Surgical procedures and complications in placement of totally implantable venous access port in pediatric hemophilia patients: A retrospective analysis.

This retrospective study at Beijing Children's Hospital (2020-2023) analyzed surgical procedures and complications in 24 pediatric hemophilia patients undergoing Totally Implantable Venous Access Port (TIVAP) insertion, primarily in the right jugular vein (RJV). We detailed the surgical process, including patient demographics and intraoperative imaging use. The choice of the RJV for TIVAP placement was influenced by its larger diameter and superficial anatomical position, potentially reducing risks like thrombosis and infection. Our findings support the RJV as a safer alternative for port placement in pediatric patients, aligning with current literature. Statistical analysis revealed no significant correlation between complications and baseline characteristics like weight and diagnosis type. However, the length of hospital stay and implant brand were significant risk factors for catheter or port displacement and removal. The limited patient number may introduce bias, suggesting a need for further studies with larger samples. Despite a 14.7 %-33 % complication rate and 5 port removals, the advantages of TIVAP, including reliable venous access, reduced discomfort, and treatment convenience, were evident. Most complications improved with symptomatic treatment, and there were no deaths due to port-related complications, underscoring the impact of TIVAP on improving pediatric hemophilia treatment.

Treatment-related outcome from patient report outcome (PRO) of children with severe and moderate hemophilia A in China: An analysis report of registration data from patient organization "hemophilia home care center".

OBJECTIVES: To assess current treatment-related outcomes for children with severe and moderate haemophilia A (cHA) in China. METHODS: This cross-section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were < 18 years old. RESULTS: Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p < .001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on-demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low-dose, 43.2% received intermediate-dose, and 13.8% received high-dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p < .001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p < .001) and disability rate (9.0% vs.18.5%, p = .032) compared to children who received on-demand treatment. CONCLUSION: The high rate of drop-out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China.

Eradication of FIX inhibitor in haemophilia B children using low-dose immune tolerance induction with rituximab-based immunosuppressive agent(s) in China.

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-times-weekly 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 received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months). CONCLUSIONS: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications.

A long term outcomes analysis of severe haemophilia A boys receiving 4 years prophylaxis on the Chinese Haemophilia Individualized escalating low dose Prophylaxis (CHIPS).

BACKGROUND: The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up. METHODS: Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system. RESULTS: A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3-6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20-25 lU/kg, every other day), 10 at step 3 (15-20 IU/kg, 3×/week), 2 at step 2 (10-15 lU/kg, 3×/week) and 1 at step 1 (10-15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score. CONCLUSION: Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings.

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

BACKGROUND: It 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/PURPOSE: To evaluate the cost-effectiveness of PR and OD treatment for children with moderate or severe HA without inhibitors in China. METHODS: A 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/FINDINGS: PR 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/IMPLICATIONS: This study indicated that PR is cost-effective compared with OD treatment for children with moderate or severe HA without inhibitors in China.

Low-dose immune tolerance induction for severe hemophilia A inhibitor patients: Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL.

Importance: It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS40 regimen). Objective: To compare the efficacy of the LD-ITI-IS200 regimen with that of the LD-ITI-IS40 regimen for SHA patients with high-titer inhibitors. Methods: A prospective cohort study on patients receiving LD-ITI-IS200 compared to those receiving LD-ITI-IS40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS200 regimen and ≥40 BU/mL in the LD-ITI-IS40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected. Results: We enrolled 30 patients on LD-ITI-IS200 and 64 patients on LD-ITI-IS40, with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS200 regimen compared to the LD-ITI-IS40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS200 vs. LD-ITI-IS40) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS200 than for LD-ITI-IS40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS200 regimen) and 28 IS-using (on LD-ITI-IS40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months). Interpretation: In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL.

Early immune tolerance induction is a unique predictor of favorable outcomes in hemophilia A children with intron 22 inversion and high-responding inhibitors.

BACKGROUND: The predictors of immune tolerance induction (ITI) outcomes in hemophilia A (HA) patients with the same F8 genetic background have not yet been evaluated, although the F8 genotype is strongly associated with ITI response. This study aims to explore the predictors of ITI outcomes in the same F8 genetic background by focusing on intron 22 inversion (Inv22) patients with high-responding inhibitors. METHODS: HA children with Inv22 and high-responding inhibitors who received low-dose ITI therapy over 24 months were included in this study. ITI outcomes were centrally assessed at the 24th month of treatment. The predictive ability of clinical variables to identify ITI success was determined using the receiver operating characteristic (ROC) curve, and the predictor of ITI outcomes was analyzed on the multivariable Cox model. RESULTS: Among the 32 patients investigated, 23 (71.9 %) achieved success. In univariate analysis, interval time from inhibitor diagnosis to ITI start (interval-time) was significantly associated with ITI success (P = 0.001); however, inhibitor titers showed no significance (P > 0.05). The interval-time demonstrated a good predictive value for ITI success with the area under the ROC curve of 0.855 (P = 0.002), and the cutoff value was 25.8 months (sensitivity, 87.0 %; specificity, 88.9 %). In the multivariable Cox model which considered success rate and time to success, interval-time was the only independent predictor (<25.8 months vs. ≥25.8 months, P = 0.002). CONCLUSIONS: The interval-time was first identified as a unique predictor of ITI outcomes in HA patients with high-responding inhibitors under the same F8 genetic background (Inv22). An interval-time of <25.8 months was associated with increased ITI success and reduced time to success.

