Introduction Prophylaxis has commonly become standard treatment for severe haemophilia patients. The World Federation of Hemophilia (WFH) recommends low‐dose prophylaxis in countries with resource constraints. Objective To determine efficacy and safety of low‐dose factor VIII (FVIII) tertiary prophylaxis compared to on‐demand treatment in severe haemophilia A children in Indonesia. Methods Eligible patients were randomly assigned to prophylaxis and on‐demand groups. Patients in the prophylaxis group received infusion of FVIII 10 IU/kg body weight, two times per week. Primary outcomes were the numbers of joint bleeding and total bleeding episodes; secondary outcomes were evidence of FVIII inhibitor, Hemophilia Joint Health Score (HJHS) and Hemophilia Early Arthropathy Detection Ultrasound (HEAD‐US) score. Patients were monitored for 12 months. Results Fifty patients, all with tertiary prophylaxis, 4‐18 years of age, were randomized into prophylaxis (n = 25) and on‐demand (n = 25) groups. The mean follow‐up time was 12.8 ± 0.86 vs 12.3 ± 0.54 months, respectively. Numbers of total and joint bleeding episodes were significantly lower in the prophylaxis group (P < 0.001, 95% CI −24.6;−10.7 and P < 0.001, 95% CI −14;−3, respectively). The prophylaxis group showed improvement of joint function (P = 0.004; CI 95% −3;−0.5); on the contrary, we found deterioration in the on‐demand group (P = 0.001; CI 95% 1;3). HEAD‐US scores showed improvement at month 6 in the prophylaxis group, but there was no significant difference between groups at month 12. Conclusion Low‐dose FVIII tertiary prophylaxis was effective in reducing joint bleeding episodes and improvement of HJHS compared to on‐demand FVIII treatment in severe haemophilia A children.

Background: Recurrent joint bleeds leading to arthropathy is the main problem in severe hemophilia children. This study aimed to investigate joint status in severe hemophilia A children receiving episodic treatment in Cipto Mangunkusumo Hospital, Jakarta.Methods: A cross-sectional study was conducted in Cipto Mangunkusumo Hospital as Indonesian National Hemophilia Treatment Center on children (4–18 years) with severe hemophilia A, who previously received episodic treatment, with no history of inhibitor factor VIII. Hemophilia Joint Health Score was evaluated according to HJHS version 2.1 2011. Joint ultrasonography was done for six index joints (bilateral elbows, knees and ankles) using Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) methods. Data of age of first joint bleed, number of target joints and inhibitor factor VIII were obtained from the Pediatric Hemophilia Registry and medical records.Results: There were 59 subjects aged 4 to 18 years. Twenty-nine out of 59 (49.2%) subjects experienced first joint bleed before of 2 years of age. The most common of joint bleeds was a right ankle. Mean total HJHS was 8.71±8.73. Subjects aged 4–10 years showed lower HJHS (4.6±3.7) as compared to subjects aged >10–18 years (12.3±10.3), p<0.001; 95% CI=4.9–13. Mean HEAD-US scores in subjects aged 4–10 years (18.7±5.6) was lower than in subjects aged >10–18 years (28±7.9), p<0.001, 95% CI= -12.9–-5.6.Conclusion: HJHS and HEAD-US scores of severe hemophilia A children receiving episodic treatment aged 4–10 years are lower compared to subjects aged >10–18 years, indicating more severe joint destruction in older children and progressivity of joint damage over time. It is important to start prophylactic treatment to prevent progressivity of joint damage.

