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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.)

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.

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.)

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.

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.)

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.

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.

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).)

Hemophilia A (HA) and B are inherited bleeding disorders caused by a deficiency of factor VIII or factor IX, respectively. The current standard of care is the administration of recombinant or purified factor. However, this treatment strategy still results in a high economic and personal burden to patients, which is further exacerbated by the development of inhibitors-alloantibodies to factor. The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care. Emicizumab, a bispecific antibody that mimics the function of factor VIIIa, is the first such nonfactor therapy to gain US Food and Drug Administration approval and is rapidly changing the paradigm for HA treatment. Other therapies on the horizon seek to target anticoagulant proteins in the coagulation cascade, thus "rebalancing" a hemorrhagic tendency by introducing a thrombotic tendency. This intricate hemostatic balancing act promises great things for patients in need of more treatment options, but are these other therapies going to replace factor therapy? In light of the many challenges facing these therapies, should they be viewed as a replacement of our current standard of care? This review discusses the background, rationale, and potential of nonfactor therapies as well as the anticipated pitfalls and limitations. This is done in the context of a review of our current understanding of the many aspects of the coagulation system., (Copyright © 2021 by The American Society of Hematology.)

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste., (Copyright © 2021 by The American Society of Hematology.)

Background: The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies., Objectives: To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia., Data Collection and Analysis: Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence., Main Results: Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect.   AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI.  When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons.  Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B., Methods: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis., Results: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0-7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was "excellent" or "good" for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%)., Conclusion: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%-100% for post-op days (PODs) 0-3, and at 60%-80% for PODs 4-14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:Dosage needed=%(desired FIX level-current level of FIX)×weight (kg)×1.3.This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18-24 hours. The rFIX infusion was started intraoperatively and continued after surgery to maintain target FIX activity. He was discharged on POD 9 on rFIX bolus dosing of 5000 IU every 12 hours for an additional 5 days. Using continuous factor infusion, we managed to decrease the amount rFIX used by >60% while maintaining steady state FIX activity level., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP. Comparing 6 months before, rFIX-FP reduced 68.5% FIX consumption/kg and 58.3% infusion frequency, but total costs/weight showed a slight increase. Ratio of half-life between rFIX and rFIX-FP was 3.4-3.7. This case report revealed that switch to rFIX-FP decreased frequency and FIX consumption, without adverse events and bleeds., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: The life expectancy of hemophiliacs is similar to that of the general population. As a result, the prevalence of age-related cardiovascular diseases has increased. We present our experience with hemophilia patients who underwent cardiac surgery in our Medical Center between 2004 and 2019., Methods: All hemophilia patients who underwent cardiac surgery were identified, and their peri-operative data evaluated retrospectively., Results: Ten patients were identified: six with hemophilia-A, one with hemophilia-B, and three with hemophilia-C (factor XI deficiency). Cardiac procedures included ten coronary artery bypass grafts and one aortic valve replacement. Hemophilia-A and B patients were treated with factor substitution, whereas patients with factor XI deficiency were treated with fresh frozen plasma. One patient died, and one patient suffered from non-active gastrointestinal bleeding., Conclusions: While major cardiac surgery can be performed safely on patients with hemophilia, a multidisciplinary team approach and strict postoperative monitoring are essential in order to achieve optimal results.

