Haemophilia最新文献

Introduction: Gene editing therapies offer the possibility of substantial improvement in treatment and quality of life for people with haemophilia (PWH) in a landscape of dynamic therapeutic advancement. Developing a common and understandable language to discuss gene editing will be essential to ensure these treatments can be deployed in a safe and effective manner with fully informed and shared decision-making between healthcare professionals (HCPs) and PWH. A lexicon explaining and clarifying key concepts is one potential tool to address these aims. Here we evaluate how a gene editing lexicon could be deployed to maximise impact and improve patient outcomes.

Aim: To operationalise the gene editing lexicon for successful adoption by the haemophilia community.

Methods: Through an innovative, iterative process, representatives from the haemophilia community, including multidisciplinary HCPs, PWH, and caregivers, with support from language strategy experts, developed a gene editing lexicon and evaluated operational aspects for real-world adoption of this resource.

Results: A gene editing lexicon was developed, including infographics illustrating key concepts. Infographics were adapted from the lexicon to further clarify and communicate these concepts. Infographics were found to be a potentially vital tool for enhancing the practical use of the lexicon to promote shared decision-making and attain informed consent for gene editing therapies.

Conclusion: A gene editing lexicon shows promise for improving the understanding of gene editing for all stakeholders in the haemophilia community. Ensuring the lexicon remains up to date with current therapies and appropriate strategies for adoption such as infographics will enable this resource to have maximum impact.

Introduction: Infants with haemophilia, due to parental overprotection, have difficulty developing their full motor repertoire of typical gross motor development. It is of great clinical importance to evaluate the motor development of these infants with a standardized assessment tool.

Aim: To study the gross motor development in infants with haemophilia, using the Alberta Infant Motor Scale (AIMS) and compare it with full-term (FT) and preterm infants (PT).

Methods: Fifteen FT infants with severe or moderate haemophilia A and B were assessed with the AIMS (Group D). The scale is already standardized in FT Greek infants (Group A). Two groups of PT infants were also included, with gestational age >32 weeks and ≤32 weeks, Groups B and C, respectively. The mean Z-scores were tested with the ANOVA procedure, followed by post hoc pairwise comparisons with Bonferroni correction.

Results: The four groups had significantly different mean Z-scores. Infants in Group A had a mean Z-score of 0 ± 1. Infants in Group B lagged significantly behind by one standard deviation. Preterm infants in Group C had a mean Z-score significantly lower than Group B. Infants in Group D had a mean Z-score significantly lower than Group C.

Conclusions: Motor development in infants with haemophilia significantly lags behind both FT and PT infants. Differences in AIMS scores could be attributed to the reduction of movement activity, since infants with haemophilia are often deprived of certain positions, being held and carried in the parents' arms, as well as from free play time on the floor.

Background: Arthroplasty is the standard treatment for end-stage haemophilic knee arthritis; however, the choice between single knee arthroplasty (SKA) and bilateral knee arthroplasty (BKA) in a single operation remains controversial due to the risks specific to haemophiliacs.

Methods: Two independent researchers conducted searches across CNKI, CBM, Wanfang, PubMed, Cochrane Library, Embase, and Web of Science, with the last search performed on 15 October 2024. Study results include joint function, complication and various cost. Literature quality was assessed using the Newcastle-Ottawa Scale (NOS). Outcomes were evaluated with fixed-effects or random-effects models, while heterogeneity and publication bias were also assessed.

Results: Nine studies involving 309 haemophilia patients were included, with 166 in SKA group and 143 in BKA group. No statistically significant differences were observed between the SKA and BKA groups in range of motion (95% CI: -0.22 [-3.57, 3.13], p = 0.90), Hospital for Special Surgery score (95% CI: -2.13 [-4.89, 0.64], p = 0.13), flexion degree (95% CI: -2.38 [-7.22, 2.46], p = 0.33), cost (95% CI: -0.24 [-0.94, 0.45], p = 0.49), complication rate (95% CI: 1.31 [-0.79, 2.17], p = 0.29), hospital stay (95% CI: 0.25 [-2.06, 2.57], p = 0.83), and coagulation factor usage (p = 0.49). However, The SKA group outperformed the BKA group in terms of operative time, postoperative drainage, and transfusion volume (p < 0.001).

Conclusions: Our study indicates that, apart from differences in operative time, transfusion volume, and blood loss, SKA and BKA show no significant differences in postoperative joint function, complication rates, or costs.

