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Objective: To explore the factors that affect the efficacy of knee replacement surgery in hemophiliacs. Methods: A retrospective analysis was conducted on 87 patients with hemophilia (PWH) (117knees) who underwent knee arthroplasty in our hospital from January 2012 to December 2020 (mean follow-up 70.8 ± 22 months). General information, hemophilia information, surgical information, follow-up information and psychological assessment information were collected. The knee joint efficacy was evaluated using the Hospital for Special Surgery (HSS) knee score, the American Knee Society's Clinical (KSC) and Functional (KSF) scores, flexion contracture degree (FC), range of motion (ROM), and wound healing. The excellent and poor groups were divided based on these factors. Logistic regression analysis was used to analyze factors that may affect the knee joint efficacy of patients. Results: Seventy-four cases of excellent knee joints and 43 cases of poor knee joints were included. Single factor analysis: The pre-ROM, SF-12MCS, HSS, KSF, and KSC of the excellent group were significantly higher than those of the poor group (P < 0.05); the Hamilton Depression Scale (HAMD), Preoperative Visual Analogue Scale(Pre-VAS), pre-FC degree of the excellent group were significantly lower than those of the poor group (P < 0.05). The proportion of patients undergoing Simultaneous bilateral knee replacement, severe hemophilia, and quadricepsplasty during surgery in the excellent group was significantly lower than that in the poor group (P < 0.05). Logistic regression: Pre-ROM and Simultaneous bilateral knee replacement are independent risk factors affecting knee joint efficacy. Pre-ROM is positively correlated with knee joint efficacy, while Simultaneous bilateral knee replacement is negatively correlated. Conclusion: In PWH, the efficacy of knee replacement surgery is related to preoperative ROM and Simultaneous bilateral knee replacement. Better preoperative knee joint mobility is associated with improved outcomes, whereas Simultaneous bilateral knee replacement negatively impacts surgical efficacy. [ABSTRACT FROM AUTHOR]

Background: Patients with hemophilia A can develop joint hemarthroses, degenerative changes, and eventually undergo total shoulder arthroplasty (TSA). Few data exist concerning complications and prosthesis survival after TSA in this population. Questions/purposes: (1) Is hemophilia A associated with more bleeding and thromboembolic adverse events after TSA relative to matched controls? (2) Is 5-year TSA prosthesis survival reduced in patients with hemophilia A compared with matched controls? Methods: The 2010 to 2022 PearlDiver M161 database was used to identify patients who underwent primary anatomic or reverse TSA. Given that the X-linked recessive condition hemophilia A presents nearly exclusively in males, male patients with hemophilia A who underwent TSA were matched 1:10 with male patients without hemophilia who underwent TSA based on age and Elixhauser comorbidity index (ECI). This yielded 73 patients with hemophilia A who underwent TSA who were matched 1:10 with 729 patients without hemophilia. Ninety-day adverse events were compared with multivariable analysis. Revision within 5 years was assessed using Kaplan-Meier analysis. Results: Compared with the control cohort, patients with hemophilia had greater odds of bleeding issues (hematoma, OR 6.8 [95% CI 3.0 to 15.3]; p < 0.001; anemia, OR 2.5 [95% CI 1.5 to 4.2]; p < 0.001, transfusion, OR 5.0 [95% CI 2.4 to 10.3]; p < 0.001), venous thromboembolic events (VTE) (OR 1.9 [95% CI 1.1 to 3.1]; p = 0.01), and prosthetic loosening (OR 3.5 [95% CI 1.4 to 8.0]; p = 0.004). Based on available data, 5-year implant survival was not different in patients with hemophilia (97.3% [95% CI 93.6% to 100.0%]) relative to matched controls (95.2% [95% CI 93.4% to 97.2%]; p = 0.60). Conclusion: The elevated risks of both 90-day bleeding complications (hematoma, anemia, and transfusion) and VTE (DVT and PE) in patients with hemophilia emphasize the special challenges of carefully balancing factor replacement and VTE prophylaxis pre-, intra-, and postoperatively on an individual patient basis with careful hematologist coordination. Further study on Factor VIII levels and targets as well as tranexamic acid and VTE prophylaxis in this population is necessary to provide further guidance. Furthermore, 5-year implant survival was not different between patients with hemophilia and matched controls (patients without hemophilia) based on available data, suggesting that TSA survivorship remains durable and may be offered to patients in this population as indicated. Level of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

The mainstay of treatment for persons with hemophilia A (PwHA) with severe bleeding phenotype is prophylaxis. The pharmacokinetic (PK) profile of native factor VIII (FVIII) imposes the need for rather frequent intravenous injections to ensure effective prophylaxis, but this represents a relevant treatment burden and is associated with suboptimal adherence to treatment. In this light, the advent of extended half-life (EHL) FVIII molecules has improved prophylaxis feasibility and outcomes by favoring treatment individualization and tailoring protection according to specific clinical and nonclinical needs. Different technologies have been used to enhance FVIII PK properties including Fc-fusion and conjugation with polyethylene glycol. Data from clinical development programs for such molecules, together with growing real-world experience, have shown numerous benefits related to the use of EHL FVIII in PwHA. Recently a new class of ultra-long-acting EHL FVIII has been developed to further improve protection against bleeding episodes and achieve the ambitious goal of providing PwHA with hemostatic protection in the nonhemophilia range over longer time periods, hence ensuring very low bleeding rates and improving joint health and quality of life. In this review, the achievements and perspectives of replacement therapies for PwHA are summarized and discussed. [ABSTRACT FROM AUTHOR]

Non-factor replacement therapies (NFTs) have been developed to address the limitations of conventional replacement therapies, aiming to improve hemostasis and provide enhanced protection against bleeding episodes and long-term joint damage for patients both with and without inhibitors. Factor VIII (FVIII)-mimetic agents, such as emicizumab, have transformed the management of hemophilia A with inhibitors, offering a lower treatment burden and an effective alternative for those without inhibitors as well. Rebalancing agents, including anti-tissular factor pathway inhibitor agents (concizumab and marstacimab) and serpin inhibitors like fitusiran, have shown promising efficacy for patients with hemophilia B with inhibitors and other hemophilia subtypes. Administered subcutaneously, NFTs generate stable thrombin levels and feature a long half-life, which can shift severe hemophilia toward a milder phenotype. These therapies are effective regardless of inhibitor status and hold potential for application in other bleeding disorders. Evaluating the potential thrombotic risk after implementing mitigation measures, along with the development of anti-drug antibodies (ADAs), remain critical areas for further analysis. NFTs pose additional challenges due to their complex mechanism of action and the absence of a standardized laboratory assessment method. Unresolved issues include optimal management strategies for major surgeries and tailored approaches for safe use in older populations. This review highlights the progress and future potential of NFTs in treating persons with hemophilia. [ABSTRACT FROM AUTHOR]

Historically, the aim of treatment for hemophilia, the congenital X-linked hemorrhagic disorder due to deficiencies of coagulation Factor (F) VIII (hemophilia A) or FIX (hemophilia B), has been the replacement through factor concentrates, whose regular administration (i.e., prophylaxis) has been shown to be highly effective in preventing bleeding complications and it is currently considered the gold standard of hemophilia treatment. However, continuous technological progress (i.e., plasma-derived factor concentrates, recombinant standard and extended half-life [EHL] products) has allowed clinicians operating at hemophilia treatment centers to individualize the management of persons with hemophilia, improving outcomes, adherence to therapy, and their quality of life. The achievement of normal hemostasis, the final goal that now seems possible with new-generation EHL products, non-replacement and gene therapies, will translate into normalization of life for persons with hemophilia, also addressing health equity (i.e., rendering them indistinguishable from their healthy peers). The evolution of hemophilia treatment and, in parallel, of therapeutic targets in the management of hemophilia patients over the last decades will be critically discussed in this narrative review. [ABSTRACT FROM AUTHOR]