Background: Ankles and knees are commonly affected in people with hemophilia and thus are targets for prevention or rehabilitation. However, to our knowledge, no studies have evaluated muscle activity and safety during exercises targeting the lower limbs in people with hemophilia; this lack of information hinders clinical decision-making., Objective: The aim of this study was to compare the tolerability of, safety of, and muscle activity levels obtained with external resistance (elastic or machine)-based and non-external resistance-based lower limb exercises in people with hemophilia., Design: This was a cross-sectional study., Methods: Eleven people who had severe hemophilia and were undergoing prophylactic treatment participated. In a single experimental session, participants performed knee extension and ankle plantar flexion during 3 exercise conditions in random order: elastic band-based resistance (elastic resistance), machine-based resistance (machine resistance), and no external resistance. Exercise intensities for the 2 external resistance-based conditions were matched for perceived exertion. Muscle activity was determined using surface electromyography (EMG) for the rectus femoris, biceps femoris, gastrocnemius lateralis, and tibialis anterior muscles. Participants were asked to rate exercise tolerability according to a scale ranging from "very well tolerated" to "not tolerated" and to report possible adverse effects 24 and 48 hours after the session., Results: No adverse effects were reported, and exercise tolerability was generally high. In the knee extension exercise, the rectus femoris normalized EMG values during the elastic resistance and machine resistance conditions were similar; 29% to 30% higher activity was obtained during these conditions than during the non-external resistance condition. In the ankle plantar flexion exercise, the gastrocnemius lateralis normalized EMG value was 34% higher during the machine resistance condition than without external resistance, and the normalized EMG values during the elastic resistance and other conditions were similar., Limitations: The small sample size and single training session were the primary limitations of this study., Conclusions: Exercises performed both with elastic bands and with machines at moderate intensity are safe, feasible, and efficient in people with severe hemophilia, providing comparable activity levels in the agonist muscles., (© 2019 American Physical Therapy Association.)

Introduction: Concern about weight gain among people has been high due to negative health consequences in addition to the increasing prevalence of the problem. Overweight and obesity also occur in patients with hemophilia. Analysis of literature shows that increased body weight might have a biomechanical effect on the spatial orientation of the pelvis and the lumbar spine. The aim of this study was to determine the correlation between body mass index (BMI) and the parameters characterizing the alignment of the sacrum (SS, sacral slope), the pelvis (PT, pelvic tilt; PI, pelvic incidence) and the angle value of lumbar lordosis (LL, lumbar lordosis) assessed in the sagittal plane among patients with hemophilia. Materials and methods: A total of 49 patients were subjected to the study, 23 of whom met the inclusion criteria. Body weight and height were measured. Measurement of the angle values of indicators characterizing the position of the lumbar-pelvic complex was established based on X-ray imaging analysis. Results: Analysis of the correlation between the BMI and sacral, pelvic, and lumbar indicators evaluated in the sagittal plane in the study group of patients with hemophilia showed a correlation between BMI and SS ( r = 0.48). SS values were significantly and positively related to PI ( r = 0.6; p = 0.002) and LL ( r = 0.46; p = 0.02). The results obtained indicate the BMI relationship with the setting of the sacrum in the sagittal plane (SS). After adjusting for the knee flexion contracture, the correlation on the border of significance ( b = 0.73, p = 0.07) between the body mass index and the spatial orientation of the pelvis and the spine was revealed. Conclusion: We hypothesize that increased body weight among people with hemophilia might have an effect on the positioning of the lumbosacral region. Therefore, it is believed that preventing obesity among people with hemophilia can contribute to a smaller number of intra-articular hemorrhages and better orthopedic condition of the limb joints, and thus could avoid changes in the lumbosacral region as well as their consequences.

Intracranial haemorrhage (ICH) is the most serious event in haemophiliacs, resulting in high rates of mortality and disability. Although the use of a prophylaxis regimen has improved outcomes, the mortality caused by ICH is still around 20%. ICH is more frequent at two different ages: in childhood (mostly in children aged ≤2 years) and in adulthood (with known risk factors such as hypertension and age ≥60 years). Our review shows how ICH remains one of the worst problems of patients with haemophilia. Greater attention to risk factors and early symptoms, together with an appropriate early prophylaxis, may reduce the risk of severe intracranial haemorrhagic events.

Background Repeated haemarthroses affect approximately 90% of patients with severe haemophilia and lead to progressive arthropathy, which is the main cause of morbidity in these patients. Diagnostic imaging can detect even subclinical arthropathy changes and may impact prophylactic treatment. Magnetic resonance imagining (MRI) is generally the gold standard tool for precise evaluation of joints, but it is not easily feasible in regular follow-up of patients with haemophilia. The development of the standardized ultrasound (US) protocol for detection of early changes in haemophilic arthropathy (HEAD-US) opened new perspectives in the use of US in management of these patients. The HEAD-US protocol enables quick evaluation of the six mostly affected joints in a single study. The aim of this prospective study was to determine the diagnostic accuracy of the HEAD-US protocol for the detection and quantification of haemophilic arthropathy in comparison to the MRI. Patients and methods The study included 30 patients with severe haemophilia. We evaluated their elbows, ankles and knees (overall 168 joints) by US using the HEAD-US protocol and compared the results with the MRI using the International Prophylaxis Study Group (IPSG) MRI score. Results The results showed that the overall HEAD-US score correlated very highly with the overall IPSG MRI score (r = 0.92). Correlation was very high for the evaluation of the elbows and knees (r ≈ 0.95), and slightly lower for the ankles (r ≈ 0.85). Conclusions HEAD-US protocol proved to be a quick, reliable and accurate method for the detection and quantification of haemophilic arthropathy.

