Severe Hemophilia A Research Articles

Genetic Analysis and Reproductive Interventions for Two Rare Families Affected by Severe Haemophilia A.

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 21.345Kbp, 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.

Intracranial hemorrhage before start of prophylaxis in children with hemophilia: incidence, timing, and potential for prevention.

Children with hemophilia have a significantly higher risk of intracranial hemorrhage (ICH) compared to the normal population. Prophylaxis reduces the risk of ICH and earlier initiation of prophylaxis may now be feasible, especially in hemophilia A (HA). The aim of the study is to explore the potential for preventing ICH by earlier start of prophylaxis by assessing the natural course of ICH before the initiation of prophylaxis and describe timing and incidence. In total, 2727 children (2275 with HA; 452 with HB) were included from the PedNet Registry, followed from 28 days until 36 months of life. ICH was observed in 61 children (incidence 2.2%; 10 per 1000 patient years), with 75% of cases occurring before one year of age. Cumulative incidence was significantly lower in HB (0.9%) compared to HA (2.5%) and in non-severe HA (0.7%) compared to severe HA (3.5%). ICH occurred early, with a rise at 3 months, and a median age of 7.0 months in severe HA and 5.4 months in severe HB. In 40% of children, ICH occurred before the diagnosis of hemophilia was established, underscoring the importance of early diagnosis. Assuming that prophylaxis would have been started at the time of diagnosis and preventing all ICH in children with severe HA, the number needed to treat with prophylaxis would be 44 patients to prevent one ICH. Hopefully, prophylaxis options allowing initiation early in life, ideally before 3 months of age for children with severe HA, will reduce the incidence of ICH in the future.

Efanesoctocog Alfa Versus Emicizumab in Adolescent and Adult Patients With HaemophiliaA Without Inhibitors.

The phase3 XTEND-1 trial (NCT04161495) demonstrated that efanesoctocog alfa prophylaxis provided superior bleed protection compared with pre-trial factorVIII (FVIII) prophylaxis in patients with severe haemophiliaA. The aim of this study was to indirectly compare the efficacy of efanesoctocog alfa with non-factor replacement therapy emicizumab in adolescent and adult patients with severe haemophiliaA without inhibitors. A systematic literature review was conducted to identify phase3 trials of emicizumab. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds, and joint health (measured using Hemophilia Joint Health Score [HJHS]), between efanesoctocog alfa and emicizumab. Estimated effects for different emicizumab regimens were pooled using random-effect meta-analysis to evaluate the overall difference in bleed outcomes between efanesoctocog alfa and emicizumab. One emicizumab trial was included (HAVEN3), which investigated three dosing regimens. In meta-analyses, efanesoctocog alfa once-weekly (Q1W) was associated with significantly lower ABRs for any (incidence rate ratio [95%CI] 0.33 [0.20; 0.53]), any treated (0.49 [0.30; 0.80]) and treated joint (0.51 [0.28; 0.91]) bleeds compared with emicizumab Q1W in non-inhibitor patients with prior prophylaxis or on-demand treatment. Efanesoctocog alfa Q1W was also associated with a significantly better improvement from baseline in HJHS Joint Score (mean difference [95%CI] -2.06 [-3.97; -0.14]) and Total Score (-2.37 [-4.36; -0.39]) versus emicizumab Q1W or every 2weeks. Efanesoctocog alfa prophylaxis was associated with significantly lower rates of any, treated, and joint bleeds and improved joint health compared with emicizumab in patients with severe haemophiliaA.

Evaluating the Effectiveness of Prophylactic Strategies for Hemophilia A Management: A Real-World, Longitudinal Observational Study.

