PURPOSE:This study evaluated the dental care experiences and parental attitudes amongst children with haemophilia in China. METHODS:A cross-sectional questionnaire surveyed parents of children with haemophilia A or B, covering demographics, dental experiences and attitudes toward dental care. Descriptive statistics and chi-square tests were used to analyse the data. RESULTS:A total of 125 valid questionnaires were obtained. 45.6% (57 parents) reported that their children had experienced dental pain in the past year, yet 26.3% (15 parents) did not seek dental treatment. Of those without dental pain, 60.3% (41 children) had not visited a dentist. Common reasons included parents considering the dental issues not severe and believing that primary teeth would eventually fall out, making treatment unnecessary. Although 55.2% (69 children) had visited a dentist, 30.4% (21 children) of them had been denied dental care due to their haemophilia. Additionally, amongst the 125 surveyed parents, 18.4% (23 parents) chose to conceal their child's haemophilia history when visiting a dentist, mainly due to concerns about being denied treatment. Even with standardised treatment guidelines, 40% (50 parents) of them distrusted dentists unfamiliar with haemophilia to provide appropriate dental care for their children based on the guidelines. CONCLUSION:Significant gaps exist in oral health awareness and dental care access for children with haemophilia in China. Addressing the gaps requires educational efforts for parents and enhanced training for dental professionals.

BACKGROUND:The incidence of pediatric venous thromboembolism (VTE) has been increasing in recent years. Due to the unique hemostatic characteristics of children, thrombi are often difficult to resolve once formed and may result in long-term sequelae. Rivaroxaban has been approved for the treatment of pediatric VTE; however, real-world data on its use in Chinese pediatric populations remain limited. OBJECTIVES:This study aimed to evaluate the effectiveness and long-term safety of rivaroxaban in children with VTE and to provide real-world evidence to support its clinical use. METHODS:This single-center retrospective observational study included children aged >28 days and <18 years who were diagnosed with VTE and received rivaroxaban treatment for at least one month at Beijing Children's Hospital between January 2022 and April 2025. Demographic characteristics, clinical data, and treatment information were collected. Effectiveness outcomes included thrombus resolution and changes in thrombus burden assessed by imaging. Safety outcomes included bleeding events and adverse drug reactions. All patients were followed up for 3 months during treatment, with an additional 3 months of subsequent follow-up. RESULTS:A total of 189 pediatric patients with VTE treated with rivaroxaban were included between January 1, 2022 and April 1, 2025. The median age was 8.6 years, and 53.97% were male. The most common VTE risk factor was pulmonary disease (pneumonia) (58.20%), followed by catheter-related thrombosis (33.33%). At 3-month follow-up, complete thrombus resolution was achieved in 24.34% of patients, partial improvement in 57.67%, and no improvement in 14.29%. Thrombus recurrence occurred in 2.12% of patients, with no fatal VTE or death observed. Univariable logistic regression showed no significant predictors of thrombus recanalization (all P > 0.05). No significant difference in efficacy was found between patients with and without cancer (P = 0.148). For safety, bleeding events were rare and mostly mild (4.79% clinically relevant non-major bleeding), with one discontinuation due to melena and no fatal or intracranial hemorrhage. No significant risk factors for bleeding were identified in univariable analysis. CONCLUSIONS:In this real-world pediatric cohort, rivaroxaban demonstrated favorable effectiveness and an acceptable safety profile, consistent with findings from previous clinical trials. Larger multicenter real-world studies are warranted to further define the clinical value of rivaroxaban in pediatric VTE.

BackgroundPredictors for the successful eradication of neutralizing anti-FVIII alloantibodies (inhibitors) in hemophilia A patients receiving immune tolerance induction (ITI) therapy remain limited. Maternal microchimerism (MMc) showed potential to protect hemophilia A patients from inhibitor development.ObjectivesTo investigated the role of MMc in ITI therapy.Patients/MethodsThis observational study enrolled 121 pediatric with hemophilia A and inhibitors. MMc was determined using droplet digital PCR. Low-dose ITI (FVIII ~50IU/kg every other day) was administered, with adjunctive rituximab given to patients with higher risk clinical features.ResultsOf the 101 patients evaluable for MMc, 88 completed ITI, 18 were MMc positive (MMc+) and 70 were MMc negative (MMc-). Success was achieved in 75 (85.2%) patients, including 16 of 18 MMc+ patients (88.9%) and 59 of 70 MMc- patients (84.3%). Compared with MMc- patients, MMc+ patients had a lower peak inhibitor during ITI (median, 5.3 vs. 37.8 BU/ml, p = 0.029), less frequent rituximab use (27.8% vs. 61.4%; p = 0.011), and a shorter time to ITI success (median, 3.0 vs 9.9 months; p = 0.009). Multivariate Cox regression identified MMc+ (HR = 2.770), pre-ITI inhibitor <10BU/ml (HR = 2.663), peak inhibitor during ITI<200BU/ml (HR = 4.954) and non-large deletion/duplication F8 mutations (HR = 2.344) as independent predictors of shorter time to ITI success.ConclusionMMc was associated with more rapid ITI success in children with hemophilia A and inhibitors receiving low-dose ITI regimen, suggesting the potential role of MMc in facilitating the eradication of FVIII inhibitors.