Introduction: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987., Patient Concerns: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected., Diagnosis: Burkitt lymphoma and hemophilia B., Interventions: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely., Outcomes: The patient died of infection and bleeding after chemotherapy., Conclusion: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.

Haemorrhagic disorders combined with soft tissue inflammation and infection may lead to severe bleeding complications before, during or after dental treatment. In selected cases, a combined therapeutic approach involving clinical therapies and systemic and local medication could improve the treatment outcomes and the patient's quality of life. This clinical case report, presents for the first time a successful combined approach, completed in a 38-year-old male patient with severe type-B haemophilia in which an infected tooth was extracted, an immediate implant was inserted, bone grafting was performed and early implant loading was successfully applied. In addition to the clinical therapy, medication was provided orally, systemically and locally, thus preventing the haemorrhagic complications and improving the patient's quality of life., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Increased number of patients with hemophilia have been identified to have osteoporosis at early ages. Low bone mineral density in the setting of hemophilia has been associated with decreased mobility, sedentary life style, on demand treatment or delayed prophylaxis, low body weight and viral infections. The aim of this study was to investigate the impact of hemophilia on bone health of adult patients living in a middle income country. A total of 61 adult patients with hemophilia who were followed at the Hematology Department of Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa were consecutively included in this study. Bone health of the patients was assessed using the bone mineral density (BMD) and vitamin D levels. Z and t scores are used for evaluation of BMD in patients with hemophilia aged < 50 and ≥ 50 years, respectively. Information on treatment and co-morbidities including viral diseases were obtained from the medical files of the recruited patients. Bone mineral density was found normal in 30, and low in 29 patients. Vitamin D levels were below 20 ng/ml in 46 patients. No significant relationship was found between the severity of hemophilia and bone density. Vitamin D levels were significantly lower in patients who had a history of joint intervention. Neither annual bleeding rate nor the treatment modality (on demand versus prophylaxis) were associated with the bone mineral density and vitamin D levels. Annual factor consumption was higher in patients whose bone mineral densities was low both in femoral and lumbar regions. The results of this study depicting the situation of adult hemophilia population from a middle income country show that bone mineral density and vitamin D levels were decreased in a considerable amount of patients at early ages.

There has been an ongoing debate as to whether hemophilia A (HA) is more severe than hemophilia B (HB), and there are studies supporting each side of the argument. The study aimed to investigate whether any differences in major bleeding events exist between patients with severe HA and HB. A nationwide, population-based retrospective cohort study using the National Health Insurance Research Database was conducted. We compared 658 patients with severe HA and 137 patients with severe HB without inhibitors from 1997 to 2013, during the period when adult patients older than 18 years old were treated with the on-demand therapy since birth. There was no significant difference between patients with severe HA and HB in the rate of major bleeding events, with an adjusted relative ratio of 0.79 (95% confidence interval [CI]: 0.36-1.71, P = .548). There was also no significant difference in the incidence rate of major bleeding events between adult patients with HA and HB with the on-demand therapy, and an adjusted hazard ratio (HR) of 0.82 (95% CI: 0.65-1.02). However, patients with HA had a lower incidence rate of intracranial hemorrhage, with an adjusted HR of 0.44 (95% CI: 0.25-0.79). In addition, no significant difference in the frequency of major bleeding events requiring hospitalization between patients with HA and HB was found, P > .05. In conclusion, the study demonstrated that patients with severe HB encountered a similar rate of major bleeding events to those with severe HA.