Hemophilia A (HA) treatment strategies aim to manage bleeding episodes and improve patients' quality of life. This study investigates the effectiveness of a preventative approach using intermediate-dose prophylaxis with standard half-life FVIII products in reducing bleeding rates and enhancing the quality of life for patients with severe HA. A 4-year prospective longitudinal study followed 35 patients with severe HA (without FVIII inhibitors) who transitioned from a reactive treatment approach to intermediate-dose prophylaxis in Taiwan from 2014 until 2018. The study tracked annual bleeding rates (ABR) and annual joint bleeding rates (AjBR) alongside associated costs and patient-reported quality-of-life measures. Prophylaxis significantly reduced both ABR and AjBR compared with the previous treatment. After one year, ABR and AjBR decreased by 76.9% and 72.5%, respectively, with further reductions to 91.0% and 90.8% after 4 years (p<0.001). While the average annual cost of factor VIII concentrate increased by 41.0% in the first year, the incremental cost-effectiveness ratio demonstrated ongoing benefits from ABR avoidance over the 4 years. Additionally, patients reported significant improvements in quality-of-life measures following the switch to prophylaxis (p=0.036). Intermediate-dose prophylaxis effectively reduced bleeding rates and improved quality of life in patients with severe HA. Despite initial cost increases, the intervention became cost effective over time. This study provides valuable data for healthcare policymakers, highlighting the long-term benefits of prophylaxis as a preventative approach for managing bleeding and improving overall well-being in patients with severe HA.

Prophylactic Administration of Glucocorticoids and Tacrolimus in AAV8-F8 Gene Therapy of Severe Haemophilia-a Achieved a Significant Long-Term Efficacy

Prophylactic Administration of Glucocorticoids and Tacrolimus in AAV8-F8 Gene Therapy of Severe Haemophilia-a Achieved a Significant Long-Term Efficacy

Intermediate-dose Immune Tolerance Induction Outperforms with Faster Success, Less Bleeding and No Added Cost in Comparison with Low-dose: a Multicenter Randomized Clinical Trial

BackgroundLow-dose (LD) or intermediate-dose (MD) immune tolerance induction (ITI) are effective in severe hemophilia A (SHA) children with high-titer inhibitors (HTI) and are attractive in countries with economic constraints. However, high-quality evidence for their use is lacking. ObjectivesThis is a multicenter randomized clinical trial comparing the efficacy, safety and medication cost between LD-ITI and MD-ITI for SHA-HTI children. MethodsSHA children less than 8 year-age with historical/pre-ITI inhibitor-titer 5-200 Bethesda Units/mL in 3 centers were randomized 1:1 to receive LD-ITI (recombinant [r]FVIII 50 IU/kg every-other day) or MD-ITI (rFVIII 100 IU/kg/day) from January 2022 to June 2024 (ChiCTR2200056603, https://www.chictr.org.cn.). ResultsThirty-one patients (16 in MD-ITI, 15 in LD-ITI) were enrolled and followed for more than 24 months (median 26.9, range 24.0-29.5 months). The 2 groups had similar baseline clinical characteristics and similar success rate (93.8% [MD-ITI] vs. 86.7% [LD-ITI]). Compared to LD-ITI, MD-ITI patients took shorter median time to success (4.2 months vs. 10.1 months), to partial success (2.7 months vs. 6.6 months) and had lower mean rates for all bleeding (0.38/month vs. 1.40/month) and joint bleeding (0.11/month vs. 0.83/month). Between the 2 groups, although MD-ITI group had higher rFVIII consumption (12775 vs. 7680 IU/kg), their total medication costs to success were similar (3626.49 vs. 3240.38 US$/kg). ConclusionsFor SHA-HTI children, success rate and cost for MD-ITI and LD-ITI regimens were similar. MD-ITI regimen would be a priority for regions with economic constraints considering the shorter time to success, better bleeding control, and no increase in medication cost.

Inverse Shifting-PCR Modified by Capillary Electrophoresis for Detecting F8 int22h and int1h Inversions in Severe Hemophilia A Patients and Probable Carriers.

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.

CHIEF: A retrospective self-control study of children with severe hemophilia A without inhibitors comparing emicizumab to FVIII prophylaxis.