Strides in advancements of care of persons with hemophilia include development of long-acting factor replacement therapies, novel substitution and hemostatic rebalancing agents, and most recently approved gene therapy. Several decades of preclinical and clinical trials have led to development of adeno-associated viral (AAV) vector-mediated gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA). Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant improvement in bleeding rates and use of factor replacement therapy; however, sustainability and duration of response show variability with overall decline in FVIII expression over time. Further challenges include untoward adverse effects involving liver toxicity requiring immunosuppression and development of neutralizing antibodies to AAV vector rendering future doses ineffective. Real-life applicability of gene therapy for HA will require appropriate patient screening, infrastructure setup, long-term monitoring including data collection of patient-reported outcomes and innovative payment schemes. This review article highlights the success and development of HA gene therapy trials, challenges including adverse outcomes and variability of response, and perspectives on approach to gene therapy including shared decision-making and need for future strategies to overcome the several unmet needs. [ABSTRACT FROM AUTHOR]

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL. [ABSTRACT FROM AUTHOR]

Type 3 von Willebrand disease (VWD), the most severe form of VWD, is an inherited recessive bleeding disorder caused by the complete deficiency of von Willebrand factor (VWF). The reported prevalence is 1 per million but varies worldwide according to the frequency of consanguineous marriages. The clinical phenotype is characterized not only by mucocutaneous bleedings, but also by hemarthroses and muscle hematoma, as in patients with moderate hemophilia. Long-term prophylaxis with factor (F)VIII/VWF concentrates is recommended in patients with a history of severe and frequent bleeds. A rare complication of replacement therapy is the development of alloantibodies against VWF, with the consequences of an ineffective therapy and risk of anaphylactic reactions upon treatment. Emicizumab is the first bispecific monoclonal antibody that mimics FVIII coagulant activity and is approved for prophylaxis of bleeding in patients with inherited hemophilia A with or without inhibitors and recently also for acquired hemophilia. In this manuscript we report and discuss available data in the literature on the use of emicizumab in type 3 VWD and describe the case of a female patient with type 3 VWD with a history of alloantibodies against VWF and posttransfusion anaphylaxis, recently and successfully put on off-label prophylaxis with emicizumab. [ABSTRACT FROM AUTHOR]

This perspective discusses the critical role of laboratory assessments in assessing factor VIII (FVIII) inhibitors. These are auto- and alloantibodies that can develop against both endogenous and exogenous FVIII, respectively. Assessment for inhibitors represents a key part of the management of both congenital hemophilia A (CHA), an inherited deficiency, and acquired hemophilia A (AHA), an autoimmune condition. Both conditions pose significant bleeding risks, necessitating careful monitoring of FVIII levels and inhibitor presence and level. Laboratory assays, particularly the Bethesda assay, are essential for detecting these inhibitors and assessing their levels. The complexities of FVIII inhibitor kinetics may pose challenges to interpretation of assay results, such that even normal FVIII levels do not always exclude inhibitor presence. Clinical practice guidelines recommend ongoing monitoring of AHA/CHA patients until inhibitors are no longer detectable. Overall, timely laboratory evaluations are essential to optimizing treatment strategies for patients with hemophilia, aiming to improve patient outcomes and quality of life. We summarize our approach to the laboratory assessment of FVIII inhibitors, as reflecting our perspective and as informed by local practice. [ABSTRACT FROM AUTHOR]

Hemophilic arthropathy is a common complication of hemophilia A and can lead to chronic synovitis, joint damage, and eventually ankylosis. We present a case report of a 39-year-old male patient with a history of recurrent hemorrhages into the joints. He had a history of traumatic injury to both upper limbs and lower limbs. The patient was on bed rest for 6 months. Subsequently, he developed ankylosis of both elbows in 30° of flexion and ankylosis of the right (Right) knee in 40° of flexion with tricompartmental arthritis of the left knee joint. Radiologically, the left knee joint showed reduced joint space with tricompartmental arthritis. The patient was managed by the tumor prosthesis for the Rt knee. He was advised for management of the elbow joints for which he was not willing. Postoperatively, he was allowed knee range of motion exercises and walking with a walker for 4 weeks followed by a stick for 1 month. At 6-month follow-up, he was able to walk effortlessly without support. The Knee Society Score improved from 47 preoperatively to 75 at 6-month follow-up. [ABSTRACT FROM AUTHOR]

Background: New treatments for patients with bleeding disorders (PWB) have emerged, including products with extended half‐life and subcutaneous administration. These less frequent treatments can potentially enhance quality of life (QoL), but adherence becomes critically important. Aim: To investigate adherence and QoL among PWB and explore the correlation between treatment adherence and QoL in adult patients with haemophilia A (HA), haemophilia B (HB) and Von Willebrand disease (vWD) in Denmark. Method: This survey used disease‐specific patient‐reported questionnaires: Veritas‐PRO and Veritas‐PRN to measure adherence, and Haemo‐A‐QoL and VWD‐QoL to assess QoL. Results: Responses were obtained from 149 patients with HA, 32 with HB and 118 with vWD. Adherence was reported by 87.1% of patients on prophylaxis and 71.2% of patients treated on demand, according to Veritas‐PRO and Veritas‐PRN cut‐off scores. High QoL was generally reported, decreasing with age in HA and HB, but not in vWD. Conclusion: Danish patients with HA, HB and vWD reported high QoL and high adherence to prescribed treatments. There was no correlation between treatment adherence and QoL among the different patient groups. These findings highlight the need for further research to better understand adherence behaviours and identify opportunities to further improve QoL in PWB. [ABSTRACT FROM AUTHOR]

Hemophilia is a hemorrhagic condition characterized by a deficiency of clotting factor VIII (hemophilia A) or factor IX (hemophilia B). Patients with this condition suffer hemorrhagic episodes throughout their lives and may experience pain and low levels of quality of life. Objective: Analyze the relationship between pain perception and health-related quality of life in pediatric patients with hemophilia and their parents. A total of 173 patient and parent/guardian dyads from central Mexico participated. The study involved the application of three questionnaires: 1. an ad hoc questionnaire on sociodemographic data, 2. the Pediatric Quality of Life Questionnaire (PedsQL), and 3. the Pediatric Pain Questionnaire. The results show a difference between patients and their parents' perceptions of quality of life and pain. According to the visual analog scales, parents reported a higher pain level in their children. In addition, significant correlations resulted between quality of life and pain with some sociodemographic variables. In conclusion, the presence of pain affects the quality of life of the hemophilia patient and is associated with variables such as age, severity, and complications. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Methods Results Conclusion Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.The study aims to assess all‐cause and intracranial haemorrhage (ICH)‐specific mortality of PWH in India.This is a retrospective, observational, multi‐centric cohort study of 1020 haemophilia patients from three centres in India. The mortality data in the family was collected from personal interviews, and subsequently confirmed with the corresponding haemophilia treatment centres (HTCs). The demographic and clinical data, along with other comorbidities, were collected from the medical records.Among 170 reported deaths, 73 (42.9%) were caused by ICH, and 44 (25.9%) resulted from accidents or trauma. Gastrointestinal (GI) bleeding was the third most common cause of death, accounting for 27 cases (15.9%). The average and median ages at death were 27.7 and 26 years, respectively. None of the deceased cases were receiving any prophylactic or immune tolerance induction (ITI) therapy, and all had severe haemophilia. In addition, the prevalence of inhibitors and hypertension was significantly higher in deceased cases compared to that in the general haemophilia population (p < 0.05).Severity of haemophilia, episodic treatment, hypertension and inhibitors showed significant association with mortality. ICH continues to be the leading cause of death among haemophilia patients in the country. This underscores the challenges in managing haemophilia and the need for improved treatment strategies to increase the life expectancy of PWH. [ABSTRACT FROM AUTHOR]