Objectives Antithrombin (AT) is a critical anticoagulant whose deficiency, which is common in many clinical conditions, requires precise management, although accurate laboratory measurements of low AT levels are challenging. This study aims to evaluate the precision and comparability of AT activity assays across different analytical systems, particularly at low activity levels, with the goal of developing validated optimization strategies to improve performance and interlaboratory harmonization. Methods Standardized lyophilized plasma materials (with AT activities of 10%, 15%, 35% and 100% of normal) were distributed to nine clinical laboratories via Systems A and B, with bovine thrombin as the reagent, and System C, with bovine activated coagulation factor Ⅹ as the reagent. Baseline performance was assessed through a laboratory evaluation and external quality assessment style comparison. Optimization measures (standardized reagent reconstitution, calibration curves at low levels, enhanced quality control protocols) were then applied in laboratories with better baseline performance, followed by a re-evaluation study to assess improvements. Results The initial evaluation confirmed significant variability at low AT activity levels: Systems A and B demonstrated closer agreement with target levels, whereas System C exhibited significant bias and poor reproducibility and was consequently excluded from optimization. After implementation of the optimization protocols, low-level AT activity measurements showed markedly reduced bias and improved precision. At the 10% and 15% levels, both the interlaboratory coefficients of variation and the recovery rates significantly improved. In the re-evaluation study, Systems A and B demonstrated enhanced performance across all participating laboratories. Conclusions: This multicenter evaluation established the feasibility of significantly improving AT activity assay performance through targeted methodological optimization. Through the use of quality control materials and harmonized procedures, the method achieved reliable low-level activity measurements, thereby paving the way for the reliable clinical application of AT activity measurements.

Background Emicizumab has markedly improved bleed prevention in hemophilia A, but its high cost remains a challenge, especially in resource-constrained settings. Many regions are now exploring dose reduction strategies to alleviate financial burden. However, empirical dose minimization without clear guidance may risk inadequate hemostatic protection and breakthrough bleeding. While standard weight-based dosing ensures efficacy, a personalized, pharmacokinetic/pharmacodynamic (PK/PD)-guided dosing strategy may reduce treatment burden without compromising bleed protection. Evidence supporting such individualized approaches in real-world remains limited. Objective This study aimed to evaluate the feasibility, safety, and preliminary effectiveness of PK/PD-guided emicizumab dose reduction in Chinese pediatric patients with hemophilia A, following an initial period of standard prophylaxis. Methods This was a prospective, single-center observational study conducted in a real-world clinical setting. Children under 18 years of age with severe congenital hemophilia A, either with or without FVIII inhibitors, who had received standard emicizumab prophylaxis for at least 12 months, were enrolled. After this observation period, patients and their caregivers were offered the option to transition to a reduced dosing regimen guided by individualized PK and PD targets. Emicizumab concentrations were measured using a modified one-stage clotting assay, and FVIII-equivalent activity was assessed using a chromogenic assay (HYPHEN). Individual pharmacokinetic parameters were estimated based on the population PK model by Retout et al. (Clin Pharmacokinet. 2020). The dose adjustment aimed to maintain FVIII-equivalent activity between 10–15 IU/dL and emicizumab trough concentrations above 30 μg/mL (±10 μg/mL). Patients were prospectively followed for a minimum of 6 months after dose reduction, with systematic monitoring for bleeding events, thrombotic complications, and treatment-related adverse events. Results A total of 46 patients were enrolled in the study. Among them, 15 patients transitioned to the PK/PD-guided Individualized dose reduction strategy after completing 12 months of standard emicizumab therapy. The median age of this subgroup was 2.0 years, with a range from 0.9 to 16.3 years. Of the 15 patients, 13 were negative for FVIII inhibitors, 2 had a history of inhibitors. The median monthly emicizumab dose was reduced from 5.4 mg/kg (range: 3.2–6.2) to 3.2 mg/kg (range: 2.6–4.0). Correspondingly, the median trough concentration decreased from 48.5 μg/mL (range: 36.5–68.7) to 32.1 μg/mL (range: 27.0–38.4). Despite the dose reduction, FVIII-equivalent activity remained within the target range in most patients, with a median of 12.3 IU/dL (range: 12.0–18.5). Throughout the 6-month follow-up under reduced dosing, no bleeding events, thrombotic complications, or treatment-related adverse events were observed. In addition, joint ultrasound assessments performed before and after dose adjustment showed no evidence of new or progressive damage, suggesting preserved joint health throughout the reduced dosing period. Conclusion This prospective real-world study demonstrates that emicizumab dose reduction guided by PK/PD targets is feasible, safe, and effective in pediatric patients with hemophilia A after an initial period of standard prophylaxis. The individualized approach maintained excellent bleed protection while substantially reducing drug exposure. These findings highlight the potential of PK/PD-guided dosing to improve access and cost-efficiency of emicizumab in settings where treatment affordability is a concern. Larger-scale, multi-center studies with extended follow-up are needed to confirm these promising results and support broader adoption of this strategy.