Background: Factor VIII (FVIII) inhibitor diagnosis and surveillance in Indonesia are challenging owing to geographic conditions and the lack of laboratory facilities nationwide for inhibitor assays. This study aimed to determine the prevalence of FVIII inhibitors in children diagnosed with hemophilia A (HA) in Indonesia. Methods:A cross-sectional study was conducted in 12 hospitals in eight provinces of Indonesia between 2020 and 2021. Factor VIII inhibitor screening was performed in a central hemostasis laboratory for all children with HA (18 yr) who had received a minimum of 10 exposure days to clotting factor concentrates. The FVIII inhibitor titer was determined using the Bethesda assay.Results: Children (388) were enrolled in this study, including 219 (56.4%), 131 (33.8%), and 38 (9.4%) with severe, moderate, and mild HA, respectively. The prevalence of children who developed FVIII inhibitors was 37 out of 388 (9.6%). Factor VIII inhibitors were found in 25/219 (11.4%) severe, 11/131 (8.3%) moderate, and 1/38 (2.6%) children with mild HA. Thirteen children had low-titer inhibitors and 24 had high-titer inhibitors, with a median of 9.44 (1.48-412.0) Bethesda Units. Among 13 children with low-titer inhibitors, eight underwent a confirmation test, of which five tested negative and were classified as transient. A significant difference in annual joint bleeding rate was found between patients with low and high inhibitor titers and those without inhibitors (P<0.001). Conclusion:Factor VIII inhibitor prevalence in Indonesia was relatively low. However, the risk factors that may contribute to FVIII inhibitor development among Indonesian patients require further study.

Background Repeated bleeding in hemophilic arthropathy (HA) may result in severe degenerative changes and joint destruction. The gradient-recalled echo (GRE) sequence MR is proved to be the best method to detect hemosiderin deposition. However, MR is not widely available in developing countries, including Indonesia. Some studies have proposed ultrasonography (US) as an alternative tool in evaluating hemophilic joint. However, there is still some disagreement on the ability of US to detect hemosiderin deposition. Objective To evaluate the association between US and GRE-sequence MR imaging in detecting hemosiderin deposition in hemophilic ankle joint. Material and methods A total of 102 sites from 17 ankle joints of 11 boys with severe hemophilia A underwent US examination using a high-frequency linear array transducer. GRE-sequence MR examination was performed in sagittal view consistent with the sites scanned by US. Both examinations were performed on the same day, but MR interpretation was performed blindly at different times. The association between US and GRE-sequences in detecting hemosiderin deposition was analyzed using McNemar’s test. Results Statistical analysis showed a significant association (p value < 0.001) between US and GRE MR in detecting hemosiderin deposition, but the association is weak (R = 0.26). Sensitivity and specificity of US for detecting hemosiderin deposition were 46.84% (95%CI: 35.51–58.40) and 95.65% (95%CI: 78.05–99.89), respectively, with positive predictive value 97.37% (95%CI: 84.29–99.61), negative predictive value 34.38% (95%CI: 29.50–39.60) and accuracy 57.84% (95%CI: 47.66–67.56). Conclusion There was a weak association between US and GRE-sequences in detecting hemosiderin deposition of hemophilic ankle joint. ​​

Latar belakang. Gejala perdarahan pada hemofilia A bergantung pada kadar faktor VIII, namun pada kadar faktor koagulasi yang sama dapat terjadi perbedaan karakteristik dan luaran klinis. Tujuan. Mengidentifikasi pola perdarahan, terapi dan komplikasi pada anak hemofilia A. Metode. Penelitian kohort retrospektif pada anak ≤18 tahun di RSCM. Data diambil dari rekam medis (Januari 2014 – Juni 2016) meliputi data usia awitan perdarahan sendi, usia saat diagnosis, kekerapan perdarahan, lokasi perdarahan, penggunaan faktor VIII, dan komplikasi yang dialami. Hasil. Terdapat 109 anak lelaki terdiri dari 2,8% hemofilia A ringan, 27,5% hemofilia A sedang, dan 69,7% hemofilia A berat. Perdarahan tersering ditemukan pada sendi (60,6%) terutama pada lutut (37,2%). Dibandingkan hemofilia A ringan dan sedang, anak hemofilia A berat menunjukkan usia awitan perdarahan sendi lebih dini (median 12,5 (4-120) bulan), kekerapan perdarahan sendi lebih sering (median 8 (1-44) kali/tahun), dan menggunakan konsentrat faktor VIII lebih banyak (median 712 (131-1913) IU/kg/tahun). Komplikasi terbanyak adalah artropati dan sinovitis kronik (46,8%) serta inhibitor faktor VIII (7,3%). Terdapat 9 dari 71 (12,6)% subjek hemofilia A berat menunjukkan karakteristik klinis lebih ringan. Kesimpulan. Pola perdarahan pada anak hemofilia A sesuai kadar faktor VIII, tetapi pada hemofilia A berat terdapat variabilitas subjek dengan gejala klinis lebih ringan.