Background: Acquired haemophilia A (AHA) is an acquired bleeding disorder resulting from autoantibodies against Factor VIII (FVIII). Previous studies have reported differences in FVIII inhibitor kinetics (type I or type II) in AHA compared to severe haemophilia A.

Aim: To characterise inhibitor kinetics in AHA and evaluate the proportions displaying type I, II or indeterminate kinetics.

Methods: Single-centre retrospective study of inhibitor kinetics in adults with AHA. Type I kinetics were defined as linear FVIII inhibition with ≥ 97% FVIII inactivation. Type II kinetics were defined as non-linear kinetics and inability to completely neutralise FVIII. Inhibitor titres were calculated using two methods outlined by the International Council for Standardisation in Haematology.

Results: Baseline samples from 34 patients were included. Fifteen samples (44.1%) exhibited type I kinetics, 16 samples (47.1%) exhibited type II kinetics and 3 (8.8%) were indeterminate. Plateau mean residual FVIII:C was higher for inhibitors displaying type II compared to type I kinetics (18.6 vs. 2.9 IU/dL, p < 0.0001). Non-linear regression using a dose-response curve without categorisation for kinetics type yielded a poor fit (R² = 38%), which improved with refitting using categories of type I or II kinetics that explained 87% and 85% of the variability. The median difference in inhibitor titre between the two reporting methods was 5% and 15% in the type I and II kinetics groups, respectively.

Conclusion: FVIII autoantibodies demonstrate either type I or type II kinetics. Greater discrepancy in reported inhibitor titres depending on the method used is seen for inhibitors with type II kinetics.

Introduction: Rare coagulation disorders (RCDs) constitute an important health risk. Data on epidemiology, quality of life (QoL), access to care, and impact of the ongoing economic crisis on RCDs in Lebanon is limited.

Aim: We aimed to address these gaps by evaluating effect of the crisis on the management of RCDs.

Methods: We performed a retrospective chart review of RCD pediatric patients in a tertiary hospital between 2003 and 2023. Patients with deficiencies of fibrinogen, factor (F)II, FV, combined FV and FVIII, FVII, FXI, FXII, FXIII, and congenital deficiency of vitamin K-dependent factors (VKCFDs) underwent a qualitative assessment of the impact of the economic crisis on care and quality of life by an interview aimed at investigating obstacles to diagnosis, disparities in access to treatment, impact of the crisis on QoL and disease management, and opinion on governmental efforts to solve the health crisis.

Results: 46 patients were included. The response rate for the interview was 63%. Among the cohort, 21 (72.4%) reported difficulty accessing treatment since the start of the crisis and 18 (62%) reported "lack of healthcare coverage for necessary treatments" as the main issue. Most participants reported that the Lebanese government did not adequately address their needs during the crisis.

Conclusion: Our study showcased that management of RCD patients in Lebanon has been severely affected by the economic crisis. Combined efforts by public and private sectors are needed to appropriately address this issue. Lessons can be learned from the Lebanese experience to appropriately screen for actionable factors in vulnerable populations.

Introduction: Patients with haemophilia (PWH) often have difficulty accessing dental services.

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Highlights: 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.

Introduction: Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.

Aim: To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A.

Methods: A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses.

Results: Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.

Conclusions: Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.

Introduction: Diagnosing moderate haemophilia A (MHA) solely based on deficient FVIII protein levels limits its optimal management and delays the initiation of prophylaxis. Updating protocols and incorporating new variables into its diagnosis could prevent underestimating disease severity, avoiding early arthropathies and impairing patients' quality of life.

Aim: To propose recommendations to improve the comprehensive management of people with MHA.

Methods: Recommendations from a Spanish panel of eight experts from public comprehensive care centres (CCCs) for people with haemophilia and over 140 people with MHA in follow-up. In a previous analysis, the panel identified the unmet needs of people with MHA and the necessity to develop new specific recommendations for their management.

Results: The panel proposed recommendations in four areas: diagnosis, treatment, follow-up and referrals. They detailed the necessary steps and procedures for the diagnosis, adding other variables to the FVIII levels like bleeding phenotype, genetic profile and joint status to specify the severity and risk classification of people with MHA. Experts proposed an algorithm with unique independent criteria to facilitate the decision to initiate prophylaxis, where the recommended FVIII levels and variables coexist for treatment decision-making. Follow-up proposals addressed periodicity, recommended tests and required visits to CCCs. For referrals, experts proposed criteria and situations considered urgent for a transfer to a CCC for haemophilia patients.

Conclusion: The proposals agreed upon by this expert panel can contribute to update and optimize the management of people with MHA, delaying joint deterioration, pain and disabilities, and improving their quality of life.