AbstractBackground: In 2020, the hemophilia care team at Beijing Children’s Hospital initiated a study entitled LEAPS (Pharmacokinetics and complementary evaluation system-based recommendations on prophylaxis for pediatric patients with hemophilia A in China using Kovaltry). This paper presents the results of a two-year follow-up research on children with hemophilia A from the LEAPS program.Objective: Clinical follow-up was based on the LEAPS protocol. Patients will get periodic joint evaluations, FVIII trough level measurements, and pharmacokinetic (PK) tests. A dose escalation prophylaxis treatment plan will be implemented based on the PK test results and the graded low-dose prophylaxis therapy program.Patients/Methods: Clinical follow-up was based on the LEAPS protocol. 60 patients got periodic joint evaluations, factor VIII (FVIII) trough level measurements, and PK tests. A dose escalation prophylaxis treatment plan was implemented based on the PK test results and the graded low-dose prophylaxis therapy program.Results: 60 children diagnosed with severe hemophilia A two-year follow-up was conducted. Zero bleeding rate (ZBR) and zero joint bleeding rate (ZJBR) climbed from 68.33% and 45% pre-enrollment to 76.67% and 58.33% at the first-year follow-up, and further ascended to 80.00% and 70.00% at the second-year follow-up. The average ultrasonography score per joint at enrollment was 0.62, which declined to 0.49 by the conclusion of the two-year follow-up.Conclusions: The 2-year follow-up results of 60 hemophilia A patients in LEAPS confirmed the long-term efficacy of prophylaxis treatment guided by PK and comprehensive evaluation system in reducing bleeding events, maintaining joint health, and improving the quality of life of patients.

Hemophilia A is a rare inherited bleeding disorder typically managed with coagulation factor VIII (FVIII) replacement therapy. Designing personalized prophylactic regimens requires accurate pharmacokinetic (PK) characterization; current population PK (popPK) and Bayesian approaches provide a principled framework for individualized dosing, but their routine clinical implementation may still be constrained by model specification requirements and practical considerations in data collection and analysis. Here we present a machine learning (ML) framework, incorporating state-of-the-art language models, to predict individual FVIII PK parameters in pediatric patients. Using minimal sampling and routinely collected clinical data, our approach achieves superior performance over the widely adopted WAPPS-Hemo platform in predicting in vivo recovery (IVR) and FVIII half-life. These findings highlight the potential of AI-driven methods to reduce patient burden while improving accuracy in individualized treatment planning for children with severe hemophilia A.

Background and Objective: Avatrombopag is a thrombopoietin receptor agonist that has demonstrated clinical efficacy in rapidly increasing platelet counts and achieving bleeding control in children with chronic immune thrombocytopenia. Early prediction of treatment response is critical for reducing unnecessary drug exposure and guiding personalized treatment strategies. However, accurate prediction remains challenging due to the inherent characteristics of clinical tabular data, including missing values caused by inconsistent data recording, small sample size, and high-dimensional clinical features. This study aims to develop an effective computational framework for early prediction of treatment response under these conditions. Methods: We propose a multi-view learning framework that constructs multiple views by applying diverse imputation methods to the same dataset, with each view capturing unique assumptions about missingness. A feature selection encoder is employed to reduce feature redundancy and improve model interpretability. Multi-view fusion and co-regularization are integrated at the prediction level to learn complementary patterns across different views. In addition, contrastive learning is introduced to alleviate the small data problem and enhance representation robustness. Results: Experiments on real-world clinical data of children treated with avatrombopag demonstrate that the proposed method consistently outperforms multiple competitive baseline models in predicting treatment response. Conclusions: This study provides a practical and interpretable multi-view learning framework for early identification of treatment response in chronic immune thrombocytopenia, supporting more personalized and efficient treatment decisions in pediatric hematology.