Background Thalassemia major (TM) patients are susceptible to liver dysfunction due to iron deposition. Pediatric TM patients often present with bleeding. Blood loss necessitates transfusions, leading to increased iron absorption from the gut. Objective To study hemostatic abnormalities in children with TM and iron deposition in the liver. Methods This cross-sectional study involved 190 non-splenectomized children with TM. Liver iron deposition was evaluated using T2* MRI. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet counts were assessed from blood specimens. Results Most subjects were diagnosed with β-thalassemia and β-thalassemia/HbE. The majority of subjects were on deferiprone (DFP) treatment. Approximately 89.5% of subjects had liver iron overload. Prolongation of PT and aPTT, as well as thrombocytopenia were observed in 60%, 27.9%, and 19.5% of subjects, respectively. Prolonged aPTT and thrombocytopenia were observed three times more frequently in subjects with moderate - severe liver iron overload than in subjects with normal - mild liver iron overload (P=0.04 and 0.001, respectively). Conclusion Most TM subjects have liver iron overload ranging from mild to severe. Prothrombin time and prolongation, as well as aPTT prolongation, and thrombocytopenia are easily found in TM children. There were significantly more moderate - severe liver iron deposition patients with aPTT prolongation and thrombocytopenia than normal – mild patients with these conditions. Hence, we suggest that pediatric TM patients undergo liver iron deposition evaluations and use iron chelators in an optimal manner, in order to limit the risk of bleeding.

Background Pharmacokinetic (PK) studies of low‐dose prophylaxis (LDP) of coagulation factor VIII (FVIII) in children with severe haemophilia A (SHA) are scarce. Objective This study aims to investigate the PK profile of children with SHA receiving LDP of FVIII. Methods Paediatric patients receiving FVIII infusions (10 IU/kg twice weekly) were included. PK profiles were estimated using the Web Accessible Population Pharmacokinetic Service for Haemophilia (WAPPS‐Haemo). The primary outcomes were the terminal half‐life (t1/2), concentration–time profile, and time to reach an FVIII level of < 1%. The secondary outcome was the suggested dosing interval of FVIII prophylaxis based on the individual PK profile. Results Twenty‐five patients were recruited; their mean age was 12.3 ± 3.0 years. The t1/2 differed among patients receiving LDP of FVIII twice weekly, with a median of t1/2 was 14.8 h (IQR 12.6–16). The median time to reach an FVIII level of < 1% was 73.8 h (IQR 58.8–80.3). Most patients could maintain a trough level of FVIII > 1% longer than 48 h. At 72–96 h, patients needed a second dose of FVIII infusion because the FVIII level was < 1%. The suggested dosing interval of FVIII prophylaxis ranged from daily to every 96 h, depending on the individual PK profile. Conclusion Our study identified inter‐individual differences in the PK parameters using LDP of FVIII twice weekly. The inter‐individual results in different dosing intervals advise the timing of LDP. Estimating individual PK parameters enables the identification of the optimal prophylaxis frequency to prevent bleedings.

Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. Objective Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. Methods A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. Results A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1–71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life ([Formula: see text]-phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction<1.8%). Conclusions The Fanhdi/Alphanate/Koate model is appropriate for Bayesian forecasting in the WAPPS-Hemo platform, providing a comparable prediction capability for low and normal dosing regimens (10 vs 50 IU/Kg).