Introduction Aim Methods Results Conclusions Physical therapy benefits patients with haemophilia (PWH), but its impact on the health‐related quality of life (HRQOL) remains unclear.This systematic review and meta‐analysis investigated the association of physical therapy, including therapeutic exercise, manual therapy, and physical agent modality, with HRQOL improvement in PWH.Databases PubMed, Embase, MEDLINE, and Scopus were searched from inception until April 2024. This review included randomised controlled trials (RCTs) that compare the HRQOL between the physical therapy and control groups. Relevant data and outcome values of included study were collected. Cochrane collaboration's tool and the grading of recommendations, assessment, development, and evaluation approach were used for risk of bias (ROB) and evidence‐level assessment, individually.The systematic review included eight RCTs that involved 298 male PWH. The meta‐analysis for HRQOL improvement revealed a significant difference in favour of physical therapy (standardised mean difference [SMD] = .92; 95% confidence interval [CI]:.50–1.33; p < .001). Therapeutic exercise exhibited more benefits in HRQOL improvement than the control groups (SMD = 1.02; 95% CI:.49–1.55; p < .001). Physical therapy effectively improved HRQOL in PWH with better joint status (SMD = 1.74; 95% CI:.97–2.51; p < .001). Of the eight RCTs, six were rated as high ROB. The comparisons revealed a moderate certainty of evidence.Physical therapy, especially therapeutic exercise, effectively improved the HRQOL of PWH. Maintaining better joint status and timely physical therapy intervention is crucial for HRQOL improvements in PWH. Cautious interpretation is required due to evidence limitations. [ABSTRACT FROM AUTHOR]

Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10–400 IU/dL) (Fanhdi®/Alphanate®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Methods Results Conclusion Acquired haemophilia A (AHA) is characterized by the development of autoantibodies against factor VIII, reducing its activity and potentially resulting in bleeding.To assess the characteristics of people with AHA undergoing rehabilitation and/or with low activities of daily living (ADL) scores, thereby characterizing unmet needs in the management of AHA and informing treatment optimization.ORIHIME II, the largest epidemiological and treatment survey of AHA in Japan, is a descriptive, retrospective, observational study conducted using health claims data from April 2008 to October 2021. The primary outcome measures were rehabilitation practice and ADL scores on hospital admission and discharge; use of haemostatic agents and immunosuppressive therapy were also assessed.Overall, 427 patients in Japan were eligible for the study. Median (Q1–Q3) age was 78.0 (70.0–84.0) years; 264 patients (61.8%) were male. Median (Q1–Q3) time to start rehabilitation was 9 (4–21) and 14 (6–31) days for those with an admission ADL score of <85 and ≥85, respectively. Of the 427 patients, 249 underwent rehabilitation. The most common rehabilitation type was for disuse syndrome; haemostatic agents were more commonly used in patients undergoing earlier rehabilitation.The physical condition of the patient at hospitalization was associated with rehabilitation practice and the ability of the patient to perform day‐to‐day activities independently. Treatment strategies should be optimized to allow initiation of rehabilitation as early as possible in the course of AHA. [ABSTRACT FROM AUTHOR]

Introduction Aim Methods Results Conclusion Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom.To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial.To treat mild/moderate bleeding episodes (BEs), subjects administered an initial 75  or 225µg/kg dose of eptacog beta, followed (if necessary) by additional 75µg/kg doses at predefined intervals until bleed control. This analysis used subject‐reported rebleeding to determine a rebleeding incidence for the first 24 h. Rebleeding through later timepoints was an exploratory, intention‐to‐treat analysis of bleed treatment data.Four hundred and sixty‐five BEs were analysed. Through 24 h, the proportion of rebleeds was 0% (initial 75µg/kg dose) and 0.5% (initial 225µg/kg dose). Through 48 h, the proportion of rebleeds was 3.2% (75µg/kg initial dose) and 5.6% (225µg/kg initial dose); the difference between initial dose strategies was not statistically significant. The majority of rebleeds were controlled with a single dose of eptacog beta and no subject who treated a rebleed required hospitalization.Subjects with haemophilia with inhibitors who used eptacog beta to treat mild/moderate BEs experienced a low incidence of rebleeding. Rebleeds that did occur were effectively controlled with eptacog beta (median, one dose) without the need for hospitalization. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion To assess the real‐world efficacy and safety of recombinant factor IX albumin fusion protein (rIX‐FP) in patients with hemophilia B (HB) in France.Data on dosing frequency, weekly consumption, and bleeds before‐and‐after switching to rIX‐FP, were collected from December 2021 to February 2024. Annualized (spontaneous) bleeding rates [A(s)BRs] were calculated only in patients on prophylaxis with a follow‐up ≥ 6 months.This interim analysis focused on 77 patients ≥ 12 years; 62 (81%) had severe HB. After switching to rIX‐FP, the infusion interval was 14 (7–14) days. Weekly consumption was 43 (35.5–53) IU/kg. ABRs and AsBRs were 0.5 (0–1.9) and 0 (0–0.7) (n = 63) at 18.2 (12.3–21.9) months of follow‐up. Prophylactic efficacy of rIX‐FP was considered ‘Excellent’/‘Good’ in 65/68 (95%) patients. Among the 43 patients previously treated with rFIXFc, 21 increased the infusion interval from 7 (7–11) days with rFIXFc to 14 (7–14) days with rIX‐FP; 33/43 (77%) reduced weekly factor IX (FIX) consumption from 59.95 (46.35–77.93) to 42.5 (35.88–50.25) IU/kg. Patients maintained good protection against bleeds.This analysis confirmed that switching to rIX‐FP allows for reducing injection frequency and FIX consumption while maintaining good bleed protection. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aim Methods Results Conclusion Haemophilia A (HA) is a rare bleeding disorder caused by variants in F8. Although traditional mutational analyses have identified numerous pathogenic variants, the aetiology of HA in certain patients remains unclear. Furthermore, female patients with severe HA are rare.To investigate the molecular defects underlying severe HA in two patients and provide personalised reproductive interventions for their families.Two patients diagnosed with severe HA without other clinical phenotypes were enrolled in the study. A combination of whole‐exome sequencing, real‐time quantitative polymerase chain reaction and long‐read sequencing (LR‐sequencing) was performed to reveal the molecular defects of them, followed by the application of different reproductive intervention strategies.Proband 1, a 29‐year‐old man with FVIII activity of 0.8%, did not exhibit common F8 variants, including Inv1 or Inv22, in the coding region. However, he carried a rare maternal novel inversion on ChrX:154148973_154170321, spanning approximately 21.345 Kbp, with breakpoints in introns 13 and 14 of F8. Finally, the couple of Proband 1 opted for assisted reproductive technology using preimplantation genetic testing and successfully conceived. Proband 2, a 20‐year‐old female with severe HA and FVIII activity of 0.6%, carried inv22 of F8. Further investigation combining whole exome sequencing (WES) and pedigree analysis revealed that she carried a maternal cross‐deletion encompassing exons 1–22 of F8, FUNDC2, BRCC3 and CLIC2, along with a de novo missense variant c.5852T>C (p.Leu1951Ser) on her paternal X‐chromosome. Chromosome X‐inactivation (XCI) analysis demonstrated a highly skewed inactivation of the maternal X chromosome, with a ratio of 98:2. Subsequently, prenatal diagnosis confirmed that the third child in this family did not carry any of the F8 variants present in Proband 2.Our findings provide novel insights into the genetic aetiology of HA and emphasise the importance of a definitive diagnosis in guiding genetic counselling and personalised reproductive interventions for affected individuals and their families. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze the influencing factors of immune-related adverse drug reactions in the treatment of non-small cell lung cancer (NSCLC) with programmed death receptor 1 (PD-1) / programmed death receptor ligand 1 (PD-L1) inhibitors, and to construct the predictive model. METHODS: A total of 280 patients with NSCLC admitted into the hospital from Jan. 2021 to Oct. 2023 were retrospectively analyzed, which were randomly divided into the modeling set (196 cases) and validation set (84 cases) according to a ratio of 7 ∶ 3, and the patients in the modeling group were divided into complicating group and non-complicating group according to whether there were complicated with immune-related adverse drug reactions during treatment. Multivariate Logistic regression was used to analyze the influencing factors of immune-related adverse drug reactions in NSCLC patients, and R software was used to construct the prediction model. Bootstrap method was adopted to conduct internal validation on the model, the receiver operating characteristic curve (ROC), calibration curve and decision curve (DCA) were drawn to evaluate the predictive efficacy, calibration degree and clinical net benefit of the model respectively. RESULTS: The incidence of immune-related adverse drug reactions in NSCLC patients treated with inhibitors was 32. 50% (91 / 280); the proportion of patients age ≥65 years old, with smoking history and low expression of PD-L1, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), neutrophil / lymphocyte ratio (NLR) and platelet / lymphocyte ratio (PLR) of the complicating group were higher than those of the non-complicating group, with statistically significant differences (P < 0. 05). Results of further Logistic regression analysis showed that age ≥65 years old, smoking history, low expression of PD-L1, elevated IL-6, TNF-α, NLR and PLR were risk factors for immune-related adverse drug reactions in NSCLC patients (P < 0. 05); the areas under the predictive curve of the modeling set and the validation set were 0. 863 and 0. 851, respectively; the P values of Hosmer-Lemeshow test results of both the modeling set and the validation set were > 0. 05, with good degree of fitting; results of DCA showed that the nomogram models of both the modeling set and the validation set had good clinical net benefits. CONCLUSIONS: This study has identified the influencing factors of immune-related adverse drug reactions in NSCLC patients treated with PD-1/ PD-L1 inhibitors, and the predictive model constructed accordingly is helpful for clinical identification of high-risk patients, so as to intervene in advance to reduce adverse drug reactions. [ABSTRACT FROM AUTHOR]