Hemophilia A (HA) is an X-linked bleeding disorder diagnosed by a deficiency in factor VIII (FVIII). For severe HA (SHA), prophylaxis clotting factor concentrates (CFC) has become the standard of care; however, it imparts a high treatment burden and typically results in an annualized bleeding rate (ABR) of 2-6. Emicizumab, a subcutaneously administered FVIII substitute, has become the de facto standard-of-care prophylaxis for children with SHA in many countries. Previous clinical trials of emicizumab have assessed ABR in patients greater than 12years without inhibitors, and in children less than 12years with inhibitors; however, there is little information published regarding the ABR of emicizumab compared to CFC in non-inhibitor SHA children. Using a retrospective electronic medical record chart review, we conducted a self-control analysis of 15 patients less than 12years of age during equivalent periods of CFC versus emicizumab prophylaxis. The mean ABR on CFC and emicizumab was 1.79 and 1.13 (p=.092), respectively, with a substantially decreased rate of joint bleeds (CFC 0.94; emicizumab 0.33; p=.001) and spontaneous bleeds (CFC 0.79; emicizumab 0.23; p=.008). No safety events were recorded for patients while administering emicizumab. The mean annual cost of CFC prophylaxis was $515,340 (SD $199,540), compared to $328,410 (SD $137,230) for emicizumab prophylaxis (p<.001). Emicizumab resulted in an improved ABR compared to CFC, especially for joint and spontaneous bleeds, had fewer administration complications, and was substantially less expensive compared to CFC prophylaxis; however, more research is necessary for a complete understanding of the effect of emicizumab on joint health and muscle bleeds.

Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model

BackgroundInhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI. Estimating the individual chance of ITI success allows clinicians, patients, and their families to support shared decision-making. ObjectivesWe aimed to identify clinical predictors of ITI success and to develop a clinical prediction model to estimate the chance of successful ITI in persons with severe HA. MethodsThis multicenter study included persons with severe HA who received ITI. Clinical data were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. A multivariable logistic regression model was developed. Model performance and internal validation were performed. ResultsOf 206 participants with a median age of 19.8 months (IQR, 12.1-38.8) at ITI start, 148 (71.8%) achieved ITI success. Our clinical prediction model included 4 predictors of ITI success: cumulative number of FVIII exposure days at inhibitor development, peak inhibitor titer, ethnicity, and F8 mutation type. The C statistic was 0.801 (95% CI, 0.70-0.87). ConclusionIn our study, including 206 people with severe HA and inhibitors, we developed a clinical prediction model to estimate the chance of successful ITI. After future external validation, this clinical prediction model may be useful for informing clinicians and families.

Cost-effectiveness Analysis of Prophylaxis Versus On-demand Treatment for Children With Moderate or Severe Hemophilia A in China

BackgroundIt is still being determined if prophylaxis (PR) has superior cost effectiveness compared with on-demand (OD) treatment for moderate or severe hemophilia A (HA) children in China. Objective/PurposeTo evaluate the cost-effectiveness of PR and OD treatment for children with moderate or severe HA without inhibitors in China. MethodsA retrospective cost-effectiveness study was conducted on 640 HA children (373 and 267 children were on the PR and OD treatment, respectively) from January 2021 to November 2022. The Markov model was used to estimate the economic and clinical outcomes and would run for 17 yearly cycles with the initial age at 2 years. The transfer probabilities were extracted from the data of “Hemophilia Home Care Center” and the literature published. All patients’ drug costs were collected from the data of “Hemophilia Home Care Center”. One-way and probabilistic sensitivity analyses were conducted on the data to evaluate the robustness of the results. Results/FindingsPR was consistently associated with higher overall quality-adjusted life years (QALYs) compared with OD treatment (9.59 QALYs vs. 6.85 QALYs). The incremental cost-effectiveness ratio (ICER) of PR compared with the OD treatment was calculated to be approximately US$12,151.35 (RMB¥81,778.55) per QALY gained. This amount was lower than the willingness-to-pay (WTP) threshold of US$38,212.74 (RMB¥257,171.71). One-way sensitivity analysis found that the results were sensitive to the cost of OD and PR treatments. Conclusions/ImplicationsThis study indicated that PR is cost-effective compared with OD treatment for children with moderate or severe HA without inhibitors in China.

Dental Implant Application in a Patient with Severe Hemophilia-A

Dental Implant Application in a Patient with Severe Hemophilia-A

Clinical and Humanistic Burden of Non-inhibitor HaemophiliaA in Five European Countries: Insights from the CHESSII Study.

HaemophiliaA (HA) is a congenital bleeding disorder caused by a deficiency/absence of factorVIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESSII) study. CHESSII was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18years) individuals with haemophiliaA or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Emicizumab in Children with Severe Hemophilia A.

