Haemophilia最新文献

Introduction: Inhibitor development remains one of the most serious complications of replacement therapy in patients with hemophilia. Tumour necrosis factor-alpha (TNF-α) is a key pro-inflammatory cytokine, and its genetic variants have been implicated in immune-related conditions. The association between TNF-α gene polymorphisms and inhibitor formation in hemophilia has been explored.

Aim: To systematically review and quantitatively synthesize available evidence on the association between TNF-α gene polymorphisms and the development of inhibitors in patients with hemophilia.

Methods: A comprehensive literature search was conducted in PubMed and SciELO from inception to 11 February 2025. Eligible studies evaluated TNF-α polymorphisms in patients with hemophilia and reported data on inhibitor status. Data extraction and quality assessment (using the Q-Genie tool) were performed independently by two reviewers. Meta-analyses were conducted using the Mantel-Haenszel method, where pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Results: Nineteen studies met the inclusion criteria for the systematic review, and ten were included in the meta-analysis. A significant association was observed between the rs1800629 (-308G>A) polymorphism and inhibitor development under the A-recessive model (OR = 2.00; 95% CI: 1.13-3.54). No significant associations were found for other TNF-α polymorphisms.

Conclusion: This meta-analysis suggests that the TNF-α rs1800629 polymorphism may be associated with an increased risk of inhibitor development in patients with hemophilia. These findings highlight the potential role of inflammatory genetic variants in modulating the immune response to replacement therapy. Further large-scale, multi-ethnic studies are needed to confirm these results and better understand the underlying mechanisms.

Introduction: Magnetic resonance imaging (MRI) is the gold standard for assessing haemophilic arthropathy using the IPSG scale. However, MRI-detected abnormalities often correlate poorly with pain, suggesting that structural damage alone cannot explain symptoms. Assessing additional features such as bone marrow oedema (BME) may better capture disease activity and pain in people with haemophilia (PwH).

Aim: This study aimed to evaluate the presence and extent of bone BME in the ankles of PwH, assess the reproducibility of MRI scoring for BME and IPSG, and examine correlations between MRI findings, clinical parameters, pain, and ultrasound results.

Methods: A prospective study was conducted on 56 PwH, assessing 108 ankle joints via MRI using a 3T scanner. IPSG and BME scores were independently assessed by two blinded radiologists. Statistical analyses assessed inter-reader agreement, correlations between MRI scores, and their associations with ultrasound (HEAD-US), joint health (HJHS), and pain intensity over the past 24 h and 4 weeks.

Results: BME was observed in 45% of left and 34% of right ankles. Both IPSG and BME scores showed high reproducibility. BME scores correlated strongly with pain (ρ = 0.61-0.68) and moderately with joint health (HJHS, ρ = 0.56), whereas IPSG total scores showed moderate correlations with pain (ρ = 0.46-0.51). Resampling analyses confirmed stronger BME-pain associations.

Conclusions: This study shows that BME is common in haemophilic ankles and more strongly associated with pain and joint health than IPSG scores. Integrating BME into MRI assessments may enhance evaluation and monitoring of haemophilic joint disease.

Introduction: Sufficient sleep is essential for maintaining both physical and mental health, yet data on sleep health among persons with haemophilia (PwH) remain limited.

Aim: This study aimed to assess sleep in PwH compared to healthy controls (Con) and identify factors associated with impaired sleep quality (SQual) in PwH.

Methods: 100 PwH A or B and 100 Con participated. Sleep metrics were assessed using the German sleep questionnaire (Schlaffragebogen B revised), comparing SQual, trouble falling asleep (TFA), trouble staying asleep (TSA), feeling of being restored after sleep (RAS), and sleep quantity (SQuan) between groups. Additionally, variables potentially associated with SQual in PwH, i.e. age, BMI, current pain (NRS_now), pain over four weeks (NRS-4w), joint health (Haemophilia Joint Health Score (HJHS)), and quality of life (QoL), were analysed using a multiple regression model.

Results: Age-adjusted comparisons revealed significantly worse SQual (p < 0.001) and RAS (p = 0.037) in PwH compared to Con, with no significant differences in TFA, TSA, and SQuan. Regression analysis identified only NRS-4w (p = 0.012) and QoL (p = 0.008) as significant predictors of worse SQual in PwH (R² = 0.17), while age, BMI, and HJHS had no significant effect.

Conclusion: PwH exhibit poorer SQual and RAS compared to Con, with pain and diminished QoL being key factors contributing to impaired SQual. Other sleep indices such as TFA, TSA and SQuan were unaltered. Given the adverse health impacts of poor SQual and its association with pain, integrating sleep assessment into routine care may enhance patient outcomes.

Background: Limited existing research on mental health and health-related quality of life (HRQoL) in people with hemophilia (PwH) suggests these patients still may have poor mental health despite treatment advances significantly improving somatic outcomes.

Objectives: This multicenter study aimed to systematically assess mental health and HRQoL and their association with disease severity, age and treatment regimen among PwH.

