Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors

Research output: Contribution to journalArticle


Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII<1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per fiveyear birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990–1994 (lowest) to 30.9 % in 2000–2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990–1994 to 10.5 % in 2005–2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06–2.83) in 2000–2004 and 2.34 (1.42–4.92) in 2005–2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.


  • H. Marijke van den Berg
  • S. Mojtaba Hashemi
  • Kathelijn Fischer
  • Pia Petrini
  • Rolf Ljung
  • Anne Rafowicz
  • Manuel Carcao
  • Günter Auerswald
  • Karin Kurnik
  • Gili Kenet
  • Elena Santagostino
External organisations
  • University Medical Center Utrecht
  • Karolinska University Hospital
  • Skåne University Hospital
  • Assistance Publique des Hôpitaux de Paris
  • Hospital for Sick Children, Toronto
  • Klinikum Bremen-Mitte
  • World Orthopaedic Concern
  • Sheba Medical Center
  • Maggiore Hospital Policlinico
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Public Health, Global Health, Social Medicine and Epidemiology


  • Epidemiological studies, Factor VIII inhibitors, Haemophilia A / B, Risk factors
Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalThrombosis and Haemostasis
Issue number4
Publication statusPublished - 2016 Apr 1
Publication categoryResearch