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

People with haemophilia (PWH) experience acute pain during joint bleeds and might develop chronic pain due to joint degeneration. However, there is a lack of standardized measures to comprehensively assess pain in PWH. This study aimed to develop a multidimensional questionnaire for haemophilia-related pain, the Multidimensional Haemophilia Pain Questionnaire (MHPQ), and to present initial validation data among adults.The questionnaire distinguishes between acute/chronic pain and queries about pain locations, duration, frequency, triggering factors, intensity, interference, strategies, specialists for pain management and satisfaction with treatment. An initial version was tested with 16 patients to ensure item comprehensibility and face validity. The final version was answered by 104 adults, with 82 (78.8%) reporting haemophilia-related pain in the previous year (mean age = 43.17; SD = 13.00). The non-response analysis revealed good item acceptability. Exploratory and confirmatory factor analysis (EFA/CFA), reliability (internal consistency, test-retest, inter-item and item-total correlations) and convergent validity were analysed for the intensity and interference dimensions of the questionnaire. A combined EFA with these two constructs supported a 2-factor structure distinguishing intensity (α = 0.88) from interference items (α = 0.91). CFA was tested for the interference dimension, demonstrating suitability for this sample. Item-total correlations were >0.30 on both dimensions and most inter-item correlations were <0.70. Test-retest reliability (n = 42) was good for intensity (r = 0.88) and interference (r = 0.73), and convergent validity was confirmed for most hypotheses (r>0.30).This questionnaire is a comprehensible tool, achieving a thorough assessment of relevant pain dimensions. The MHPQ can help guide treatment recommendations by highlighting relevant topics and contributing to more effective, integrated treatments., Competing Interests: The authors have declared that no competing interests exist.

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care.Data from 13 European countries were collected at a single time-point (2011-2013). Univariate and multivariate logistic regression (MLR) analyses were performed.A total of 532 PWH were included with either hemophilia A (n = 467) or hemophilia B (n = 65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR = 17.6, P < .001), diabetes (OR = 3.0, P = .02), and HIV (OR = 1.9, P = .049) were positively associated with CLD. Total cholesterol (OR = 0.6, P = .002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR.The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted.

Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population., (© 2018 by The American Society of Hematology.)

Competing Interests: Competing interests: None declared.

Background: Joint damage remains a major complication associated with haemophilia and is widely accepted as one of the most debilitating symptoms for persons with severe haemophilia. The aim of this study is to describe how complications of haemophilia such as target joints influence health-related quality of life (HRQOL)., Methods: Data on hemophilia patients without inhibitors were drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost-of-illness assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the UK). Physicians provided clinical and sociodemographic information for 1285 adult patients, 551 of whom completed corresponding questionnaires, including EQ-5D. A generalised linear model was developed to investigate the relationship between EQ-5D index score and target joint status (defined in the CHESS study as areas of chronic synovitis), adjusted for patient covariates including socio-demographic characteristics and comorbidities., Results: Five hundred and fifteen patients (42% of the sample) provided an EQ-5D response; a total of 692 target joints were recorded across the sample. Mean EQ-5D index score for patients with no target joints was 0.875 (standard deviation [SD] 0.179); for patients with one or more target joints, mean index score was 0.731 (SD 0.285). Compared to having no target joints, having one or more target joints was associated with lower index scores (average marginal effect (AME) -0.120; SD 0.0262; p < 0.000)., Conclusions: This study found that the presence of chronic synovitis has a significant negative impact on HRQOL for adults with severe haemophilia. Prevention, early diagnosis and treatment of target joints should be an important consideration for clinicians and patients when managing haemophilia.

Aim: To develop a modeling approach to compare clinical outcomes of nonacog beta pegol to a standard-acting factor IX (FIX) product., Methods: Regression analysis linked FIX activity to bleed rates. Pharmacokinetic parameters were used to estimate FIX activity over time. The probability of bleeds was estimated for both treatment arms. A Markov model estimated the presence of target joints and annualized bleed rates (ABRs)., Results: Higher FIX activity showed reduced ABRs (p < 0.001). Target joints resulted in higher bleed rates (p < 0.001). When FIX activity levels and bleed risks were applied to the Markov model, ABRs for nonacog beta pegol and its comparator were 2.40 and 6.36, respectively., Conclusion: This model provides a starting point for assessing the added value of new FIX products.