To assess the effectiveness and tolerability of emicizumab prophylaxis in hemophilia A (HA). Emicizumab is a novel therapeutic drug which is the first and only non-factor replacement agent licensed for use in people with HA. Pediatric patients aged 1 mo to 12 y with severe HA and frequent / life threatening bleeding events, with or without coagulation protein factor VIII inhibitors were enrolled (n = 18) in this observational pre-post study. Patients were switched from therapy involving on-demand or prophylactic factor VIII/bypassing agents/immune tolerance induction to emicizumab prophylaxis and followed up for 52 wk. One year before initiating emicizumab, a total of 229 bleeding events occurred among the enrolled children. After emicizumab prophylaxis, 5 patients had one episode of bleeding event each with a mean bleeding duration of 1.2 d in one year. The mean annualized bleeding rate significantly reduced from 12.7 ± 8.61 events pre-emicizumab prophylaxis to 0.28 ± 0.46 events post-emicizumab prophylaxis (p < 0.001). Out of the total cohort (n = 18), 72.2% of patients (n = 13) had no bleeding events (95% Confidence interval: 46.4-89.3) while on emicizumab. The mean annualized joint bleeding rate reduced from 9.72 ± 7.44 to 0.17 ± 0.38 (p < 0.001). The target joint resolution was 100% and no adverse events were noted. Emicizumab was found to be effective and safe as a prophylactic agent for the treatment of severe HA with and without factor VIII inhibitors. Emicizumab prophylaxis can optimize treatment outcomes and promote a better quality of life in children with severe HA.

Thrombin generation to evaluate the complex hemostatic balance of hemophilia A plasma containing direct oral anticoagulant and supplemented by factor VIII

BackgroundThe incidence of cardiovascular diseases is increasing in persons with hemophilia A (HA). Therefore, anticoagulant therapy based on direct oral anticoagulants (DOACs) may be needed, despite the bleeding risk. In case of surgery or bleeding, such patients may be concomitantly treated with emicizumab (routine prophylaxis), factor (F)VIII products, and DOAC. Their concomitant presence constitutes a hemostatic challenge. Recent international guidelines stated that data are scarce on the hemostatic balance of plasma samples from patients with HA receiving emicizumab and DOAC. ObjectivesThe aim of this observational study was to assess the coagulation of FVIII-deficient plasma spiked with DOAC and emicizumab and to evaluate the effects of FVIII addition. MethodsProthrombin time, activated partial thromboplastin time, and thrombin generation (TG) using the calibrated automated thrombogram method were evaluated in aliquots of a commercial severe HA plasma supplemented with emicizumab (0, 12.5, 25, 50, and 100 ng/mL), DOAC (0, 50, 100, 200, and 400 ng/mL of apixaban, rivaroxaban, edoxaban, or dabigatran) and FVIII (0%, 5%, 15%, 50%, and 100%). ResultsDOAC rapidly induced a TG decrease. Emicizumab could counter this effect only for the lowest DOAC dose. FVIII addition to the FVIII-deficient plasma containing a DOAC and emicizumab improved TG and countered the anticoagulant effect of DOAC at ≤100 ng/mL. ConclusionOur findings indicate that FVIII can be safely used with emicizumab to counter the anticoagulant effect of DOAC at ≤100 ng/mL. The TG assay is an efficient tool to monitor plasma containing anti-FXa DOAC, but not dabigatran (anti-FIIa).

Relationship between mutations in severe hemophilia A and risk of inhibitor development: A large single-center study

BackgroundOne of the major problems for patients with severe hemophilia A (HA) is the development of neutralizing antibodies against factor VIII. This study aimed to analyze the molecular and clinical profiles of patients with severe HA and to determine if certain genetic variants predispose to inhibitor development in these patients. MethodsA single-center study was conducted among patients with severe HA between March 20, 2000, and June 31, 2023. Demographic data and laboratory results of patients were collected. The inverse-shifting PCR (IS-PCR) technique was initially used to screen patients for intron 22 and 1 inversions (Inv-22 and Inv-1). ResultsA total of 480 patients with severe HA (408 without inhibitors and 72 with inhibitors) were enrolled in this study. The median age of the patients at the time of diagnosis was 6 months (IQR: 3 months to 18 months). Inv-22 was observed in 199 (41.5 %) of the cases. Among those patients who developed inhibitors, 53 (73.6 %) were classified as high-titer and 19 (26.4 %) as low-titer. Inv-22, positive family history of inhibitor formation, and history of intense injections revealed a statistically significant association with the risk of inhibitor development. ConclusionThe results of this study confirm the important role of different genetic variants, family history of inhibitor formation, and history of intense injections for the formation of inhibitors in patients with severe HA. This would allow us to stratify the patients which can have important clinical implications, especially in terms of their management and outcome.

