Original Article
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Blood Res 2022; 57(4):
Published online December 31, 2022
https://doi.org/10.5045/br.2022.2022153
© The Korean Society of Hematology
FVIII inhibitor surveillance in children with hemophilia A in Indonesia: a report from the Indonesian Pediatric Hematology-Oncology Working Group
Correspondence to : Novie Amelia Chozie, M.D., Ph.D.
Pediatric Hematology-Oncology Division, Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Diponegoro street No. 71, Jakarta Pusat, DKI Jakarta 10430, Indonesia
E-mail: novie.amelia@ui.ac.id
*This study was supported by Roche Indonesia.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
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Original Article
Blood Res 2022; 57(4): 272-277
Published online December 31, 2022 https://doi.org/10.5045/br.2022.2022153
Copyright © The Korean Society of Hematology.
FVIII inhibitor surveillance in children with hemophilia A in Indonesia: a report from the Indonesian Pediatric Hematology-Oncology Working Group
Novie A. Chozie1, Djajadiman Gatot1, Bambang Sudarmanto2, Susi Susanah3, Rini Purnamasari4, Pudjo Hagung Widjajanto5, Susanto Nugroho6, Olga Rasiyanti7, Dian Puspitasari8, Muhammad Riza9, Maria C. Shanty Larasati10, Sri Suryo Adiyanti11, Made Citra Saraswati1, Fitri Primacakti1, on behalf of the Pediatric Hematology-Oncology Working Group of the Indonesian Pediatric Society
1Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 2Department of Child Health, Dr. Kariadi Hospital, Faculty of Medicine, Universitas Diponegoro, Semarang, 3Department of Child Health, Dr. Hasan Sadikin General Hospital, Bandung, Faculty of Medicine, Universitas Padjajaran, West Java, 4Department of Child Health, Tangerang General Hospital, Banten, 5Department of Child Health, Dr. Sardjito Hospital, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 6Department of Child Health, Dr. Saiful Anwar Hospital, Faculty of Medicine, Universitas Brawijaya, Malang, 7Department of Child Health, H. Adam Malik General Hospital, Faculty of Medicine, Universitas Sumatera Utara, Medan, 8Department of Child Health, Dr. Moh. Hoesin General Hospital, Faculty of Medicine, Universitas Sriwijaya, Palembang, 9Department of Child Health, Dr. Moewardi Hospital, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, 10Department of Child Health, Dr. Soetomo General Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, 11Department of Clinical Pathology, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Correspondence to:Novie Amelia Chozie, M.D., Ph.D.
Pediatric Hematology-Oncology Division, Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Diponegoro street No. 71, Jakarta Pusat, DKI Jakarta 10430, Indonesia
E-mail: novie.amelia@ui.ac.id
*This study was supported by Roche Indonesia.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords: Inhibitor, Factor VIII, Hemophilia A
Fig 1.
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Table 1 . Patient demographics..
Characteristics (N=388) N (%) Age 0–<5 years 63 (16.2) 5–<10 years 130 (33.5) 10–<15 years 128 (33.0) 15–18 years 67 (17.3) Severity Mild 38 (9.8) Moderate 131 (33.8) Severe 219 (56.4) Type of FVIII products Plasma-deriveda) 293 (75.5) Plasma-derived+recombinantb) 67 (17.3) Unknown 28 (7.2) a)Plasma-derived products used are Koate DVI, Haemoctin, Octanate. b)History of switching products from plasma-derived to recombinant owing to a clinical event. All recombinant FVIII concentrates were donated by the World Federation of Hemophilia’s Humanitarian Aid Program..
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Table 2 . Characteristics of patients with FVIII Inhibitors..
Characteristics Low-titer inhibitors (N=13) High-titer inhibitors (N=24) P d)Severity 0.811 Mild 0 (0%) 1 (4.2%) Moderate 3 (23.1%) 8 (33.3%) Severe 10 (76.9%) 15 (62.5%) Age at first time receiving FVIII concentrate 0.557 <1 year 4 (30.7%) 4 (16.7%) 1–5 years 7 (53.9%) 16 (66.6%) 6–10 years 2 (15.4%) 4 (16.7%) History of surgery 0.488 None 6 (46.1%) 15 (62.5%) Circumcision 5 (38.5%) 7 (29.1%) Appendicectomy 0 (0%) 1 (4.2%) Tooth extraction 1 (7.7%) 0 (0%) More than 1 surgery 1 (7.7%) 1 (4.2%) Major bleeding 0.682 None 9 (69.2%) 18 (75%) Intracranial hemorrhage 1 (7.7%) 3 (12.5%) Iliopsoas hemorrhage 1 (7.7%) 0 (0%) Unknown 2 (15.4%) 3 (12.5%) Annual bleeding ratea) 0.061 12/year 3 (23.1%) 10 (41.7%) 13–24/year 7 (53.8%) 7 (29.1%) 25–48/year 1 (7.7%) 7 (29.2%) Unknown 2 (15.4%) 0 (0%) Annual joint bleeding ratea) 0.097 12/year 2 (15.4%) 10 (41.7%) 13–24/year 9 (69.2%) 10 (41.7%) 25–48/year 0 (0%) 4 (16.7%) Unknown 2 (15.4%) 0 (0%) Target joint 0.274 None 2 (15.4%) 7 (29.2%) 1 joint 5 (38.5%) 10 (41.6%) More than 1 joint 4 (30.7%) 7 (29.2%) Unknown 2 (15.4%) 0 (0%) Family history of inhibitor 0.88 Yes 3 (23.1%) 4 (16.7%) No 8 (61.5%) 17 (70.8%) Unknown 2 (15.4%) 3 (12.5%) Type of FVIII products 0.261 Plasma-derivedb) 7 (38.5%) 17 (29.2%) Plasma-derived+recombinantc) 5 (53.8%) 7 (70.8%) Unknown 1 (7.7%) 0 (0%) a)1 year before FVIII inhibitor testing. b)Plasma-derived products used are Koate DVI, Haemoctin, Octanate. c)History of switching products from plasma-derived to recombinant due to a clinical event. All recombinant FVIII concentrates were donated by the World Federation of Hemophilia’s Humanitarian Aid Program. d)
P -value is calculated using Pearson’s exact test..
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Table 3 . Annual Bleeding Rate (ABR) and Annual Joint Bleeding Rate (AJBR) by inhibitor baseline..
Characteristics Patients without inhibitors (N=351) Patients with low-titer inhibitors (N=13) Patients with high-titer inhibitors (N=24) P b)Annual bleeding ratea) 0.53 12/year 106 (30.2%) 3 (23.1%) 10 (41.6%) 13–24/year 89 (25.4%) 7 (53.8%) 7 (29.2%) 25–48/year 140 (39.9%) 1 (7.7%) 7 (29.2%) Unknown 16 (4.6%) 2 (15.4%) 0 (0%) Annual joint bleeding ratea) <0.001d) 12/year 88 (25.1%) 2 (15.4%) 10 (41.7%) 13–24/year 71 (20.2%)c) 9 (69.2%)c) 10 (41.7%) 25–48/year 112 (31.9%) 0 (0%) 4 (16.7%) Unknown 80 (22.8%) 2 (15.4%) 0 (0%) a)1 year before FVIII inhibitor testing. b)
P -value is calculated using the chi square statistical method (data marked as unknown are excluded from the statistical analysis). c)Significant difference in post-hoc testing (P <0.05). d)SignificantP -value..
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