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno‐associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X‐linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler‐Najjar disease, alpha‐1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short‐ and long‐term management currently proposed to prevent or correct liver reactions in clinical practice. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hemophilia A is an X-linked recessive illness produced by a deficiency of coagulation factor VIII. This study aimed to evaluate serum vitamin D in hemophilic pediatric patients and its correlation with joint health and quality of life. Methods: This case-control study was performed on ninety children under the age of 18 years old and separated into two groups: study group of 45 children with hemophilia A and control group of 45 healthy children at an outpatient pediatric hematology clinic at the Beni-Suef University hospitals. Results: Serum vitamin D levels were significantly lower in hemophilia A patients than in controls (p < 0.001). The level of serum vitamin D was deficient in 38 (84.4%), insufficient in 4 (8.8%) and sufficient in 3 (6.6%) in the study group while deficient in 8 (17.7%), insufficient in 16 (35.5%) and sufficient in 21 (46.6%) in the control group. Total hemophilia joint health score (HJHS) had a significant negative correlation with serum total calcium (R = −0.31, p = 0.038) and serum vitamin D level (R = −0.974, p < 0.001) while also positively correlated with alkaline phosphatase (R = 0.834, p < 0.001). A quality-of-life index that is specific to total hemophilia (Haemo-Qol/Haem-A-QoL) had a significant positive correlation with total hemophilia joint health score (HJHS) (R = 0.934, p < 0.001) and negatively correlated with serum vitamin D level (R = −0.924, p-value lower than 0.001), alkaline phosphatase (R = 0.842, p < 0.001), and severity of hemophilia (R = 0.67, p < 0.001). Conclusions: patients with hemophilia A had lower vitamin D levels than healthy controls. The severity of vitamin D deficiency is related positively to (HJHS) hemophilia and quality of life hemophilia cases according to Haemo-QoL. [ABSTRACT FROM AUTHOR]

Objectives: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. Methods: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. Results: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. Discussion: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. Conclusion: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan. [ABSTRACT FROM AUTHOR]

Objectives: To describe clinical characteristics, factor consumption, and events of interest in patients with haemophilia A without inhibitors receiving prophylaxis in France, and the clinical impact of switching to Elocta® in this population. Methods: This retrospective, observational study using the Système National des Données de Santé database, analysed data from patients with haemophilia A without inhibitors using prophylactic factor VIII (FVIII) replacement therapy during 2016–2019. Clinical characteristics, treatment patterns and switches, factor consumption, and rate of events of interest were determined. In a sub-cohort of patients treated with Elocta®, clinical characteristics, factor consumption, and rate of events of interest before and after switching to Elocta® were compared. Results: For 545 patients, with mean age (standard deviation [SD]) 25.4 (17.8) years, Elocta® was the most used treatment. Bleeding events and articular non-bleeding events leading to hospitalization occurred in 15.4% and 13.9% of patients, respectively, and 9.9% of patients had surgeries or procedures related to haemophilic arthropathy. The mean (SD) FVIII product consumption was 344 (93) IU/kg/month for extended half-life treatment, and 331 (98) IU/kg/month for standard half-life products. For the sub-cohort of 146 patients, bleeding events (SD) decreased from 0.32 (2.2) to 0.09 (0.42) events/patient/year (p = 0.227) after switching to Elocta®. There was no statistically significant difference in rates of factor consumption or articular non-bleeding events before and after initiation of Elocta®. Conclusion: This study provides real-world insights that advance the understanding of treatment patterns and events of interest in patients with haemophilia A on prophylactic regimens in France. [ABSTRACT FROM AUTHOR]

Backround: Patients with hemophilia A can develop inhibitors to factor concentrates. Emicizumab, a nonfactorbased therapy, has efficacy despite inhibitors. FVIII activity assessment on emicizumab treatment requires a bovine chromogenic reagent such as TriniCHROM FVIII:C. Methods: FVIII levels were measured in 15 patients with and 35 without hemophilia and 10 patients on emicizumab therapy with a time-to-clot and the TriniCHROM FVIII:C reagents. FVIII inhibitor levels were also determined with both reagents. Results: Acceptable agreement of FVIII and FVIII inhibitor levels were obtained with the 2 reagents (R² = 0.92 and 0.96, respectively) in patients not exposed to emicizumab. The time-to-clot FVIII assay overestimated FVIII levels in patients on emicizumab therapy. The chromogenic FVIII assay delivered accurate endogenous FVIII levels in patients on emicizumab therapy. Conclusions: The TriniCHROM FVIII:C assay is compatible with routine automated coagulation analysers and delivers accurate FVIII and FVIII inhibitor levels. [ABSTRACT FROM AUTHOR]

