The influence of dead space in blood sampling needle on FVIII level and pharmacokinetic profiles in children with hemophilia.

OBJECTIVE: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia. METHODS: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t1/2), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used. RESULT: Compared with standard-collected blood samples, prolonged APTT results (P-values < 0.01) and decreased FVIII activity (P-values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2, lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group. CONCLUSION: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.

Machine learning model for predicting physical activity related bleeding risk in Chinese boys with haemophilia A.

BACKGROUND: Physical activity is a crucial part of an active lifestyle for haemophiliac children. However, the fear of bleeds has been identified as barriers to participating physical activity for haemophiliac children even with prophylaxis. Lack of evidence and metrics driven by data is key problem. OBJECTIVES: We aim to develop machine learning models based on clinical data with multiple potential factors considered to predict risk of physical activity bleeding for haemophilia children with prophylaxis. METHODS: From this cohort study, we collected information on 98 haemophiliac children with adequate prophylaxis (trough FVIII:C level > 1 %). The involved potential predictor variables include demographic information, treatment information, physical activity, joint evaluation, and pharmacokinetic parameters, etc. We applied CoxPH, Random Survival Forests (RSF) and DeepSurv to construct prediction models for the risk of bleeding during physical activities. All three survival analysis models were internally and externally validated. RESULTS: A total of 98 patients were enrolled in this study. Their median age was 7.9 (5.5, 10.2) years. The CoxPH, RSF and DeepSurv models' discriminative and calibration abilities were all high, and the RSF model had the best performance (Internal validation: C-index, 0.7648 ± 0.0139; Brier Score, 0.1098 ± 0.0015; External validation: C-index, 0.7260 ± 0.0154; Brier Score, 0.0930 ± 0.0018). The prediction curves demonstrated that the developed RSF model can distinguish the risks well between bleeding and non-bleeding patients, as well as patients with different levels of physical activity. Meanwhile, the feature importance analysis confirmed that physical activity bleeding was deduced by comprehensive effects of various factors, and the importance of different factors on bleeding outcome is discrepant. CONCLUSIONS: This study revealed from the mechanism that it is necessary to incorporate multiple factors to accurately predict physical activity related bleeding risk. In clinical practice, the designed machine learning models can provide guidance for children with haemophilia A to positively participate in physical activity.

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.

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.

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.

Real-world experience of emicizumab prophylaxis in young children with hemophilia A: retrospective data from China.

Background: As a new non-factor therapy for hemophilia A (HA), real-world study of emicizumab is still scarce. This study aimed to investigate the real-world use of emicizumab in Chinese boys with HA. Methods: Patients with moderate or severe HA were enrolled at Beijing Children's Hospital. They take emicizumab weekly (3 mg/kg) for a month and then went into a maintenance period with a different dosing regimen. After obtaining platelet-poor plasma at end of the loading period and during the maintenance period, coagulation ability and FVIII inhibitor were determined using human and bovine chromogenic Bethesda assay. Patients' bleeding rates were calculated through patients' records from 24 weeks before to at least 6 months after the switch (to emicizumab). Result: In total, 13 pediatric patients with HA (severe: moderate = 11:2) were enrolled in this study. The patients' age was 3.51 (0.73-6.65) years. Eight had FVIII inhibitors at enrollment and one of them developed FVIII inhibitors again during the switch. The coagulation level of the maintenance period was 19.6 (13.5-32.8) IU/dL (N = 10). The median dose of each emicizumab injection was 2.7 (1.3-3.8) mg/kg and the monthly consumption of emicizumab was 5.2 (3.2-6.8) mg/kg/month. After switching to emicizumab, reduced annualized bleeding rate (ABR) [0.5 (0-4) vs. 4 (0-18), P < 0.01], annualized joint bleeding rate (AJBR) [0 (0-1.1) vs. 1.0 (0-12), P < 0.01], and annualized spontaneous bleeding rate (ASBR) [0 (0-1) vs. 2.0 (0-18), P < 0.01] were observed. In patients with or without FVIII inhibitor, similar ABR [0.33 (0-4) vs. 0.5 (0-3), P = 0.78], AJBR [0 (0-1.1) vs. 0 (0-0.5), P = 0.63], and ASBR [0 (0-1) vs. 0 (0-1.5), P = 0.73] were also noticed. Five inhibitor-positive patients (at enrollment) all had their inhibitor titer reduced. In addition, all target joints vanished after switching to emicizumab. Conclusion: Emicizumab could reduce bleeds in pediatric patients with/without FVIII inhibitors and eliminate target joints.

