Hemophilia B (HB) is an inherited bleeding disorder caused by defects in the FⅨ gene, leading to severe coagulation dysfunction. This study designed eight pairs of primers covering eight exons of the FⅨ gene and used PCR and DNA sequencing to detect FⅨ gene mutations in 31 HB patients. Sequencing results were compared with normal sequences using Chromas software on Blast to identify mutation sites. Findings revealed the CpG dinucleotide region as a mutation hotspot and the 192nd nucleotide (FⅨ192) as a dinucleotide polymorphism site in the Chinese population. Pathogenic mutations included point mutations, deletions, insertions, and mutations affecting amino acids or splicing sites. For cases with only polymorphic sites, further exon sequencing is needed. This study adds new mutation data to the global HB database, supports research on racial differences in FⅨ gene mutations, and contributes to domestic HB statistics. The results aid in understanding the FⅨ gene\'s role in coagulation, elucidating HB pathogenesis, and providing a basis for future gene therapy.

BACKGROUND: There is a high prevalence of inherited bleeding disorders in Iran, such as hemophilia A (HA) and hemophilia B (HB). This study aimed to analyze the molecular and clinical profiles of patients with HB.
METHODS: A single-center study was conducted among patients with severe HB between March 20, 2000, and June 31, 2023. The polymerase chain reaction (PCR) amplification was used for all of the major regions, such as the promoter, the exons, the adjacent intronic regions, and the untranslated regions of the F9 gene. Finally, Sanger sequencing was performed on the PCR products.
RESULTS: A total of 111 HB patients (17 with HB [Leyden +] and 94 with HB [Leyden -]) were enrolled in this study. Among 94 patients with HB (Leyden -), 59 (62.8 %) had missense, 21 (22.3 %) had nonsense, and 8 (8.5 %) had frameshift mutations. Moreover, the most frequent pathogenic variant in HB (Leyden +) was c.-17 A>G in this study.
CONCLUSIONS: The results of this study confirm that HB is caused by a wide range of molecular defects in Iran. Thus, by knowing the genotypes and phenotypes, we would be able to stratify the patients which is important in terms of their management and outcome.

To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective.
Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019.
Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group.
There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs.
This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

UNASSIGNED: Purified factor IX (FIX) concentrate (IMMUNINE®, Takeda Manufacturing Austria AG, Vienna, Austria) is indicated for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia B. Data on the use of purified FIX concentrate in patients ≤6 years old with congenital hemophilia B are limited.
UNASSIGNED: Document real-world clinical experience with purified FIX concentrate in routine practice for pediatric patients with hemophilia B.
UNASSIGNED: This prospective post-authorization safety surveillance study enrolled patients ≤6 years old with moderate or severe hemophilia B (baseline FIX ≤5%) who were prescribed purified FIX concentrate, as determined by the treating physician. The planned observation period for each patient was either 12 months or ≥50 exposure days, whichever occurred first. The primary endpoints were the occurrence of treatment-related adverse events (AEs) and serious AEs (SAEs), and inhibitor development.
UNASSIGNED: Thirteen male patients (mean ± standard deviation age, 3.80 ± 1.76 years) enrolled and received ≥1 treatment with purified FIX concentrate. Thirty-two AEs were reported in 6 patients; 4 were SAEs. No AEs were considered related to purified FIX concentrate. No patients developed inhibitory antibodies. Inhibitor testing was not conducted in 2 patients. Eighteen bleeding episodes were treated with purified FIX concentrate in 6 patients. Hemostatic efficacy was rated as either \"excellent\" or \"good\" in all patients with an available rating.
UNASSIGNED: No treatment-related AEs were reported, and purified FIX concentrate was shown to be effective in treating and preventing bleeding episodes in pediatric patients ≤6 years old with hemophilia B.

BACKGROUND: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%.
OBJECTIVE: Assess how EDZ affects HRQoL in HOPE-B trial participants.
METHODS: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated.
RESULTS: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p = .0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (-6.0; p < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .0001), Future (-6.45; p = .0004) and Work/School (-5.21; p = .0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1.
CONCLUSIONS: In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.

BACKGROUND: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B.
METHODS: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 1013 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7-18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with ClinicalTrials.gov, number NCT03569891.
RESULTS: The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54-27·99), after a lead-in period of 7·13 months (6·51-7·82). In the updated analysis comparing months 7-24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0-6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]).
CONCLUSIONS: By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B.
BACKGROUND: uniQure and CSL Behring.