Introduction Aim Methods Results Conclusion Highlights Patients with haemophilia (PWH) often have difficulty accessing dental services.To determine the accessibility of dental care for PWH and to examine their perceptions of how coronavirus type‐2 (CoV‐2) disease (COVID‐19) has affected their ability to access dental treatments following the pandemic.The questionnaire survey was conducted between July 2022 and December 2022 at haemophilia treatment centres in Hungary. Variables with statistical significance (Pearson's Chi‐squared test; p < .05) were included in logistic regression analyses. Least absolute shrinkage and selection operator (LASSO) regression was used as a machine learning technique to identify the most predictive variables.Twenty‐one percent of the sixty‐eight participants reported that they had been refused dental treatment, mainly in primary care (86%). Dental refusal was influenced by infectious disease (OR: 4.48, CI: 1.14–17.69) and previous dental bleeding complications (OR: 4.23, CI: 1.10–16.27). There was correlation between dental visits and having a permanent dentist or receiving oral hygiene advice (OR: 9.95, CI: 2.86–34.62 and OR: 3.84, CI: 1.09–13.58). Participation in an oral hygiene consultation increased patients’ satisfaction with their dental care (OR: 6.28, 95% CI: .71–55.88). Twenty‐eight percent of patients had experienced difficulties since the start of the COVID‐19, but 84% had visited their dentist at least once between 2021 and 2022 (p = .002). Nevertheless, 16% of respondents went for only the most necessary treatments due to pandemic.Refusal of dental care was high among participants, especially in primary care. The COVID‐19 pandemic has exaggerated the difficulties of PWH in accessing dental treatment. Patients with haemophilia (PWH) have difficulty accessing dental care, and the coronavirus type 2 (CoV‐2) disease pandemic (COVID‐19) has created a new barrier. The study revealed a high prevalence of dental care refusal (21%), particularly in primary care (86%). This 2022 survey found that 28% of patients experienced difficulties since the pandemic started and 16% only sought necessary treatments. [ABSTRACT FROM AUTHOR]

Introduction Aim Methods Results Conclusion 2022 was a landmark year with two adeno‐associated viral vectors (AAVs) receiving conditional marketing authorization from EMA for the treatment of persons with severe haemophilia A and severe to moderately severe haemophilia B and a third in 2024. Gene therapy is a transformative, irreversible treatment with long‐lasting effects, necessitating development of new clinical pathways to ensure optimal outcomes.To develop a consensus framework and service specification for delivery of AAV gene therapy for haemophilia in adults within the UK using the hub‐and‐spoke model proposed by the European Association of Haemophilia and Allied Disorders and the European Haemophilia Consortium.The UK Haemophilia Centre Doctors Organisation (UKHCDO) set up a working party to develop expert consensus guidance, working with NHS England to ensure alignment with NHS England commissioning and the national service specification.These guidelines detail the patient pathway, counselling and governance requirements for the hub‐and‐spoke model. The national service specification requires the hub site to manage governance for AAV‐based gene therapy. Proposed regional and national multidisciplinary teams will harmonize clinical practices incorporating expertise from various specialities and professional groups. Key requirements identified include standardized documentation and multidisciplinary collaboration. Nationally agreed patient information and counselling checklists will streamline the informed consent process and facilitate data collection for long‐term safety and efficacy monitoring.These guidelines provide a structured framework for the delivery of liver‐directed gene therapy. Whilst specific to the United Kingdom they provide a framework for the implementation of gene therapy in other countries for haemophilia and other monogenic disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Health information for 17 109 people living with hemophilia A (PLwHA) is contained within the ATHNdataset. We aimed to evaluate the real‐world effectiveness of damoctocog alfa pegol (BAY 94‐9027, Jivi®) for hemophilia A.The ATHNdataset was queried for PLwHA receiving damoctocog alfa pegol between January 1, 2010 and April 30, 2022. Data captured via patient charts were analyzed.At data cutoff, 205 PLwHA were treated with damoctocog alfa pegol: 150 (73.2%) severe (1 female [0.5%]) and 55 (26.8%) mild/moderate (3 [1.5%] female). In total, 32/205 (25.9%) PLwHA received on‐demand treatment; 172 (83.9%) received prophylaxis—161 (93.6%) continuous prophylaxis. Documented bleed rates were available for 187 (91.2%) PLwHA, including those on prophylaxis and on‐demand regimens, with 150 (80.2%) treated for > 12 months. Overall annualized bleeding rates and proportion of PLwHA with zero bleeds, receiving prophylaxis during the observation period, were mean (SD) 0.26 (1.03) and 138/157 (87.9%), respectively. No new or recurring inhibitors were reported.A low number of bleeds were observed with damoctocog alfa pegol in the real world in both male and female PLwHA. Data should be interpreted with caution owing to limitations of real‐world studies and insubstantial data for female PLwHA. [ABSTRACT FROM AUTHOR]

Introduction: The haemophilia joint health score (HJHS) is a tool used to assess joint changes in patients with haemophilia. There is lack of consensus on the interpretation of HJHS scores and their clinical relevance. Aim: To evaluate available literature reporting HJHS changes over time and assess a possible cut‐off value for clinically relevant outcomes and the ideal follow‐up for a meaningful score change. Methods: We conducted a literature search of studies published between 2011 and 2023 where the HJHS version 2.1 had been adopted to detect changes in joint health in patients with haemophilia. We focused on studies that assessed clinical relevance of HJHS changes, evaluated the use of cut‐off values and reported a follow‐up over time. Results: Our search identified 213 publications of which 53 (25%) were deemed relevant for this review. Of these, 33 (62%) publications reported the total HJHS score and 20 (38%) reported a single joint HJHS score, while the way of reporting HJHS scores/change was highly variable. Ten publications (19%) assessed clinical relevance, but their methods of calculation differed (defining a cut‐off score, measuring standardised response mean or minimal detectable change). The follow‐up duration varied from 2 weeks to 8 years in these 10 studies. Conclusions: High variability in assessing HJHS change over time is the primary consequence of its low sensitivity, and the lack of consensus on interpretation and clinical relevance of the score. Therefore, more sensitive tools should be used alongside HJHS to better define the joint health status of patients with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction: Despite the progress in gene editing platforms like CRISPR/Cas9 with the potential to transform the standard of care for haemophilia, the language used to explain and discuss gene editing is not aligned across the haemophilia community. Here, we present the objective and rationale for developing a clear, consistent, and globally aligned gene editing lexicon to address these communication gaps. Methods: Effectively communicating complex gene editing concepts requires a clear and consistent vocabulary. Through collaboration with a diversity of haemophilia stakeholders, our main goal is to develop an accurate, informative lexicon which avoids overpromising or highly technical terminology. Using an innovative process, representatives from several patient and scientific haemophilia organizations and select biotechnology companies will develop and refine language concepts to be tested with approximately seventy participants across the United States of America, United Kingdom, and Germany. Participants will include lived experience experts (LEEs) and haematologists. The process will be overseen by the Lexicon Steering Committee of global experts from leading scientific and patient organizations in the haemophilia and gene editing fields. Results: Initial feedback provided a robust foundation and rationale for building clear, consistent language around gene editing. This lexicon development framework will allow for increased understanding across the haemophilia community, including the development of valid informed consent and shared decision‐making materials. Conclusion: Results provide important building blocks for stimuli development and highlight the need for a novel gene editing lexicon. In the next phase, language stimuli will be tested with LEEs and haematologists to better understand audience preferences and help shape the final lexicon. [ABSTRACT FROM AUTHOR]