Improved prevention of bleeding episodes with emicizumab in 3 patients with concomitant hemophilia A and von Willebrand disease.

The typical phenotype of hemophilia A (HA) is that of frequent bleeding episodes, up to several per month, unless prophylactic factor VIII (FVIII) replacement or alternatives are given. Related bleeding may be heightened in severity or frequency by co-morbid bleeding disorders. Based on the reported prevalence of von Willebrand disease (VWD) of up to 1% of the general population, the co-existence of HA and VWD occurs, but is likely less recognized. Prophylactic FVIII replacement may or may not adequately prevent bleeding in persons with HA and mild VWD, and plasma-derived concentrates containing FVIII and von Willebrand factor (VWF) may be used for more successful bleeding prophylaxis. However, therapy adherence remains problematic for many reasons, one being treatment via intravenous access. Emicizumab is a nonfactor subcutaneous prophylactic therapy for HA that may overcome this concern. We describe three patients, with severe HA and VWD, for whom regular FVIII/VWF prophylaxis was deemed inadequate. FVIII/VWF prophylaxis was replaced with weekly prophylactic injections of the bispecific monoclonal antibody, emicizumab. When the patients were transitioned to emicizumab, all experienced a significant reduction in their annualized bleed rate (ABR). Although the mechanism of action does not directly affect or replace VWF function, emicizumab may be an effective prophylaxis alternative to FVIII/VWF concentrate in patients with concomitant severe HA and VWD.

Comprehensive Screening of Genetic Variants in the Coding Region of F8 in Severe Hemophilia A Reveals a Relationship with Disease Severity in a Colombian Cohort.

Hemophilia A is an X-linked disorder characterized by quantitative deficiency of coagulation factor VIII (FVIII) caused by pathogenic variants in the factor 8 (F8) gene. Our study's primary objective was to identify genetic variants within the exonic region of F8 in 50 Colombian male participants with severe hemophilia A (HA). Whole-exome sequencing and bioinformatics analyses were performed, and bivariate analysis was used to evaluate the relationship between identified variants, disease severity, and inhibitor risk formation. Out of the 50 participants, 21 were found to have 17 different pathogenic F8 variants (var). It was found that 70% (var = 12) of them were premature truncation variants (nonsense, frameshift), 17.6% (var = 3) were missense mutations, and 11.7% (var = 2) were splice-site variants. Interestingly, 35% (var = 6) of the identified variants have not been previously reported in the literature. All patients with a history of positive inhibitors (n = 4) were found to have high-impact genetic variants (nonsense and frameshift). When investigating the relationship between variant location (heavy versus light chain) and specific inhibitor risk, 75% (n = 3) of the inhibitor participants were found to have variants located in the F8 light chain (p = 0.075), suggesting that conserved domains are associated with higher inhibitor risk. In summary, we identified genetic variants within the F8 that can possibly influence inhibitor development in Colombian patients with severe HA. Our results provide a basis for future studies and the development of further personalized treatment strategies in this population.

Long-term health-related quality of life and related factors in children with severe hemophilia A who received regular low-dose prophylaxiss

