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BioMed Research International
Volume 2013 (2013), Article ID 901975, 7 pages
Clinical Study

Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study

1Gerinnungszentrum Rhein-Ruhr (GZRR), 47051 Duisburg, Germany
2Department of Pediatrics, University Hospital of Munich, 80337 Munich, Germany
3Department of Pediatric Hematology/Oncology, University Hospital of Frankfurt, 60590 Frankfurt, Germany
4Outpatient Hemophilia Treatment Center, 23564 Lubbock, Germany
5Department of Pediatric Hematology/Oncology, Charite, 13353 Berlin, Germany
6The Israel National Hemophilia Centre, Sheba Medical Centre, Tel-Hashomer and the Sackler Medical School, Tel Aviv, 52621 Tel-Hashomer, Israel
7Department of Pediatrics, University Hospital of Münster, 48149 Münster, Germany
8Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L85 4K1
9Thrombosis & Hemophilia Treatment Center, Institute of Clinical Chemistry, University Hospital of Kiel, 24105 Kiel, Germany

Received 25 June 2013; Revised 30 August 2013; Accepted 31 August 2013

Academic Editor: Saulius Butenas

Copyright © 2013 Susan Halimeh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.