followed by haemarthrosis. Disease-related complications included joint complications and life-threatening bleeds. There was a delay in diagnosis in 11% PWH. Management included episodic plasma-derived factor replacement and bypassing agents for patients with inhibitors. Only 13% of PWH were on home therapy. Prevalence of inhibitor development was 18%. There was a paucity of recorded data regarding prophylaxis, genetic counselling, psychological and physiotherapy support., Conclusion: The majority of PWH were adults, and haemophilia A was more prevalent than haemophilia B. A delay in haemophilia diagnosis could be addressed by increasing the awareness of haemophilia in health facilities. Expanding home therapy and introducing prophylaxis will likely improve the quality of life in PWH. Study outputs have included compilation of diagnostic and management algorithms to optimise haemophilia care at DGMAH.

Hemophilia is a rare constitutional hemorrhagic disorder. There is insufficient epidemiological data on hemophilia in Tunisia. To describe the epidemiological, clinical, therapeutic, and outcome of a cohort of patients with hemophilia in southern Tunisia. A retrospective study was conducted on patients with hemophilia at the Hemophilia Treatment Center of Southern Tunisia in Sfax over 38 years (from January 1982 to December 2020). Data were collected in a regional hemophilia registry of the South Tunisian center. We collected 141 cases of hemophilia, 85% of whom had hemophilia A and 15% had hemophilia B. The severe form represented 65%, followed by the moderate form at 25%. The prevalence of hemophilia was 4.4 in 100 000 population. Family history of hemophilia was found in 70%. The mean age of patients at diagnosis was 28 months. Hemophilia was detected in 87% of cases after hemorrhagic syndrome. Bleeding occurred mainly in hemarthrosis (73%), hematoma (70%), and visceral bleeding (28%). Intracranial bleeding occurred in 6% of cases. Thirty-six percent of patients were on prophylactic therapy. Hemophilic arthropathy was the most important orthopedic complication in our patients (38%). Inhibitory antibodies occurred in 16% of PWH. Transfusion-transmitted infections with HIV and hepatitis C were in 2 and 31% of cases, respectively. The prevalence of hemophilia is still underestimated in our center. The severe form of hemophilia is the most frequent. Hemophilic arthropathy was the most important complication in our patients. This showed that hemophilia is still a disabling disease in our country., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patient adherence to a prophylactic regimen is important for optimal benefit of hemophilia treatment. Despite a growing number of adults with hemophilia in Poland receiving secondary prophylaxis, data on adherence to the regimen are limited., Objectives: The aim of the study was to assess adherence to secondary prophylaxis in Polish adults with severe hemophilia., Patients and Methods: Patients were recruited in 18 hemophilia treatment centers in Poland. Adherence to prophylaxis was assessed with the Validated Hemophilia Regimen Treatment Adherence Scale Prophylaxis (VERITAS‑Pro) questionnaire., Results: Data on 270 men on the prophylactic regimen (median [interquartile range, IQR] age, 37 [18-75] years; mean [SD], 38.2 [13.3] years) were analyzed. Median (IQR) VERITAS‑Pro score for the study population was 36 (24-76) years; mean (SD), 37.7 (9.9) years, indicating general adherence to the prophylactic regimen. The median subscale scores ranged from 4 for Dosing to 8 for Planning (means, 5.6 and 7.7, respectively). The most pronounced difference in the subscale scores between adherent and nonadherent patients was recorded for Dosing (median, 4 vs 10; mean, 5.3 vs 9.3) and Remembering (median, 5 vs 11; mean, 5.7 vs 10.7). The overall adherence rate was 94%., Conclusions: Our results show a high rate of adherence to hemophilia prophylaxis by Polish adults. Problems with the management of clotting factor stocks and remembering about the injection of the clotting factor were identified as potential barriers to adherence in adults with hemophilia in Poland.

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications., Aim: To characterize clinical features and outcome of ITI on HBI., Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-times-weekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens., Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months)., Conclusions: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications., (© 2022 John Wiley & Sons Ltd.)

Background: Hemophilia is a recessive hemorrhagic disease relevant to X chromosome. In mild hemophilia cases, spontaneous bleeding is rare and the blood clotting function is normal, but severe bleeding may occur after trauma or surgery. Therefore, missed diagnosis of hemophilia before operation may contribute to bleeding after hemorrhoid operation., Case Presentation: A 21-year-old male was hospitalized in the anorectal department because of repeated bleeding after hemorrhoid surgery. Despite several suture hemostasis procedures, the patient still suffered from recurrent bleeding. He had no family history of hemophilia or bleeding tendency, and had not been diagnosed with hemophilia before this admission. The diagnosis of mild hemophilia B was made after further examination of coagulation indexes. By using frozen plasma and coagulation factor complex to supplement coagulation factors, the patient's bleeding was stopped and he was discharged after 23 days in hospital. During the follow-up, lower-than-normal coagulation factors were still found in him, but no bleeding occurred again., Conclusions: The undiagnosed patient with mild hemophilia B has an increased risk of bleeding after hemorrhoid surgery because of the consumption of coagulation factors. This case report aims to address the importance of hemophilia screening before operation and reduce the risk of postoperative bleeding. For patients with recurrent bleeding after hemorrhoid surgery, hemophilia should be further excluded. Wound bleeding may recur in hemophilia patients after suture hemostasis. Therefore, prompt supplementation of coagulation factors is needed to help stop bleeding once the diagnosis of hemophilia is made., (© 2022. The Author(s).)

Objectives: To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019., Methods: Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period., Results: Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p = .164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p < .001), complications (14.3% vs. 12.3%; p < .001), and plan deviations (34.2% vs. 25.1%; p < .001)., Conclusion: The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B., Methods: Subjects with haemophilia (n = 120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate-dose prophylaxis (n = 32) or on-demand replacement therapy (n = 14)., Results: Subjects with severe haemophilia on high-dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4 mg/cm 2 (P = .17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4 mg/cm 2 , in high-dose and intermediate dose groups, respectively; P = .70). Subjects with severe disease treated on-demand had significantly lower BMD compared to subjects on a high-dose prophylactic regimen (median BMD 771.8 and 955.8 mg/cm 2 (P = .001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development., Conclusion: We show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on-demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL)., Aim: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity., Methods: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL., Results: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL., Conclusion: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)