Background: Haemophilia A (factor VIII deficiency), B (factor IX deficiency) and C (factor XI deficiency) are common genetic bleeding disorders. Most often they are caused by the absence or defective function of coagulation factors, causing inefficient blood clots., Case Report: The present manuscript describes a rare case of a combined haemophilia A and B patient, who underwent several extractions. The therapy and clinical management is presented, in the view of surgeon as well as haematologist., Conclusion: These patients are a serious challenge for the oral surgeons due to an increased number of accidents and complications. Scarce literature covering this topic contributes, as well, to the difficult management. Thus, several principles must be considered when diagnosing and treating haemophilia patients., Key Words: Haemophilia, Oral surgery.

Objective: To report the results of mid-term to long-term follow-up after primary total hip arthroplasty (THA) in hemophiliacs and to hypothesize that THA can provide satisfactory outcomes in these patients., Methods: Twenty-four primary THA performed in 21 hemophilia patients between 2002 and 2012 were reviewed retrospectively, including 20 cases of hemophilia A and 1 case of hemophilia B. The standard lateral approach was used for all implantations. Substitution therapy for factor VIII and activated prothrombin complex concentrates were administered to patients with hemophilia A and B, respectively. Total and hidden blood loss were calculated. Outcomes were assessed using the Harris hip score before surgery and at the final follow-up visit. Complications were recorded by clinical and radiographic assessment and then compared to those in previous reports., Results: The mean follow-up period was 113 months (range, 5-15 years). The average total blood loss was 3559 mL (range, 1494-7506 mL). The mean amount of red blood cell (RBC) transfusion was 4.4 U (range, 0-14 U). The mean amount of clotting factor used in the perioperative period for management of hemophilia was 14 031.3 U (range, 8100-25 200 U). Harris hip scores improved from 37 points (range, 15-81) before surgery to 90 points (range, 70-96) at the last follow-up. No signs of loosening, infection or other complications of the implant components occurred after discharge. The overall survivorship of the implants was 100% for all patients, and no revision surgery was performed., Conclusions: With modern techniques and hematological management, THA in patients with hemophilia leads to significant improvement in joint function with a relatively low incidence of complications. Increased blood loss and substitution therapy have no obvious negative influences on the mid-term to long-term results of THA., (© 2017 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Background: People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds., Objectives: To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors., Search Methods: We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016., Selection Criteria: We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors., Data Collection and Analysis: Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria., Main Results: We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study., Authors' Conclusions: The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

Hemophilia A and B are X-linked diseases that predominantly affect male patients. Patients can develop coagulation factor inhibitors, which exponentially increases the treatment cost. However, the prevalence of factor VIII and IX inhibitors in Saudi Arabia is unclear.This study aimed to determine the Saudi prevalence of factor VIII and IX inhibitors.This 4-year, 7-center, cross-sectional study evaluated the Saudi prevalences of hemophilia A and B. We collected the patients' clinical data, evaluated their disease, and tested for factor inhibitors.We included 202 patients with hemophilia (median age at diagnosis: 0.13 years, range: birth-34.8 years). The patients included 198 male patients (98%), 148 patients with hemophilia A (73.3%), and 54 patients with hemophilia B (26.7%). The patients exhibited severe factor VIII activity (<1%; 121 patients; 5.2%), moderate activity (1-5%; 7 patients; 4.9%), and mild activity (14 patients; 9.9%). Among the patients with care-related data, most patients were treated for episodic bleeding (76.8%) or received prophylaxis (22.6%); 1 patient received both treatments. Among the patients with source-related data, the factor replacements were derived from plasma (48.4%), recombinant concentrates (22.9%), both sources (14.6%), or fresh frozen plasma (14.1%). Factor VIII inhibitors were observed in 43 (29.3%) of the 147 patients, and only 1 of the 54 patients developed factor IX inhibitors. Most patients who developed inhibitors had severe hemophilia (40/44; 90.9%), and inhibitors were also common among patients who received recombinant products (14/43; 32.6%).The Saudi prevalence of factor inhibitors was similar to those among other ethnic populations., Competing Interests: The authors report no conflicts of interest.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.