Application of peripherally inserted central catheter in immune tolerance induction treatment of children with hemophilia A and accompanying inhibitors in China.

OBJECTIVE: To explore the feasibility, safety and cost effectiveness of the use of peripherally inserted central catheter (PICC) in children with hemophilia A and inhibitors who underwent ITI treatment. METHOD: This retrospective cohort study evaluated the effect of PICC placement and ITI on bleeding rates, costs, and parents' satisfaction before and within 6 months after PICC placement in children with hemophilia A and inhibitors. RESULTS: A total of 20 children with hemophilia A and high-titer inhibitors were included, with a success rate for PICC placement of 100%, at a cost of ¥6730.50. Parents' satisfaction with PICC was 100%, and the total length of catheter indwelling was 6055 days. In terms of curative effect, the success rate of ITI treatment was 75%, and the annualized bleeding rate was decreased from 10.90 ± 12.16 times before placement to 2.10 ± 3.32 times (p < 0.05). The transportation expense for children and their parents to the clinic decreased from ¥20,920 ± 32,274.57 before catheter placement to ¥2915 ± 2195.99 (p < 0.05). Time of children missed school and their parents missed work decreased from 10.85 ± 22.36 days to 1.90 ± 3.58 (p < 0.05) days and 40.33 ± 46.11 days to 3.83 ± 7.11 days (p < 0.05), respectively. CONCLUSION: The use of PICC for ITI treatment in children with hemophilia A and accompanying inhibitors in developing countries (e.g. China) can ensure the effect of ITI, reducing expense and improving the quality of life without obvious side effects.

Central venous access devices implantation in children with severe hemophilia a: data from the children comprehensive care center of China.

Objectives: To report the perioperative management experience of central venous access devices (CVAD) in Chinese children with severe hemophilia A (SHA) in China. Methods: This retrospective study included SHA children who underwent Port-A-Cath or peripherally inserted central catheter (PICC) implantation between 2020/01 and 2021/07. Collected data included baseline characteristics, factor replacement regimen and CVAD-related complications. Results: Nine patients had nine ports placed, and eight patients underwent 10 PICCs placement. Patients without or with low-titer inhibitor (<5 BU) received a port. The median preoperative and postoperative plasma-derived factor VIII (pd-FVIII) doses were 53.0 (44.4-61.1) and 315.9 (88.2-577.8) IU/kg. The median port duration was 189 (15-512) days, with infection incidence of 0.06 per 1000 CVAD days. Patients with high-titer inhibitors (>10 BU) received PICC. The median recombinant factor VIIa (rFVIIa) dose was 87.47 µg/kg before and for 5-7 doses after implantation over 2-3 days. The median PICC duration was 226.5 days, with infection incidence of 0.12 per 1000 catheter-days. Conclusions: CVADs can be safely implanted in China. PICC implantation is a practical and safe option for SHA children with high-titer inhibitors.

Low-dose immune tolerance induction therapy in severe hemophilia a children in China: Starting earlier resulted in better inhibitor eradication outcomes.

BACKGROUND: Shorter interval-time from inhibitor detection to starting immune tolerance induction (ITI) might predict better ITI outcomes for severe Hemophilia A (SHA) patients with high-risk-inhibitors. However, the prediction-impact of interval-time for these patients on low-dose ITI strategy remained unclear. OBJECTIVES: To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. METHODS: This was a single-center, retrospective study on SHA children with high-risk-inhibitors (each with immediate pre-ITI inhibitor titer>10 Bethesda Units/mL) undergoing low-dose ITI strategy for ≥24 months. ITI outcomes and their predictive factors were evaluated at the 24th month treatment for each patient. The predictive ability of interval-time on ITI success was determined using receiver operating characteristic (ROC) curve. RESULTS: Among 47 patients investigated, 34 (72.3 %) achieved success. Independent predictor for ITI-outcome on multivariate analysis included the interval-time (p = 0.007) and peak inhibitor-titer (p = 0.011). Shorter interval-time predicted ITI success [cut-off value = 22.3 months, area under ROC-curve (AUC) = 0.701] and early-ITI success within 12 month (cut-off value = 9.4 months AUC = 0.704). Linear regression analysis suggested each month interval-time delay delayed success by 0.1552 month. Unlike the interval-time, peak inhibitor-titer had no success-predictive value in high-peak inhibitor-titer patients on ITI with immunosuppressants. CONCLUSIONS: Interval-time represented a strong predictive value for outcomes in our low-dose ITI strategy for SHA patients with high-risk-inhibitors. Shorter interval-time was associated with higher success rate and earlier success achievement. The respective interval-time cut-off values were 22.3 months for ITI success and 9.4 months for early-success.