Methods: This cross-sectional study, conducted in nine Swiss hemophilia treatment centers, included participants aged six years and older with congenital hemophilia of any severity. The study procedure comprised a semi-structured psychiatric diagnostic interview and an online survey comprising age-validated psychological measures to capture mental health and HRQoL. Treatment centers provided clinical data.

Results: Of 164 PwH enrolled in the study, 156 participants completed the psychiatric diagnostic interview. 25% met the criteria for a mental disorder (MD). Most common among the MD were affective disorders, substance use disorders, and attention deficit hyperactive disorder. Moderate/severe hemophilia and lower baseline factor activity were significantly associated with higher psychopathology and lower HRQoL. Of participants with moderate/severe hemophilia, 26% of those on prophylaxis versus 45% of those on on-demand met the criteria for an MD.

Conclusions: Elevated prevalence of MD, and the association of psychopathology with disease severity and treatment regimen, highlights the continued relevance of mental health in hemophilia research. Further objective clinical research is indispensable to define targets for improved and individualized comprehensive treatment care plans.

Plain language summary: Major treatment advances have transformed hemophilia care, allowing most people with hemophilia (PwH) to have average lifespans. Reduced bleeding complications have shifted attention to overall well-being and mental health of PwH. The multicenter Swiss HERMES study examined 164 children and adults with hemophilia to explore the link between disease severity, treatment regimen, mental health, and health-related quality of life using standard questionnaires and a psychiatric interview. About one in four participants had at least one mental disorder-most often depression, substance use disorders, or ADHD. Participants with moderate or severe hemophilia, or lower clotting factor levels, reported poorer health-related quality of life. Prophylactic treatment may support mental health in participants with moderate or severe hemophilia. These findings show that mental health issues are common in PwH and highlight the need to integrate psychological screening and support into comprehensive hemophilia care.

Background: Rotational thromboelastometry (ROTEM) aims to measure the coagulation potential in whole blood. Concizumab, an anti-tissue factor pathway inhibitor (TFPI) antibody for prophylaxis in haemophilia, enhances tissue factor (TF)-initiated coagulation by preventing inhibition of activated factor X (FXa), thus increasing thrombin generation.

Objectives: To evaluate a modified ROTEM assay for monitoring patients on concizumab prophylaxis.

Methods: The TF reagent (r_exTEM) was diluted 50,000-fold to make the ROTEM assay sensitive to haemophilia and to concizumab. The effect of concizumab was evaluated in the modified ROTEM in haemophilia A (HA)-like blood (normal blood with added anti-FVIII antibody). ROTEM analysis was performed in blood from patients participating in the explorer7/8 trials during 24 weeks of concizumab prophylaxis. Rotrol N plasma was used as quality control.

Results: In vitro experiments showed concizumab concentration-dependent reduction in clot time (CT) and increase in clot development (α-angle) in HA-like blood. At three of four clinical sites, CT and clot development were stable, variance of the control plasma was ≤12.4% and TF content of the diluted reagent (r_exTEM) was consistent. At these three sites, the correlation between CT versus concizumab exposure, free TFPI and thrombin generation assay parameters was weak (-0.508 to +0.359). Prothrombin time positively correlated with CT (0.523) and negatively correlated with α-angle (-0.659).

Conclusion: Due to the poor correlation between ROTEM parameters, concizumab exposure, free TFPI and thrombin generation parameters and the lack of consistent and reliable performance of the modified ROTEM assay, it cannot be recommended for general monitoring of patients on concizumab prophylaxis.

Aim: As emicizumab shares no sequence homology with factor VIII (FVIII), in patients with haemophilia A, haemostasis can be restored irrespective of the presence of FVIII inhibitors. Emicizumab, therefore, substantially improved previously available prophylactic options. This study aims to evaluate the cost-effectiveness of using emicizumab prophylaxis therapy compared to recombinant FVIII (rFVIII) prophylaxis for the treatment of severe haemophilia A.

Methods: A Markov model from a Chinese healthcare system perspective using annual cycles was constructed to evaluate the lifelong costs and effectiveness. All patients started at age zero in a non-inhibitor state, treated with either emicizumab or rFVIII prophylaxis. On-demand rFVIII was given upon breakthrough bleeding for both groups. A part of severe patients developed FVIII inhibitors resulting from on-demand treatment. For patients with inhibitors, those previously treated with rFVIII prophylaxis switched to a recombinant activated factor VII (rFVIIa) on-demand only therapy, whereas those previously on emicizumab kept the same prophylactic regimen with rFVIIa for breakthrough bleeds. One immune tolerance induction (ITI) was allowed to eradicate inhibitors. Model inputs, including utility values, bleeding rates, adverse event rates and the success rate of ITI were from HAVEN 1 and 3 trials and the other literature.

Results: The results of both the 0-12 age group and lifetime simulations demonstrated a dominant economic advantage of emicizumab prophylaxis over rFVIII prophylaxis therapy.

Conclusion: Severe haemophilia A patients treated by emicizumab prophylaxis can benefit both patients' QoL and economic outcomes compared to those treated by rFVIII prophylaxis.