Essentials Some hemophilia B (HB) patients with complete F9 deletion present with intellectual disability (ID). We delineate six F9 complete deletions and investigate genotype/phenotype correlation. We identify SOX3 as a candidate gene for ID, acting through haploinsufficiency, in HB patients. All complete F9 deletions in ID patients should be explored with cytogenetic microarrays., Summary: Background Large deletions encompassing both the complete F9 gene and contiguous genes have been detected in patients with severe hemophilia B (HB). Some of these patients present other clinical features, such as intellectual disability (ID). Objectives/Methods In this study, we characterized six unrelated large deletions encompassing F9, by cytogenetic microarray analysis (CMA), to investigate genotype/phenotype correlation. Results Five of the six patients included in this study presented with ID associated with HB. CMA showed that the six large deletions, ranging in size from approximately 933 kb to 9.19 Mb, were located within the Xq26.3 to Xq28 bands. In all cases, the complete deletion of F9 was associated with the loss of various neighboring genes (5-28 other genes). The smallest region of overlap for ID was a 1.26-Mb region encompassing seven OMIM genes (LOC389895, SOX3, LINC00632, CDR1, SPANXF1, LDOC1, SPANXC). SOX3, our candidate gene for ID, encodes an early transcription factor involved in pituitary development. All of the patients studied who had both HB and ID had deletion of the SOX3 gene. Conclusions All HB patients with an atypical phenotype, especially if complete deletion of F9 is suspected, should be referred to a geneticist for possible pangenomic assessment, because haploinsufficiency of genes flanking F9, such as SOX3 in particular, may result in a broader phenotype, including ID. Such assessment would be of particular value for the genetic counseling of female carriers with F9 deletions, as it would facilitate analysis of the risk of transmitting HB associated with ID., (© 2016 International Society on Thrombosis and Haemostasis.)

Haemophilia is an inherited bleeding disorder that can lead to degenerative joint arthropathy due to recurrent bleeding episodes affecting the musculoskeletal system of the patient. The cause of bleeding can be either traumatic or spontaneous. The pathogenesis of haemophilic arthropathy is unclear as many factors like iron, inflammatory cytokines, and angiogenic factors contribute to this process. Blood into joints can deteriorate the bone to such an extent that the patient experiences pain, reduction of the range of movement, and deformity of the joint, conditions that could have a great impact on quality of life. Over the years, management of haemophilic arthropathy has changed. Nowadays, early diagnosis with high resolution imaging like magnetic resonance imaging along with application of prophylaxis regimens can reduce the extent of damage to the joints. However, not all haemophilia patients have access to these interventions as cost may be prohibitive for some of them. The need for new, easy, and cost-effective strategies with the ability to identify early changes could be beneficial and could make a difference in the management of haemophilic arthropathy. Understanding the mechanism of processes like angiogenesis in the mechanism of developing arthropathy could be innovative for these patients and could help in the detection of new early diagnostic and therapeutic markers., Competing Interests: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.

The introduction of clotting factor concentrates has transformed the lives of persons with inherited bleeding disorders. With the use of prophylactic treatment, it is now possible to prevent bleeding in these individuals. The early concentrates were contaminated with the HIV and hepatitis C viruses (HCV) and resulted in major morbidity and mortality in the recipients. Current products are much safer, especially in terms of infectious agents, but other adverse events such as alloantibodies (inhibitors), allergic reactions and thrombotic risks remain of concern. Approximately 30% of previously untreated patients with severe haemophilia A develop inhibitors, making this the most important issue in haemophilia care today. Recently, it was suggested that one of the most commonly used concentrates was associated with a higher inhibitor risk, but this was not supported by the evidence from all studies. Good safety surveillance systems are essential for all diseases and products but are particularly so in the group of individuals with inherited bleeding disorders treated with clotting factor concentrates who have suffered disproportionately from the adverse effects of their treatment. National and multinational systems are now in place to allow reporting of adverse events in patients with inherited bleeding disorders. All clinicians treating individuals with inherited bleeding disorders should prospectively report adverse events to treatment even if they are believed to be common and well recognized., (© 2016 The Association for the Publication of the Journal of Internal Medicine.)