Primary immune thrombocytopenia (ITP) is the most common acquired bleeding disorder in children, and management is challenging when first-line therapy fails. Hetrombopag is an oral thrombopoietin receptor agonist (TPO-RA). This phase 3 randomized, double-blind, placebo-controlled trial evaluated its efficacy and safety in children and adolescents with ITP who had an inadequate response or relapse after prior treatment. Children and adolescents aged 6–17 years were randomized 2:1 to receive once-daily hetrombopag (initial dose 2.5 mg) or placebo for 12 weeks, followed by a 12-week open-label hetrombopag extension. The primary endpoint was the proportion of patients with a platelet count ≥50 × 10⁹/L at Week 10. The key secondary endpoint was the proportion of patients with a sustained platelet response, defined as a platelet count ≥50 × 10⁹/L maintained for ≥6 weeks without rescue therapy between Weeks 5 and 12. Eighty-eight patients were randomized (hetrombopag, n=57; placebo, n=31). At Week 10, 61.4

Background Denecimig (Mim8) is a next-generation activated factor VIII mimetic bispecific antibody developed for subcutaneous prophylaxis in patients with haemophilia A (HA). Objectives To evaluate 52-week outcomes with denecimig in children from the phase 3 FRONTIER3 study (NCT05306418). Methods Children aged 1–11 years with HA, with or without factor VIII inhibitors, received subcutaneous denecimig once-every-week (QW) for 26 weeks (Part 1). In Part 2, caregivers chose to continue QW or switch to once-every-month (QM) dosing for 26 weeks. Primary endpoint: number of treatment-emergent adverse events (TEAEs). Assessed secondary outcomes included the number of treated bleeds and subtypes, injection-site reactions, anti-denecimig antibodies and caregiver-reported outcomes. Results All 70 enrolled participants completed Parts 1 and 2. During Part 2, 38 participants continued QW and 32 switched to QM. All TEAEs were mild/moderate, and none led to discontinuation. No thromboembolic events or clinical evidence of neutralising antibodies were reported; injection-site reactions were infrequent (∼1% of injections). Estimated mean annualised bleeding rates for treated bleeds were 0.53 (Part 1, QW), 0.42 (Part 2, QW), 0.25 (Part 2, QM) and 0.50 (Parts 1 and 2, QW); 74–88% of participants had zero treated bleeds; no bleeds were reported in inhibitor-positive children. All 10 baseline target joints resolved. Caregivers reported reduced treatment burden and improved physical functioning, and 98% of caregivers preferred denecimig to prior therapy. Conclusions Over 52 weeks, denecimig prophylaxis was well tolerated with no safety concerns and provided robust bleed protection, reduced treatment burden and improved overall health-related quality of life in children with HA.

Immune thrombocytopenia (ITP) is an autoimmune disorder, characterized by immune-mediated platelet destruction and decreased platelet production. To investigate metabolic alterations associated with paediatric ITP and disease chronicity, we performed untargeted plasma metabolomics analysis in 60 newly diagnosed ITP (nITP) patients, 39 chronic ITP (cITP) patients and 39 healthy controls (HC) from Beijing Children's Hospital between October 2020 and August 2024. A total of 30 differential metabolites were identified between ITP patients and HC, with altered tryptophan metabolism among the most significantly enriched metabolic pathways. Random forest analysis achieved an accuracy of 83.9% and a precision of 95.1%. Glycocholic acid demonstrated strong discriminatory performance, with an area under the receiver operating characteristic curve of 0.882 (95% confidence interval: 0.814-0.950). In addition, phosphatidylcholine-related metabolites and sphingolipid-related metabolites were associated with metabolic alterations observed between nITP and cITP. Overall, paediatric ITP was associated with distinct plasma metabolic alterations, particularly involving tryptophan metabolism, bile acid metabolism and lipid metabolism. These findings provide additional insights into metabolic alterations associated with paediatric ITP and disease chronicity.