Objective: To investigate long-term health-related quality of life (HRQoL) and related factors in children with severe hemophilia A (HA) who received regular low-dose prophylaxis. Methods: Clinical data of severe HA children who began to receive regular low-dose coagulation factor Ⅷ (FⅧ) prophylaxis in Peking Union Medical College Hospital from January 1, 2008 to December 31, 2011 were retrospectively enrolled. The longest last follow-up period was May 31, 2023. The attendance of school or work and daily physical activity during the last follow-up were investigated. The patients were divided into full attendance group and incomplete attendence group according to attendance. The patients were divided into into exercise attainment group (reached Chinese sports recommendation) and exercise nonattainment group according to the exercise status. Barthel score was used to assess activities of daily living and Haemo-QoL was used to assess quality of life. Long-term HRQoL for children aged 8-16 years and patients aged 17 years and above were assessed using Haemo-QoL SF and Haem-A-QoL versions, respectively. Spearman correlation analysis was used to examine the correlation between treatment conditions and Haemo-QoL scores. Results: A total of 22 cases were enrolled, the prophylaxis initiation age ranged from 1.8-17.9 (10.4±3.8) years old. The average prophylactic FⅧ dose during low-dose prophylaxis was 24.2 U/kg per week and the follow-up time was 6.3-15.1 (9.6±2.8) years. At the last follow-up, the age of the patients was (20.2±5.4) years, of which 14 (63.6%) were adults over 18 years old. There were 15 patients in the full attendance group and 7 patients in the incomplete attendence group. Compared with the full attendance group, the incomplete attendence group had a smaller preventive treatment dose [M(Q1, Q3), (28.4±11.1) vs (15.3±3.7) U/kg, P=0.012], shorter preventive treatment time [148. 1 (18.6, 346.5) vs 48.0 (32.0, 156.9) weeks, P=0.017], and higher annual joint bleeding rate (AJBR) [12.5 (6.0, 22.3) vs 14.2 (13.2, 17.8) times, P=0.017]. There were 7 cases in the exercise attainment group and 15 cases in the exercise nonattainment group. Compared to the exercise attainment group, the exercise nonattainment group had shorter preventive treatment time[313. 7 (156.9, 366.0) vs 48.0 (16.5, 108.9) weeks, P=0.006], a higher AJBR [7.0 (5.1, 10.0) vs 23.3 (12.5, 29.8), P=0.003] and a higher hemophilia joint health score (HJHS) [9.0 (2.0, 15.5) vs 23.0 (12.0, 27.8), P=0.014]. Barthel score showed 81.8% (18 cases) of the patients' living ability was not influenced by the illness. In Haemo-QoL score, the total score of Haemo-QoL SF in 7 cases was (47.6±17.0) scores, the total score of Haem-A-QoL in 15 cases was (45.2±22.6) scores. The daily activity dimension of the Haem-A-QoL score was the lowest [38.2 (10.9, 45.5) scores], which was positively correlated with the starting age of prophylactic initiation (r=0.501, P=0.057), and negatively correlated with the duration of prophylaxis (r=-0.545, P=0.036). Conclusions: Regular low-dose prophylaxis could improve the long-term HRQoL of some children with severe HA, and children with higher prophylactic doses and longer prophylactic treatment time have higher quality of life.

Exploring the relationship between condition severity and health-related quality of life in people with haemophilia A across Europe: a multivariable analysis of data from the CHESS II study

BackgroundHaemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5–40%), moderate (1–5%), or severe (< 1%). Within the current environment of rapid evolution in HA management, we seek to understand the interplay of condition severity and health-related quality of life (HRQoL) to characterise and differentiate unmet needs among people with HA (PwHA).MethodsA generalised linear regression model (GLM) was developed to explore the relationship between HA severity and EQ-5D-5 L index score from adult HA patients sampled in the “Cost of Haemophilia across Europe – a Socioeconomic Survey II” (CHESS II) cross-sectional, retrospective burden of illness study among adults with hereditary haemophilia A or B from eight European countries. HA patients of any severity with no active inhibitors during the 12 months prior to data capture and a completeEQ-5D-5 L response were included. A base GLM model was specified with covariates for demographic and clinical characteristics (age, body mass index, country, employment, HA severity, annual bleeding rate, problem joints, and chronic pain).ResultsOf 381 evaluable patients, 221 (58.0%) had severe HA, 96 (25.2%) had moderate HA, and 64 (16.8%) had mild HA. Among the covariates included in the GLM model and after controlling for haemophilia-related outcomes, a significant association was observed between mild HA and higher EQ-5D-5 L index score (average marginal effects, 0.084; p = 0.016) relative to severe HA. Patient country of residence and magnitude of HA-related chronic pain were also associated with significant differences in index scores, with the latter showing a negative relationship with HRQoL outcomes.ConclusionsCondition severity and chronic pain are significant predictors of HRQoL in PwHA. Durable bleeding protection and effective management of chronic pain have the potential to address unmet treatment needs in this population.

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study.

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. 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. 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. 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.