Haemophilia is a congenital disorder with bleeding episodes as its primary symptom. These episodes can result in negative outcomes including joint damage, loss of active days due to hospitalization and reduced quality of life. Effective treatment, however, can improve the outcome. Registries have been used as a valuable source of information regarding the monitoring of treatment and outcome. The two main aims of this exploratory study were to establish which haemophilia registries publish peer-reviewed outcome assessment research and then to extract, classify and report the treatment outcomes and their extent of use in the retrieved registries. Using relevant keywords, we searched PubMed and Web of Science databases for publications during the period 1990-2015. Retrieved references were screened in a stepwise process. Eligible papers were original full articles on haemophilia outcomes that used data from a computerized patient database. Descriptive results were summarized. Of 2352 references reviewed, 25 full texts were eligible for inclusion in the study. These papers were published by 11 registries ranging from local to international in coverage. It is still relatively rare for registries to produce peer-reviewed publications about outcomes, and most that currently do produce such papers are located in Europe and North America. More information is available on traditional outcomes such as comorbidities and arthropathy than on health-related quality of life or the social and developmental impact of haemophilia on patients. Inhibitors, HIV and viral hepatitis are amongst the most commonly reported comorbidities. Research has focused more on factor consumption and less on hospitalization or time lost at school or work due to haemophilia. Haemophilia registries, especially those at the national level, are valuable resources for the delivery of effective health care to patients. Validated outcome measurement instruments are essential for the production of reliable and accurate evidence. Finally, such evidence should be communicated to physicians, patients, the public and health policymakers., (© 2016 The Association for the Publication of the Journal of Internal Medicine.)

Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A., (Copyright© Ferrata Storti Foundation.)

Objective: To investigate the effectiveness of our department's therapeutic regimen and treatment of complications during the perioperative period of hemophilia-related osteoarthropathy., Methods: In this retrospective study, data on 101 patients with hemophilia who had undergone operative treatment in our hospital from January 2000 to August 2014 were assessed. Ninety-one of the patients had hemophilia A and 10 hemophilia B. All patients were male. Changes in Hospital for Special Surgery (HSS), Harris and American Orthopedic Foot and Ankle Society (AOFAS) scores, occurrence of complications during the perioperative period and the clinical treatment and prognosis pre- and postoperatively and during follow-up were analyzed. Relevant clinical data were obtained through telephone calls, outpatient follow-up, and medical clinical record searches., Results: The 101 patients who were followed up (for an average of 96 months) had 147 orthopedic operations, including joint replacement, hemophilia-related false tumor resections, and tendo-achillis lengthening. The HSS scores for knee surgeries increased from 52 points preoperatively to 86 postoperatively, Harris scores for hip joint surgery from 26 to 87 points, respectively, and AOFAS scores for foot and ankle surgeries from 39 to 81 points, respectively. Eight patients had wound complications, four intra-articular hematomas, two peroneal nerve injuries, one a proximal femur splitting fracture and one deep venous thrombosis., Conclusions: Surgical treatment is a safe and reliable choice for addressing complications including hemophilia-related osteoarthropathy given the implementation of effective measures for treatment during the perioperative period., (© 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Background: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date., Objectives: The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase and The Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 14 December 2015., Selection Criteria: Randomised and quasi-randomised controlled trials in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo., Data Collection and Analysis: Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardized forms., Main Results: While there were no eligible trials in people with Von Willebrand disease identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of epsilon aminocaproic acid published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference of -0.64 (95% confidence interval -0.93 to - 0.36) and the EACA trial a risk difference of -0.50 (95% confidence interval 0.77 to -0.22). The combined risk difference of both trials was -0.57 (95% confidence interval -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping epsilon aminocaproic acid (combined risk difference of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the epsilon aminocaproic acid trial, but overall the risk of bias appeared to be low for both trials., Authors' Conclusions: Despite the discovery of a beneficial effect of systemically administered tranexamic acid and epsilon aminocaproic acid in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with Von Willebrand disease.