BackgroundImmune tolerance induction (ITI) therapy is currently unaffordable in China. Management of hemophilia A children with high‐titer inhibitor is therefore a challenge.AimTo describe the ITI strategy using plasma‐derived factor VIII/von Willebrand factor concentrate (pdFVIII/VWF) +/− immunosuppression and to report its efficacy in children with hemophilia A having poor‐risk status for ITI success.MethodsA prospective pilot study on children with hemophilia A having poor‐risk status (all with at least inhibitor titer > 10 BU pre‐ITI initiation). Patients received ~50 IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab +/− prednisone.ResultsSixteen patients with median age 2.9 (range, 2.2‐13.2) years and median pre‐ITI inhibitor titer 30.7 (range, 10.4‐128) BU were enrolled. Analysis at median 14.7 (range, 12.4‐22.6) months’ follow‐up showed a total response rate of 87.5%. This included success (achieving inhibitor < 0.6 BU) in 13 patients (81.3%) in a median of 8.8 (range, 3.2‐11.8) months, and partial success (achieving inhibitor < 5 BU but > 0.6BU) in 1 (6.3%). Compared to the pre‐ITI period, the mean bleeds/month during ITI was 0.51 (64.0% reduction), and joint bleeds/month was 0.34 (64.3% reduction). This low‐dose ITI strategy cost less by 70% to 87% than that for the high‐dose FVIII regimen. No severe adverse events were observed.ConclusionThis low‐dose ITI strategy of pdFVIII/VWF +/− immunosuppression achieved relatively satisfactory outcomes in children with hemophilia A inhibitor having poor‐risk status. This low‐dose regimen showed economic advantages and is therefore suitable for using in China. However, further study in a larger cohort with a longer follow‐up time is needed.

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. Aim: To characterize clinical features and outcome of ITI on HBI. Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-timesweekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens.Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients

Introduction: Type of F8 gene mutation is the most important risk factor for inhibitor development in people with severe hemophilia A. However, there are few large cohort studies on the F8 mutation spectrum of people with severe hemophilia A with inhibitors.Objective: This was the first large cohort study in children with severe hemophilia A with inhibitors from China that aimed to analyze the association between F8 variant types and inhibitor status.How to cite this article: Sun J, Li Z, Huang K, et al. F8 gene mutation spectrum in severe hemophilia A with inhibitors: A large cohort data analysis from a single center in China. Res

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Introduction Microstructural alterations of brain structure in haemophilic boys were found in our previous study. Aim We investigated alterations of brain function in school‐age boys with severe haemophilia A (HA) with resting‐state functional magnetic resonance imaging (rs‐fMRI). Methods We obtained rs‐fMRI scans from 24 boys with HA and 25 demographically matched healthy children. Spontaneous brain activity parameters were calculated. Graph theoretical analyses on rs‐fMRI data at the global and regional levels were performed. Two‐sample t tests were used to analyze differences, and correlation analyses identified relationships between altered neural properties and psychological characteristics. Results Children with severe HA showed small‐worldness organization but with an increased efficiency and compactness in functional segregation. The whole brain showed an overtight connection pattern. At the regional level, significantly increased nodal efficiency in the salience network (SN), default mode network (DMN) and executive control network was found. Social Anxiety Scale for Children (SASC) scores were positively correlated with these alterations. Spontaneous brain activity alterations in regions including the cerebellum, frontal gyrus (orbital part), temporal gyrus and thalamus were observed; some of these regions have been closely related to social anxiety and family or social support. Conclusion Our study is the first to evaluate the neurological functional changes in school‐age boys with severe HA. Disruptions in topographic characteristics and abnormal activity were closely related to social conditions. These data could help us to understand early neurological alterations in haemophilic children, improve the traditional view of family support and strengthen normal school life at an early stage.

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Background:No studies evaluated the role of F8 mutations in outcomes for low-dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with hightiter inhibitors. Objectives:To explore the association between F8 mutation types and low-dose ITI outcomes in children with SHA with high-titer inhibitors. Methods:Children SHA with high-titer inhibitors who received low-dose ITI therapy at least for 1 year were included in this study. Based on the risk of inhibitor development, F8 mutations were classified into a high-risk group and a non-high-risk group.Rapid tolerance and the final ITI outcomes were assessed at the 12th and 24th month of treatment, respectively, and the predictor of outcomes was analyzed.Results: Of 104 children included, 101 had F8 mutations identified. The children with non-high-risk mutations presented a higher rate of rapid tolerance than those with high-risk mutations (61.0% vs. 29.2%; p = 0.006). Among 72 children beyond 24 months of ITI, 55 children (76.4%) achieved success, 3 (4.2%) achieved partial success, and 14 (19.4%) failed. The children in the non-high-risk group showed a higher success rate (86.8% vs. 43.8%; p = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; p = 0.04) compared to those in the high-risk group. In multivariable logistic regression, F8 mutations were an independent predictor of ITI success (non-high-risk group vs. high-risk group, adjusted odds ratio [OR], 20.3; 95% confidence interval [CI], 3.5-117.8), as was the interval from inhibitor diagnosis to ITI