Although studies have identified deep intronic variants associated with hemophilia B in patients undiagnosed by conventional genetic testing, knowledge in this field remains limited. Long range-PCR of entire F9 gene was used to screen variants of three unrelated genetically unresolved severe hemophilia B patients. In silico analysis and minigene assay with two minigene plasmid construction methods were conducted to explore the effects of candidate deep intronic variants on splicing. Three novel putative pathogenic deep intronic variants (c.278-765_278-764ins6.1kb, c.392-903A>G and c.724-751T>G) and one variant of uncertain significance (c.723+2708del) in F9 were identified in three patients. All the three putative pathogenic variants created de novo donor splice site and utilized cryptic acceptor splice site to generate pseudoexon. We successfully developed antisense oligonucleotide-mediated exon-skipping correction strategies for the three identified putative pathogenic variants and the previously reported c.392-864T>G. However, the results obtained from minigene assay revealed certain discrepancies with the clinical phenotype. It is still challenging to accurately characterize the pathogenicity of deep intronic variants in vitro. Overall, our results highlight the complementary role of whole-gene sequencing of F9 to conventional genetic diagnosis. Furthermore, we provide insight into a potential therapeutic approach based on antisense oligonucleotide technology-mediated exon-skipping.

Background: Prophylaxis in children with hemophilia B (HB) lacks quantitative approaches that integrate both plasma exposure and tissue distribution. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model of factor IX (FIX) for pediatric HB. The model incorporated the binding of FIX to type IV collagen (Col4) to characterize its distribution in both plasma and extravascular tissues. Methods: A total of 20 children with severe HB were included, contributing 219 plasma samples. The base PBPK model was first established and verified using adult and plasma-derived FIX (pdFIX) data. It was subsequently extrapolated to children by integrating FIX-CTBB parameters and pediatric observations for model calibration. The validated model was used to characterize plasma pharmacokinetics, predict tissue distribution and target attainment, and simulate alternative prophylactic dosing regimens. Results: The model adequately described the plasma pharmacokinetics of FIX in children and predicted substantial extravascular distribution. Total extravascular exposure was approximately sixfold higher than plasma exposure. Marked heterogeneity in target attainment was identified across tissues. Lower target attainment was observed in the colon, pancreas, and brain, whereas delayed attainment occurred in bone and muscle. Simulations of prophylactic dosing regimens suggested that 75 IU/kg twice weekly may provide a favorable balance among sustained FIX exposure, tissue-level target attainment, and treatment burden. Conclusions: This PBPK model provides a mechanistic and quantitative framework for characterizing plasma and tissue exposure to FIX in children with HB and may support individualized optimization of FIX prophylactic dosing.

Background Large F8 deletions are generally associated with unfavorable immune tolerance induction (ITI) outcomes in children with severe hemophilia A (SHA). Whether intragenic deletion location further stratifies ITI outcomes remains unclear. Objective To evaluate the association between the location of F8 large deletion and ITI outcome in children with SHA and to exploratorily assess residual F8 expression across patients with different deletion locations. Methods This single-center retrospective cohort included 34 children with SHA, F8 large deletions, inhibitors, and evaluable ITI outcomes. Deletions were mapped to FVIII domains and categorized as isolated A1-domain or non-isolated A1-domain deletions. Exploratory F8 mRNA and protein analyses were performed in patients with available blood samples. Results Thirteen patients achieved ITI success or partial success, and 21 experienced ITI failure. Success or partial success was more frequent with isolated A1-domain than non-isolated A1-domain deletions (8/9 vs. 5/25; P < 0.001). Higher historical peak, pre-ITI, and on-ITI peak inhibitor titers were associated with failure in univariate analyses. After multivariable adjustment, isolated A1-domain deletion remained associated with higher odds of success or partial success (adjusted OR, 21.59; 95% CI, 1.24-375.60; P = 0.035). Residual downstream F8 transcripts were detected in the isolated A1-domain subgroup; their biological relevance remains uncertain. Conclusions Intragenic location of F8 large deletions was associated with ITI outcome in this cohort. Isolated A1-domain deletions may identify patients with a more favorable ITI prognosis. Exploratory expression findings require confirmation in larger studies using physiologically relevant models.

Eltrombopag (ELT) is a second-line therapy for pediatric immune thrombocytopenia (ITP), but inter-individual variability in metabolism leads to wide plasma concentration differences at the same dose, affecting efficacy and adverse drug reactions (ADRs). To validate the feasibility of individualized drug regimens based on blood drug concentration guidance in pediatric persistent/chronic ITP (P/CITP) and to provide a new method of individualized treatment with eltrombopag for pediatric P/CITP. This prospective, observational cohort study enrolled 70 children with refractory persistent/chronic ITP (P/CITP) to evaluate the feasibility and value of plasma concentration–guided individualized dosing. Patients were assigned to a conventional group (dose titration by platelet counts and bleeding events) or an individualized group (dose adjustments additionally guided by ELT concentrations), with 6-month follow-up. Although no statistical significance was observed, the individualized group achieved a higher overall response rate (82.9