Background: Major advances in haemophilia care have not translated equitably across all populations. Individuals with rare bleeding disorders (RBDs), people living in low- and lower-middle-income countries (LMICs) and women and girls with inherited bleeding disorders (WGWBD) continue to face significant diagnostic, therapeutic and research disadvantages.

Objective: To critically evaluate the current evidence base for these underserved groups, identify persistent knowledge and implementation gaps and outline strategic priorities to strengthen diagnostic capacity, research infrastructure and equity in care delivery.

Methods: A comprehensive literature review of studies published between 2018 and 2025 was conducted across PubMed, Scopus and Google Scholar, focusing on epidemiology, diagnostic pathways, clinical outcomes, access to treatment and effectiveness of targeted interventions.

Results: Approximately 75% of individuals with inherited bleeding disorders in LMICs remain undiagnosed, with diagnostic delays historically lasting decades. RBDs account for 3%-5% of bleeding disorders but are characterised by limited natural history data and minimal comparative-effectiveness research. WGWBD experience median diagnostic delays of 8 years, with heavy menstrual bleeding affecting 55%-74% and significantly impairing quality of life. Training initiatives, gynaecology-based screening and international registries have improved case detection, though robust evidence on long-term sustainability and cost-effectiveness is lacking.

Conclusions: Strengthening diagnostic systems, expanding harmonised registries, advancing implementation research and prioritising equity-driven strategies are essential to closing critical evidence gaps and improving care for these underserved populations.

Introduction: Women and girls with bleeding disorders (WGBD) face challenges in accessing timely and specialized care. There is a need for comprehensive data, particularly regarding care and clinical management, to inform advocacy initiatives and policy decisions to standardize and improve access to care.

Aim: To conduct a survey of World Federation of Hemophilia (WFH) National Member Organizations (NMOs) on the provision of care and various services for WGBD.

Methods: WFH NMOs completed a questionnaire comprising six themes related to care for WGBD: (1) socioeconomic and cultural challenges, (2) access to healthcare services/programmes/treatments, (3) level of awareness of patients and providers regarding WGBD, (4) availability of programmes and services, (5) challenges in addressing specific needs and (6) challenges in data collection for advocacy, education, and training.

Results: Socioeconomic and cultural challenges included women not recognizing/identifying themselves as patients, poverty-related barriers, discrimination and sexism. Obstacles to receiving care encompassed limited awareness and use of diagnostic tools and lack of special clinics. Level of awareness on topics related to WGBD varied greatly across NMOs. Almost half (45%) of NMOs responded they collected data for advocacy purposes; challenges in data collection were mainly due to limited access to reliable and comprehensive data sources.

Conclusion: The survey identified key challenges in providing and delivering care to WGBD. Strategies and initiatives should focus on raising awareness, expanding access to care, establishing special clinics, and improving outreach, as well as increasing women's representation on committees and boards and increasing education initiatives.

Introduction: Haemophilia, an X-linked disorder, is linked to reduced bone mineral density (BMD). Emicizumab, a factor VIII (FVIII) mimetic, provides a model to study the role of FVIII in bone health.

Aim: To evaluate BMD in adults with severe haemophilia under different prophylactic regimens, focusing on whether emicizumab maintains bone health comparable to FVIII prophylaxis.

Methods: Forty male adults with severe haemophilia A or B were prospectively enrolled at a single centre (2019-2024) and assigned to five prophylactic groups: emicizumab (with/without inhibitors), FVIII, factor IX (FIX) or investigational agents. Annual assessments included dual-energy X-ray absorptiometry, joint status, mobility and bone turnover markers.

Results: Of the 40 patients, 18 received FVIII, 10 FIX, 4 haemophilia A with inhibitors on emicizumab, 4 haemophilia A without inhibitors on emicizumab and 4 investigational therapies. At baseline, spine BMD z-scores were comparable to age-matched norms, whereas hip BMD was significantly lower (median -0.8; p < 0.001). After 1 year, spine and hip BMD changes did not differ significantly across treatment groups (p = 0.9010 and p = 0.8073, respectively). Lower annual bleeding rate, middle age and BMI extremes were associated with BMD improvement. Emicizumab-treated patients, with or without inhibitors, showed non-inferior BMD outcomes compared to those receiving FVIII, with all 95% confidence intervals within the predefined margin (±0.5).

Conclusion: BMD outcomes did not differ across regimens. Emicizumab was comparable to FVIII, suggesting bleed control, not factor replacement, is key to bone health in haemophilia.

Plain language summary: People with haemophilia often have problems with joint bleeding, which can limit movement and reduce bone strength. Different treatments are now available to prevent bleeding, including factor replacement and newer medicines such as emicizumab. It is not clear whether these treatments affect bone health differently. In this study, we followed 40 adults with haemophilia and measured their bone health for 1 year. We found that bone outcomes were similar across all treatment groups. Emicizumab worked just as well as factor VIII in maintaining bone strength. This means that good bleeding control may be the key to keeping bones healthy in haemophilia, regardless of the treatment type.