16. Genetic Basis for Inhibitor Development

  1. Emérito-Carlos Rodríguez-Merchán MD, PHD2,3 and
  2. Leonard A. Valentino MD4
  1. Johannes Oldenburg MD, PhD and
  2. Anna Pavlova MD, PhD

Published Online: 12 MAY 2011

DOI: 10.1002/9781119979401.ch16

Current and Future Issues in Hemophilia Care

Current and Future Issues in Hemophilia Care

How to Cite

Oldenburg, J. and Pavlova, A. (2011) Genetic Basis for Inhibitor Development, in Current and Future Issues in Hemophilia Care (eds E.-C. Rodríguez-Merchán and L. A. Valentino), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781119979401.ch16

Editor Information

  1. 2

    Department of Orthopedic Surgery and Hemophilia Unit, La Paz University Hospital, Spain

  2. 3

    School of Medicine, Autonomous University, Madrid, Spain

  3. 4

    Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA

Author Information

  1. University Clinic Bonn, Bonn, Germany

Publication History

  1. Published Online: 12 MAY 2011
  2. Published Print: 13 MAY 2011

ISBN Information

Print ISBN: 9780470670576

Online ISBN: 9781119979401



  • hemophilia;
  • inhibitor;
  • risk factors;
  • MHC;
  • immune-regulatory gene polymorphisms


Approximately 30% of patients with hemophilia A (HA) and 3% with hemophilia B (HB) develop inhibitory antibodies to factors VIII or IX, respectively, as a complication of replacement therapy. The strongest identified determinant of inhibitor development risk is the mutation type in the F8 or F9 gene. Large deletions, nonsense mutations and inversions are associated with a high risk of inhibitor development ranging from 20 to 75%. In non-severe haemophilia patients, missense mutations represent the main mutation type, with an inhibitor prevalence of 5%, conferring a low risk. However, accumulating evidence indicates that other genetic factors including major histocompatibility complex alleles and polymorphisms of immune-regulatory genes (IL-10, TNF-α and CTLA-4) may influence the inhibitor risk. These genetic factors constitute the individual genetic risk profile of a haemophiliac patient. Understanding the pathomechanism of inhibitor formation might lead to development of preventive measures towards inhibitor development and improved treatment as it is recently discussed the application of a new, early prophylaxis regimen.