Background: The development of haemophilic arthropathy causes joint damage that leads to functional impairment that limits the performance of activities in patients with haemophilia. The aim was to identify the best predictive model for performing instrumental activities of daily living in adult patients with haemophilia arthropathy. Methods: Cross‐sectional cohort study. 102 patients were recruited. The dependent variable was the performance of instrumental activities of daily living (Lawton and Brody scale). The dependence on the performance of activities of daily living was the dependent endpoint (Barthel scale). The secondary variables were joint damage (Hemophilia Joint Health Score), pain intensity, and clinical, anthropometric, and sociodemographic variables. Results: The degree of dependence, joint damage, pain intensity, and marital status (Cp = 5.60) were the variables that best explain the variability in the performance of instrumental activities of daily living (R2adj = 0.51). Loss of predictive capacity is acceptable with good mean internal (R2 mean = 0.40) and external (R2‐r2 = 0.09) validation. According to the predictive pattern obtained, patients with haemophilia, who were married, without joint pain or damage, and independent in their day‐to‐day lives, had a score of 7.91 points (95% CI: 7.42; 8.39) in the performance of instrumental activities of daily living. Conclusions: The predictive model for the functional capacity of instrumental activities of daily living in haemophilia patients encompasses factors such as level of autonomy, joint impairment, pain severity, and marital status. Notably, despite the presence of joint damage, individuals with haemophilia exhibit a significant level of independence in carrying out both basic daily tasks and instrumental activities of daily living. International registration number: Id NCT04715100. [ABSTRACT FROM AUTHOR]

Introduction: The management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies. Aim: To provide real‐world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis. Methods: This is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement. Results: Twenty‐four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first‐line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%–72% more cost‐effective than eptacog alfa. No safety concerns or adverse events were reported. Conclusions: In this case series, eptacog beta was safe, effective, and economical as first‐line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors. [ABSTRACT FROM AUTHOR]

Background: There is limited research on body composition in persons with haemophilia (PwH). The literature describes an increased body fat distribution and decreased lean mass in PwH compared to healthy controls using bioimpedance analysis. Using dual x‐ray absorptiometry (DXA), which is known to be the most accurate method, this investigation aims to postulate reference data for body composition parameters within haemophilia severity phenotypes and age groups. Methods: Persons underwent whole body DXA screening using Horizon. Body fat percentage, estimated visceral adipose tissue (VAT), appendicular fat and lean mass, and lean and fat mass in relation to body height were assessed. Haemophilia severity and five age groups were distinguished. Results: Two hundred and one persons with mild (n = 44), moderate (n = 41), or severe (n = 116) haemophilia A/B (median age 40 [28–55; 1.IQ–3.IQ] years) were analysed. The median body fat percentage was 28.7% [25.5%–33.9%] and median estimated VAT was 657 g [403–954 g] with no significant difference between severity phenotypes (p =.474; p =.781). Persons with severe haemophilia had less lean mass compared to moderate and mild haemophilia (p =.013; p =.034). Total and appendicular fat is increased in older PwH (aged ≥40 years) compared to younger PwH (aged ≤29 years; p <.05). Lean mass did not differ between age groups. Conclusion: This study provides valuable reference data for body composition parameters in PwH. Persons with severe haemophilia show significantly less lean mass compared to persons with moderate or mild haemophilia. Body fat percentage and VAT did not differ between severity phenotypes, but increased with age. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Patients with hemophilia A can safely undergo cardiac surgery. Combining continuous infusion and boluses of factor VIII is both safe and cost‐effective. Interdisciplinary approach and meticulous planning are crucial in the prevention of bleeding complications. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. Methods: The prospective, non‐interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient‐reported outcomes, including treatment burden, were assessed. Results: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. Conclusion: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hemophilia B is a hereditary bleeding disorder due to the production of liver malfunctional factor IX (FIX). Gene therapy with viral vectors offers a cure. However, applications are limited due to pre-existing antibodies, eligibility for children under 12 years of age, hepatotoxicity, and excessive costs. Lipid nanoparticles are a potential alternative owing to their biocompatibility, scalability, and non-immunogenicity. However, their therapeutic applications are still elusive due to the poor transfection efficiencies in delivering plasmid DNA into primary cells and target organs in vivo. To develop efficient liver-targeted lipid nanoparticles, we explored galactosylated lipids to target asialoglycoprotein receptors (ASGPRs) abundantly expressed on hepatocytes. Methods: We developed 12 novel liposomal formulations varying the galactose lipid Gal-LNC 5, cationic lipid MeOH16, DOPE, and cholesterol. We evaluated their physicochemical properties, toxicity profiles, and transfection efficiencies in hepatic cell lines. Among the formulations, Gal-LNC 5 could efficiently transfect the reporter plasmid eGFP in hepatic cell lines and specifically distribute into the liver in vivo. Toward developing functional factor IX, we cloned Padua mutant FIX-L in a CpG-free backbone to enhance the expression and duration. Results: We demonstrated superior expression of FIX with our galactosylated lipid nanoparticle system. Conclusions: The current research presents a specialized lipid nanoparticle system viz. Gal-LNC which is a specialized lipid nanoparticle system for liver-targeted gene therapy in hemophilia B patients that has potential for clinical use. The Gal-LNC successfully delivers a CpG-free Padua FIX gene to liver cells, producing therapeutically relevant levels of FIX protein. Among its benefits are the ideal qualities of stability, targeting the liver specifically, and maximizing efficiency of transfection. Optimization of liver-targeting lipid nanoparticle systems and function FIX plasmids will pave the way for novel lipid nanoparticle-based gene therapy products for hemophilia B and other monogenic liver disorders. [ABSTRACT FROM AUTHOR]

Patients with hemophilia frequently require supplementary interventions, either invasive (suturing, gel foam, or cauterization) or non-invasive (fibrin sealant/glue), to attain hemostasis post dental procedures. This study aimed to compare the efficacy of fibrin sealant against traditional methods for achieving hemostasis post dental surgery. The medical records of patients with factor VIII or IX deficiency, or von Willebrand disease, who underwent dental procedures in the Department of Dentistry, Seth GSMC and KEM Hospital, were evaluated for inclusion in this retrospective matched cohort study. Cohort-1 included those treated with a fibrin sealant (Tisseel Lyo) with/without traditional hemostatic measures post-procedure, while cohort-2 (controls) included those in whom no fibrin sealant was used. A total of 128 patients, 64 in each group, were evaluated. There was no statistically significant difference in demographics, disease-related variables, dental complaints, or preoperative treatment given between the groups. However, there was a significant reduction (P < 0.001) in the requirement for secondary procedures for hemostasis (suturing, gel foam application, and/or cauterization) and postoperative requirement for factor replacement (P = 0.003) in the fibrin glue group as compared to the controls. In this study, fibrin sealant demonstrated superior efficacy in mitigating the necessity for active hemostasis control. [ABSTRACT FROM AUTHOR]

Aim: Hemophilic pseudotumor (HP) is a very rare complication of hemophilia seen in only 1–2% of the cases. Although it is much more common in long bones, pelvis and small bones of hands and feet and very rarely involving jaw bones. Method and result: In the present case, the presence of a rare hemophilic pseudotumor of the mandible with the positive history of Hemophilia B justifies that the history, clinical and radiological examinations were sufficient to arrive at conclusive diagnosis precluding invasive diagnostic procedures such as biopsy hence avoiding the risk of hemorrhage, infection, or fistula. This case also highlights that patient was conservatively managed with Factor IX replacement alone with a very good clinical outcome. Conclusion: HP should be considered as a differential diagnosis of any progressive swelling of hard and soft tissues occurring in a patient with severe haemophilia. [ABSTRACT FROM AUTHOR]