Low-dose immune tolerance induction in children with severe hemophilia A with high-titer inhibitors: Type of factor 8 mutation and outcomes.

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 high-titer 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 start (adjusted OR, 0.95; 95% CI, 0.90-0.99). They remained the significant predictors when success time was taken into account in a Cox model. Conclusions: Types of F8 mutation were a key predictor of outcomes for low-dose ITI in children with SHA with high-titer inhibitors. It can help to stratify the prognosis and guide clinical decisions.

Low-dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors.

BACKGROUND: In developing countries, children with hemophilia A (HA) with high-titer inhibitor and poor immune tolerance induction (ITI) prognostic risk(s) cannot afford the recommended high- or intermediate-dose ITI. OBJECTIVES: To determine the efficacy of low-dose ITI (plasma-derived factor VIII [FVIII]/von Willebrand factor at 50 FVIII IU/kg every other day) by itself (ITI-alone) or combined with immunosuppressants rituximab and prednisone (ITI-IS) in children with HA with high-titer inhibitor. METHODS: All enrolled patients had pre-ITI inhibitor ≥10 BU. We used ITI-alone if inhibitor titer was <40 BU pre-ITI and during ITI, and ITI-IS if titer was ≥100 BU (historic) or ≥40 BU (pre- or during ITI) or if the patient was nonresponsive on ITI-alone. RESULTS: Fifty-six children were analyzable, with median historic peak inhibitor titer 48.0 BU and followed for median 31.4 months. Overall, 35 (62.5%) achieved phase 2 success with negative inhibitor and normal FVIII recovery. The phase 2 success rate was 95% for the 20 patients receiving ITI-alone. For the 36 patients receiving ITI-IS, the phase 2 success rate was 44.4%, but would increase to 63.6% if the 14 patients with historic peak inhibitor titer ≥100 BU (and having phase 2 success rate of only 14.3%) were excluded. One patient developed repeated infection after IS treatment. Relapse occurred in 11.4% (4/35) patients with phase 2 success associated with rapid ITI dose reduction or irregular post-ITI FVIII prophylaxis. Our strategy reduced the cost from high-dose ITI by 74% to 90%. CONCLUSION: The use of low-dose ITI with or without immunosuppressants according to ITI prognostic risk(s) is a clinically and economically feasible strategy for eradicating inhibitors in children with HA, particularly for those with historic peak inhibitor titer <100 BU.

Significant reduction in hemarthrosis in boys with severe hemophilia A: The China hemophilia individualized low-dose secondary prophylaxis study.

INTRODUCTION: In countries with restricted access to clotting factor concentrates, early implementation of low-dose prophylaxis is recommended over episodic treatment. OBJECTIVE: The objective of this 1-year prospective secondary prophylaxis study was to evaluate the efficacy of a dose/frequency escalating protocol in young boys with hemophilia A in China. METHODS: Boys were started on a low-dose protocol (minimum 10-15 IU/kg of factor VIII [FVIII] twice weekly). Escalation was based on index joint bleeding, swelling/persistent joint swelling, and serial ultrasound (gray scale and color Doppler) examinations of index joints. RESULTS: Thirty-three boys, median age 4.8 years (interquartile range, 3.8-6.1) were enrolled in a 3-month observation period that preceded a 1-year prophylaxis phase. A significant reduction in total bleeding events (43.0%, P = .001), index joint bleeds (53.2%, P = .002), and target index joint bleeds (70.0%, P = 0.02) was observed during the prophylaxis phase. During the prophylaxis period, 40% of target joints resolved. The percentage of boys with zero index joint bleeds increased significantly (P = .004) from 51.5% during the observation phase to 81.8% in last quarter of the prophylaxis phase (months 10-12). There was no progression of arthropathy based on physical examination (Hemophilia Joint Health Score), X-ray, and ultrasound obtained at entry into the prophylaxis phase and at study exit. The median FVIII consumption over the prophylaxis phase was 1786 IU/kg/y. CONCLUSION: A low-dose, individualized prophylaxis protocol, guided by individual bleeding profiles and serial assessment of joint status, enables escalation of treatment intensity in boys with severe hemophilia A, leading to a significant reduction in bleeding events and reduction in target joint bleeding.

The Efficacy of Recombinant FVIII Low-Dose Prophylaxis in Chinese Pediatric Patients With Severe Hemophilia A: A Retrospective Analysis From the ReCARE Study.

OBJECTIVE: This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population. METHODS: This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed. RESULTS: A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline ( S = 408.5, P < .001), with median ABR rates of -4.0 (-8.0 to -3.1), -4.0 (-24.0 to 8.0), and -13.9 (-110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups ( P = .008). Median AJBR reduction rates were -2.3 (-6.3 to 8.4) and -14.9 (-61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups ( P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding ( P = .024). CONCLUSION: Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.