OBJECTIVE: To evaluate pattern of use and clinical outcomes in pediatric/adolescent patients enrolled in the IDEAL study.
METHODS: This post-hoc analysis of IDEAL retrospective-prospective observational study focused on patients <18 years, 100% on prophylaxis during the entire observation period.
RESULTS: Thirteen subjects (median age 10.0 years; 61.5% ≤ 11 years) were analyzed. The infusion frequency changed from 2/week in 84.6% (N = 11) of patients with previous rFIX, to less than 1/weekly in 76.9% (N = 9) with rIX-FP and the annualized number of infusions reduced of 57% (p = .002), from a mean ± SD of 95.1 ± 22.77 to 40.4 ± 6.79, respectively. Annualized mean consumption decreased of about 56% (p = .001), from 3748.4 ± 1155.40 IU/kg with previous rFIX, to 1656.8 ± 456.63 IU/kg of rIX-FP. Mean FIX trough level changed from 3.0% ± 1.98% to 10.92% ± 3.6%. Low mean Annualized Bleeding Rate was maintained across all prophylaxis regimens (0.8 ± 1.69 vs. 0.3 ± 0.89) and zero bleeding patients moved from 69.2% (N = 9) with previous rFIX to 84.6% (N = 11) with rIX-FP (p = .63). Two adverse events, none related to rIX-FP, occurred in two patients. No inhibitors development was reported.
CONCLUSIONS: The results in this pediatric/adolescent subgroup support rIX-FP prophylaxis may reduce infusion frequency, while providing high FIX trough levels, stable annualized bleeding rate and a good safety profile.

BACKGROUND: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted.
OBJECTIVE: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB).
METHODS: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years.
RESULTS: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01).
CONCLUSIONS: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.

UNASSIGNED: Elevated levels of coagulation factors (F) II (FII), FV, FVII, FIX, FX, and FXI have often been related with coronary heart disease, ischemic stroke, and venous thrombosis (VT). However, there are few studies on their associations with all-cause mortality.
UNASSIGNED: We explored whether elevated levels of FII, FV, FVII, FIX, FX, and FXI are associated with an increased risk of death in patients who had VT and in individuals from the general population.
UNASSIGNED: We followed 1919 patients with previous VT and 2800 age- and sex-matched community controls in whom coagulation factor levels were measured. A high coagulation factor was defined as the >90th percentile of normal in the controls. Cox regression analyses were adjusted for age and sex and for being a patient with VT or being a control subject.
UNASSIGNED: The median age at time of enrolment was 48 years for both patients and controls, and slightly more women than men were followed. Over a median follow-up of 6.1 years for patients and 5.0 years for controls, there were 79 and 60 deaths in patient and controls respectively. There was no association of FII, FV, FVII, FIX, FX, and FXI with all-cause mortality in patients or in control individuals.
UNASSIGNED: Elevated levels of FII, FV, FVII, FIX, FX, and FXI levels may not be associated with an increased risk of all-cause mortality. Only for cardiac death, an association with high FX and FXI was found, which confirms the findings of previous studies, but numbers were small.

The administration of 4-factor prothrombin complex concentrate (4F-PCC) has expanded beyond its Food and Drug Administration (FDA)-approved indication for the emergent reversal of vitamin K antagonists (VKAs). Therefore, this study aimed to evaluate the risks and benefits associated with the expanded use of 4F-PCC. We conducted a single-center retrospective review of 4F-PCC administrations at our university hospital. Of the 159 patients who received 4F-PCC, 76% (n = 121) and 24% (n = 38) received it for the FDA-approved indication in the vitamin K-related coagulopathy (VKA) group and for expanded use in the nonvitamin K-related coagulopathy (nVKA) group, respectively. The expanded use of 4F-PCC was associated with a less robust reduction in the international normalized ratio (INR) (INR of -0.7 ± 1.3 vs INR of -1.6 ± 1.8, P = .002), and fewer patients in the nVKA group achieved a postadministration INR of less than1.5 (11% vs 79%, P = .001) than those in the VKA group. Furthermore, the 30-day mortality rate was significantly higher in the nVKA cohort than in the VKA cohort (42% vs 20%, P = .04). Notably, based on our data, underlying differences in the patient\'s comorbidities, particularly advanced liver disease, may have contributed to the observed outcome variations, including mortality rate. Therefore, factors, including comorbidities and the underlying etiology of coagulopathy, should be considered when deciding on the expanded use of 4F-PCC. Further research is needed to better understand the potential risks and benefits of 4F-PCC in expanded use scenarios, and the clinical decision to use 4F-PCC outside its FDA-approved indication should be made carefully, considering this information.