Background: Rabies remains a major public health problem in low- and middle-income countries. However, human rabies deaths are rarely laboratory-confirmed or sequenced, especially in Africa. Five human rabies deaths from Tanzania and Kenya were investigated and the causative rabies viruses sequenced, with the aim of identifying implications for rabies control at individual, healthcare and societal levels. Case presentation: The epidemiological context and care of these cases was contrasting. Four had a clear history of being bitten by dogs, while one had an unclear biting history. Two individuals sought medical attention within a day of being bitten, whereas three sought care only after developing rabies symptoms. Despite seeking medical care, none of the cases received complete post-exposure prophylaxis: one patient received only tetanus vaccination, one did not complete the post-exposure vaccination regimen, one followed an off-label vaccination schedule, and two did not receive any post-exposure vaccinations before the onset of symptoms. These cases highlight serious gaps in health-seeking behaviour, and in health systems providing appropriate care following risky exposures, including in the accessibility and effectiveness of post-exposure prophylaxis as it is administered in the region. Conclusions: The viral genomic and epidemiological data confirms dog-mediated rabies as the cause of each of these deaths. The phylogenetic investigation highlights the transboundary circulation of rabies within domestic dog populations, revealing distinct rabies virus clades with evidence of regional spread. These findings underscore the importance of coordinated cross-border control efforts between the two countries. Urgent action is needed to improve awareness around the need for emergency post-exposure vaccines that should be accessible in local communities and administered appropriately, as well as investment in coordinated dog vaccination to control dog-mediated rabies, the underlying cause of these deaths. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions The 24‐month, prospective, non‐interventional, European multicenter A‐SURE study evaluated the real‐world effectiveness of prophylaxis using an extended half‐life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half‐life (SHL) FVIII products in patients with hemophilia A.Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses.Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of −0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of −54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development.rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption. [ABSTRACT FROM AUTHOR]

Alu-elements comprise a large part of the human genome and some insertions have been shown to cause diseases. Here, we illuminate the protective role of an Alu-element in the 3'UTR of the human Factor 9 gene and its ability to ameliorate a poly(A) site mutation in a hemophilia B patient, preventing him from developing a severe disease. Using a minigene, we examined the disease-causing mutation and the modifying effect of the transposon in cellulo. Further, we simulated evolutionary scenarios regarding alternative polyadenylation before and after Alu insertion. A sequence analysis revealed that Old World monkeys displayed a highly conserved polyadenylation sites in this Alu-element, whereas New World monkeys lacked this motif, indicating a selective pressure. We conclude that this transposon has inserted shortly before the separation of Old and New World monkeys and thus also serves as a molecular landmark in primate evolution. [ABSTRACT FROM AUTHOR]

Background: Hemophilia is a rare X-linked bleeding disorder. Prophylaxis has improved outcomes, but there are still unmet needs to be addressed. The aim of this study was to develop a patient journey in pediatric patients with hemophilia, a visual tool that illustrates patients' relationship with the healthcare provider through time useful for identifying patient needs, potential concerns ("pain points"), and gaps in care. Methods: qualitative study in a pediatric hemophilia unit using a human-centered design methodology. First stage: discover and empathize: (a) semi-structured interviews to patients/families and stakeholders; (b) observation techniques ("shadowing") to patients/families and professionals. Second stage: analyzing the collected information to create the patient journey. Results: A preliminary "clinical journey" was built using information from eight interviews with professionals from the interdisciplinary hemophilia team. Interviews with patient association representatives, 13 patients/families, and six "shadowing" techniques with patients and professionals were used to compare the "clinical journey" with the patient's reported experience. Main "pain points" were detected before diagnosis, at diagnosis, during assimilation, at treatment initiation, during training, and when patients start asking about their condition. The empowerment process was detected as a potential moment to improve patient/family experiences. Conclusions: The patient journey helps to better understand patient/family experiences related to the disease in different scenarios. Caregivers and patient learning and empowerment processes are significant moments where the interdisciplinary team should focus to offer valuable solutions to improve outcomes. Further research is required in this area, particularly empirical research to amend or confirm the suggested patient journey. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the status of anti-thrombus treatment in patients with left ventricular thrombus (LVT), analyze the use of oral anticoagulant drugs and clinical outcomes of patients with LVT, so as to provide reference for the treatment of LVT. METHODS: Patients with LVT diagnosed in the medical record system of the hospital from May 2018 to Sept. 2023 were included. The use of anticoagulant drugs was retrospectively analyzed. The thrombus resolution, thromboembolism events and bleeding events treated with anticoagulation or nonanticoagulation, new oral anticoagulant drugs (NOAC) or warfarin were investigated. RESULTS: A total of 156 patients were included, and 120 patients (76. 9%) received anticoagulant therapy, including 87 patients (55. 8%) treated with NOAC and 33 patients (21. 2%) treated with warfarin. The incidence of thromboembolism events in the anticoagulation group was significantly lower than that in the non-anticoagulation group [5. 0% (6 / 120) vs. 16. 7% (6 / 36), P = 0. 032], and the incidence of bleeding events was not increased [13. 3%(16 / 120) vs. 25. 0%(9 / 36), P= 0. 094]. There was no statistically significant difference in the incidence of thromboembolism events and bleeding events between the NOAC group and warfarin group (P > 0. 05). Further analysis of thrombus regression in 106 patients with imaging records showed complete regression of left ventricular thrombus in 72 patients (67. 9%). The thrombus regression rate in the anticoagulation group was significantly higher than that in the non-anticoagulation group [72. 4%(63 / 87) vs. 47. 4%(9 / 19), P = 0. 034], and the median time of thrombus regression was shorter than that in the non-anticoagulation group [48. 0 (32. 0, 120. 0) d vs. (167. 4 ± 113. 0) d, P = 0. 035], with statistically significant difference. The thrombus regression rate was similar between NOAC group and warfarin group, with no statistically significant difference [71. 4% (45 / 63) vs. 75. 0% (18 / 24), P = 0. 739]. Compared with the warfarin group, the thrombus regression rate was faster in the NOAC group, the difference was statistically significant [43. 0 (32. 0,85. 0) d vs. 106. 0 (32. 8, 239. 8) d, P = 0. 049]. CONCLUSIONS: Anticoagulant therapy can improve thrombotic regression, reduce thromboembolic events and do not increase the risk of bleeding in patients with LVT, the proportion of anticoagulants still needs to be improved. NOAC could be considered as an alternative treatment for warfarin, especially in patients with warfarin intolerance. [ABSTRACT FROM AUTHOR]

Objectives: Haemophilia B (HB), characterised by deficient factor IX (FIX), leads to spontaneous bleeds. Severe cases require prophylactic FIX replacement. This post hoc analysis assessed the first spontaneous bleeds among previously untreated patients (PUPs) with HB treated with recombinant FIX Fc fusion protein (rFIXFc) (NCT02234310) to identify factors influencing bleeds. Methods: Subjects included paediatric PUPs with HB (≤2 IU/dL endogenous FIX). Analyses described treatment patterns (on demand [OD] vs. prophylaxis) and prophylaxis type (started on vs. switched to prophylaxis). Kaplan–Meier analyses assessed the time to first spontaneous bleed, including median time to event and fitting models with predictors for treatment regimen and/or baseline age. Results: PUPs B‐LONG enrolled 33 subjects. Baseline age did not influence the time to first spontaneous bleed for any rFIXFc regimen. Those who started on prophylaxis with rFIXFc (n = 11), compared with those treated OD (n = 22), had an extended time to first spontaneous bleed. Starting prophylaxis afforded a 93% reduced risk of first spontaneous bleed versus starting OD (hazard ratio [95% confidence interval]: 0.071 [0.009–0.592]) (p =.015). Conclusion: rFIXFc prophylaxis, particularly starting early, reduced the risk of bleeding and delayed time to first spontaneous bleed compared with rFIXFc OD. Hence, initial treatment regimens impact bleed patterns in paediatric PUPs. [ABSTRACT FROM AUTHOR]