Exploration of the minimum necessary FVIII level at different physical activity levels in pediatric patients with hemophilia A.

Background: Physical activity can increase joint stability and reduce the risk of injury in hemophilia patients. There is limited clinical data on target trough FVIII levels during physical activity in hemophilia A patients. Hence, this study aimed to explore the target trough FVIII level required to avoid bleeding during different physical activities in hemophilia A patients. Methods: Patients with severe or moderate hemophilia A, who underwent pharmacokinetics (PK) tests at our center were enrolled in this study. Physical activities and clinical information such as bleeding were recorded. The FVIII level during physical activity was calculated by the WAPPS-Hemo. Results: A total of 105 patients were enrolled in this study. A total of 373 physical activities were recorded, of which 57.6% (215/373) was low-risk activities and the remaining 42.4% (158/373) was medium-risk activities. Most common physical activities were bicycling (59.0%), swimming (43.8%), running (48.6%), and jumping rope (41.0%). The FVIII trough level of low-risk physical activity was 3.8 IU/dl (AUC = 0.781, p = 0.002) and moderate-risk physical activity was 7.7 IU/dl (AUC = 0.809, p < 0.001). FVIII trough levels [low-risk activities: 6.1 (3.1, 13.2) IU/dl vs. 7.7 (2.3, 10.5) IU/dl, moderate-risk activities: 9.6 (5.8, 16.9) IU/dl vs. 10.2 (5.5, 11.0) IU/dl] were not statistically different between the mild arthropathy group and the moderate-severe arthropathy group. Multiple bleeding risk tended to increase with physical activities classified as moderate-risk (OR [95% CI]: 3.815 [1.766-8.238], p = 0.001). Conclusion: The minimum necessary FVIII level increased with higher risk physical activity, irrespective of arthropathy.

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.

Individualised prophylaxis based on personalised target trough FVIII level optimised clinical outcomes in paediatric patients with severe haemophilia A.

INTRODUCTION: As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. AIM: This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol. METHODS: Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS-Hemo. RESULTS: Fifty-eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were: < 1 IU/dl, 17.2% (10/58); 1-3 IU/dl, 53.5% (31/58); 3-5 IU/dl, 15.5% (9/58); > 5 IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p < .0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p < .0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%-69.0%) and zero joint bleeding proportion (46.5%-81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p = .04) and HJHS (p = .02) were also reported at study exit. CONCLUSION: Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis.

F8 gene mutation spectrum in severe hemophilia A with inhibitors: A large cohort data analysis from a single center in China.

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. Methods: The single-center retrospective cohort study was conducted on children with severe hemophilia A with inhibitors admitted from January 2015 to December 2021. The clinical data were collected, and F8 genetic tests were performed. Results: Among the 203 patients investigated, a mutation in F8 was identified in 196 cases. Most patients had deleterious mutations (153; 75.4%), including 82 cases of intron 22 inversions (40.4%); 40 cases of nonsense mutations (19.7%), with 15 cases in the light chain and 25 cases in the heavy chain; and 31 cases of large deletions or insertions (15.3%), with 29 cases involving more than one exon and 2 cases involving one exon. The large deletions or insertions encompassing multiple exons and nonsense mutations residing in the light chain were associated with not only the progression to a high-titer inhibitor (P < .05) but also higher peak inhibitor titer (P < .05). Conclusion: The F8 gene deleterious mutations, including intron 22 inversions, nonsense mutations, and large deletions or insertions, constitute the main mutation types in people with severe hemophilia A with inhibitors in China, with the latter mutation types (large deletions or insertions in multiple exons, and nonsense mutations in the light chain) signifying for a higher peak titer of inhibitor.

