Blood Journal
Leading the way in experimental and clinical research in hematology

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

  1. Samantha C. Gouw1,
  2. H. Marijke van den Berg2,
  3. Kathelijn Fischer3,
  4. Günter Auerswald4,
  5. Manuel Carcao5,
  6. Elizabeth Chalmers6,
  7. Hervé Chambost7,
  8. Karin Kurnik8,
  9. Ri Liesner9,
  10. Pia Petrini10,
  11. Helen Platokouki11,
  12. Carmen Altisent12,
  13. Johannes Oldenburg13,
  14. Beatrice Nolan14,
  15. Rosario Pérez Garrido15,
  16. M. Elisa Mancuso16,
  17. Anne Rafowicz17,
  18. Mike Williams18,
  19. Niels Clausen19,
  20. Rutger A. Middelburg20,
  21. Rolf Ljung21, and
  22. Johanna G. van der Bom22,*
  1. 1 Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands;
  2. 2 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands;
  3. 3 Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands;
  4. 4 Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany;
  5. 5 Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada;
  6. 6 Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom;
  7. 7 Service d'hematologie pediatrique, Hopital La Timone & Aix-Marseille Univ, Inserm U1062, Marseille, France;
  8. 8 Dr. v. Haunersches Kinderspital, University of Munich, Munich, Germany;
  9. 9 Hemophilia center, Department of Haematology, Great Ormond Street Hospital for children, London, United Kingdom;
  10. 10 Department of Pediatrics, Clinic of Coagulation Disorders, Karolinska Hospital, Stockholm, Sweden;
  11. 11 St. Sophia Children's Hospital, Hemophilia-Hemostasis Unit, Athens, Greece;
  12. 12 Unitat Hemofilia, Hospital Traumatologica, Hospital Vall d'Hebron, Barcelona, Spain;
  13. 13 Institut fuer Experimentelle Haematologie und Transfusionsmedizin, Universitaetsklinikum Bonn, Bonn, Germany;
  14. 14 Department of Paediatric Haematology, St. James's Hospital, Dublin, Ireland;
  15. 15 Hospital General Unidad de Hemofilia, Hospitales Universitarios Virgen del Rocio, Sevilla, Spain;
  16. 16 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy;
  17. 17 CRTH Bicetre, Service Hematologique, Paris, France;
  18. 18 Department of Haematology, The Children's Hospital, Birmingham, United Kingdom;
  19. 19 Department of Pediatrics, University Hospital of Aarhus at Skejby, Aarhus, Denmark;
  20. 20 Center for Clinical Transfusion Research, Sanquin Foundation, Leiden, Netherlands;
  21. 21 Department of Pediatrics and Malmo Center for Thrombosis and Hemostasis, Skanes Universitetssjukhus, Malmo, Sweden;
  22. 22 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
  1. * Corresponding author; email: j.g.vanderbom{at}

Key points

  • High-dosed intensive factor VIII treatment increases the risk of inhibitor development in severe hemophilia A patients

  • In severe hemophilia A patients factor VIII prophylaxis decreases the inhibitor risk, especially in patients with low-risk F8 mutations.


The study objective was to examine the association of the intensity of treatment, ranging from high-dosed intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity <0.01 IU/mL born between 2000-2010, followed during their first 75 FVIII exposure days. Intensive FVIII treatment for hemorrhages or surgery at start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio (aHR) 2.0; 95% confidence interval [CI] 1.3-3.0). High-dosed FVIII treatment was associated with a higher inhibitor risk than low-dosed FVIII treatment (aHR 2.3 (CI 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days to FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR 0.61, CI 0.19-2.0 and 0.85, CI 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases the inhibitor risk and prophylactic FVIII treatment decreases the inhibitor risk, especially in patients with low-risk F8 mutations.

  • Submitted September 20, 2012.
  • Accepted March 12, 2013.