Globally, intron 22 inversions (Inv22s) of the factor VIII gene (F8) are the most frequent pathogenic variants and account for 45–50% of severe hemophilia A (SHA) cases, while intron 1 inversion (Inv1) explains 1–5% of SHA cases. The detection of both inversions by an inverse shifting-polymerase chain reaction (IS-PCR) is the first choice worldwide for the diagnosis of patients and carriers of SHA. To improve its sensitivity and reproducibility in the visualization of PCR products, we approached the IS-PCR with fluorescent capillary electrophoresis instead of agarose electrophoresis. Based on the original protocol, we modified two primers by 5'-end labeling with FAM™ fluorescent dye for the detection of the PCR products by capillary electrophoresis. Additionally, the "fast enzymes" BclI and T4-Ligase were incorporated for work saving in the genomic digestion and ligation reactions, respectively. Once we accomplished the standardization and verified the reproducibility of the modified IS-PCR method, we applied it for the diagnosis of a cohort of SHA patients and carriers. The modified IS-PCR by fluorescent capillary electrophoresis for PCR product detection is more sensitive than agarose electrophoresis. The method was also improved by using the new rapid enzymes to save time in the whole process. [ABSTRACT FROM AUTHOR]

Haemarthrosis is an inherent clinical feature of haemophilia, a disease characterised by an absence or reduction in clotting proteins. Patients with severe haemophilia experience joint bleeding leading to blood-induced ankle arthropathy (haemarthropathy). Altered biomechanics of the ankle have been reported in people with haemophilia; however, the consequence of this on joint health is little understood. The aim of this study was to assess the changes in joint contact due to haemophilia disease-specific gait features using patient-specific modelling, to better understand the link between biomechanics and joint outcomes. Four, image-based, finite element models of haemophilic ankles were simulated through consecutive events in the stance phase of gait, using both patient-specific and healthy control group (n = 36) biomechanical inputs. One healthy control FE model was simulated through the healthy control stance phase of the gait cycle for a point of comparison. The method developed allowed cartilage contact mechanics to be assessed throughout the loading phase of the gait cycle. This showed areas of increased contact pressure in the medial and lateral regions of the talar dome, which may be linked to collapse in these regions. This method may allow the relationship between structure and function in the tibiotalar joint to be better understood. [ABSTRACT FROM AUTHOR]

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Objective: To observe the joint lesions in patients with hemophilia A using conventional ultrasound, power Doppler imaging (PDI), and super-micro flow imaging (SMI) techniques, and evaluate the preventive treatment efficacy of different treatment regimens in hemophilia patients. Methods: Severe hemophilia A patients who were admitted to North China University of Science and Technology Affiliated Hospital were collected and divided into four groups according to different treatment regimens: Pharmacokinetics (PK) guided individualized preventive treatment group (group A), standard dose preventive treatment group (group B), low dose preventive treatment group (group C), and on-demand replacement treatment group (group D). Haemophilic Early Arthropathy Detection Results: As the treatment time increased, the HEAD-US-C scores in group A, B, and C decreased, with a more significant decrease in group A than group B and C, while there was an increase in group D. The AJBR in all four groups increased, with a more significant change in group D than the other three groups, and the change in group A was the lowest. There was a correlation between HEAD-US-C score and AJBR. Conclusion: Preventive treatment can slow down the progression of joint lesions in hemophilia patients, effectively alleviate joint inflammation and reduce bleeding times. PK guided individualized preventive treatment is superior to other preventive treatments and on-demand replacement treatment. The HEAD-US-C can be used to assess joints, which has certain application value for evaluating the therapeutic effect of hemophilia, providing imaging evidence for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsTo evaluate the efficacy of an immersive movement visualization intervention in patients with hemophilia and hemophilic knee arthropathy.Randomized, single-blind clinical study. Twenty-eight patients with hemophilia were recruited. Patients were randomized to an experimental group (four weeks of immersive movement visualization) and a control group (no intervention). The intensity of pain, pressure pain threshold in the knee, tibialis anterior muscle, lower back level, conditioned pain modulation, range of knee motion, and lower limb functionality were evaluated.There were statistically significant differences in the intergroup effect on knee pain intensity (F = 23.71; p < 0.001) and lower limb functionality (F = 7.11; p = 0.003). 42.86% of the patients in the experimental group exhibited changes greater than the minimum detectable change (MDC) in functionality. 39.29% of the patients subject to the intervention experienced changes greater than the MDC in the knee pressure pain threshold.Immersive motion visualization can improve the intensity of joint pain and functionality in patients with hemophilic knee arthropathy. Functionality, pressure pain threshold, and pain intensity improved in those patients who conducted immersive movement visualization.Implications for rehabilitationImmersive visualization of movement significantly improves intensity of joint pain, functionality, pressure pain threshold, joint health, and conditioned pain modulation in patients with hemophilic knee arthropathy.The fact that it is a therapy without potential aversive stimuli makes it a possible access pathway for patients with high levels of kinesiophobia and/or catastrophism.This low-cost, home-based technology allows its use in patients far from hemophilia reference centers or with difficult access to physiotherapy treatments.The immersive visualization of movement influences the democratization of treatment, in accordance with the WHO's Sustainable Development Goal 3 (health and well-being for all).Immersive visualization of movement significantly improves intensity of joint pain, functionality, pressure pain threshold, joint health, and conditioned pain modulation in patients with hemophilic knee arthropathy.The fact that it is a therapy without potential aversive stimuli makes it a possible access pathway for patients with high levels of kinesiophobia and/or catastrophism.This low-cost, home-based technology allows its use in patients far from hemophilia reference centers or with difficult access to physiotherapy treatments.The immersive visualization of movement influences the democratization of treatment, in accordance with the WHO's Sustainable Development Goal 3 (health and well-being for all). [ABSTRACT FROM AUTHOR]

INTRODUCTION: Very low-dose prophylaxis of antihemophilic factor (AHF) in hemophilia involves administration of minimal amounts of clotting factor concentrates, typically below standard doses, to maintain baseline levels and reduce bleeding episodes. This method uses smaller, more frequent doses to balance bleeding prevention and cost-effectiveness. Close monitoring ensures adequate protection while avoiding overtreatment, offering a tailored, cost-effective approach to improve the quality of life (QoL) of the hemophiliacs. AIM: The study aims to study the bleeding risks in patients with severe hemophilia who are on very low-dose AHF prophylaxis. It also seeks to assess the annual consumption of AHF in the hemophiliacs. In addition, the research will determine the QoL in both groups using the social functioning (SF)-36 questionnaire,evaluate patient compliance with the prophylactic regimen, and check functional disability using the Functional Independence Score in Hemophilia (FISH). MATERIALS AND METHODS: The patients selected for the study were diagnosed with cases of hemophilia and were planned for any surgical procedure. The study was a cross-sectional study lasting 12 months. Patients over 13 years were included and patients with any other bleeding tendencies were excluded from the study. RESULTS: The differences found in the study, were significant in terms of annual bleed rate (ABR), amount of AHF consumed, SF-36, and FISH scores. CONCLUSION: Our study found that very low-dose prophylaxis significantly reduced the ABR in hemophilia patients. Functional independence worsened in the control group but remained stable in the test group, which showed significant improvements in SF-36 domains. The test group had no inhibitor development and showed a decline in severe bleeds, proving the efficacy and superiority of low-dose prophylaxis over on-demand therapy. [ABSTRACT FROM AUTHOR]