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.

Enhanced pharmacokinetics and reduced bleeds in boys with hemophilia A after switching to Kovaltry from other standard half-life factor VIII concentrates.

Background: BAY81-8973 (Kovaltry; Bayer, Berkeley, CA, USA) was reported with enhanced pharmacokinetic (PK) profiles compared with some other standard half-life (SHL) factor VIII (FVIII) concentrates. Limited head-to-head comparative studies were conducted in a real-world setting. Objective: To make head-to-head comparisons of PK and clinical outcomes between Kovaltry and three other SHL FVIII concentrates. Methods: Forty-seven boys with severe hemophilia A were enrolled and divided into three groups according to their previously used FVIII concentrates (Kogenate FS, N = 22; Advate, N = 14; GreenMono, N = 11). Two separate PK tests were conducted in each participant with a five-point assay during the study period from 6 months before switching to 6 months after switching. FVIII levels were detected by one-stage assay, and PK profiles were calculated by noncompartmental assay. Annualized bleeding rates were collected through participant' bleed logs. Results: Longer half-life time (Kogenate FS group: 14.4 vs 11.9 hours, P < .0001; Advate group: 13.4 vs 9.7 hours, P < .0001; GreenMono group: 15.1 vs 10.7 hours, P < .001]) and lower clearance (Kogenate FS group: 3.3 vs 3.9 mL/kg/h, P < .01; Advate group: 3.7 vs 5.9 mL/kg/h, P < .01; GreenMono group: 3.0 vs 5.1 mL/kg/h, P < .01) were observed with Kovaltry. In addition, longer mean residential time (P < .01) and higher area under the curve (P < .01) were demonstrated. No statistical difference was found in in vivo recovery between Kovaltry and the other FVIII products. Participants who switched to Kovaltry from three other FVIII concentrates with the same dosing regimens obtained higher trough FVIII levels and better protection with reduced annualized bleeding rates. Conclusion: Compared with Kogenate FS, Advate, and GreenMono, Kovaltry showed enhanced PK profiles, which contributed to reduced bleeding rates.

Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A.

INTRODUCTION: As the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population. MATERIALS AND METHODS: Pediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles. RESULT: Sixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = -0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20-30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10-20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed. CONCLUSION: This study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.

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.

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.

Pharmacokinetic-guided prophylaxis improved clinical outcomes in paediatric patients with severe haemophilia A.

BACKGROUND: The traditional weight-based dosing regimen can lead to under- or overdosage due to the interindividual variability of pharmacokinetic (PK) parameters. PK-guided prophylaxis can be an optimized therapy choice. AIM: This study aimed to investigate the clinical outcomes of PK-guided prophylaxis in 46 boys with severe haemophilia A. METHODS: Forty-six boys with severe haemophilia A were enrolled in Beijing Children's Hospital. The PK tests were performed using a five-point assay. PK parameters were calculated using WinNonlin software. The dosing regimen and bleeding rates recorded during the observation period. The adjustment was based on PK evaluation, bleeding details, doctor's advice and patients' choice. RESULTS: The half-life time, in vivo recovery and clearance of Kovaltry were 14.34 ± 2.68 h, 1.78 ± 0.29 kg/dl and 3.38 ± 0.94 ml/kg/h, respectively. In 18 patients without any change in the dosing regimen, the trough level was 4.0 ± 2.41 IU/dl and the bleeding rates were similar after PK tests. For patients with a higher trough level after adjustment, higher dose and frequency were observed, as well as a higher trough level. Also, reduced annual bleeding rate (ABR), annual joint bleeding rate and annual spontaneous bleeding rate (ASBR) were found. In five patients with a reduced trough level, lower infusion frequency and weekly coagulation factor VIII (FVIII) consumption were observed, with no statistically significant difference in ABR and ASBR. CONCLUSION: PK-guided prophylaxis can help haemophiliac patients improve quality of life by decreasing bleeds with appropriate FVIII consumption and reducing infusion frequency without increments in bleeds, thus optimizing haemophilia treatment.