Thromb Haemost 2016; 115(04): 729-737
DOI: 10.1160/TH15-08-0692
Coagulation and Fibrinolysis
Schattauer GmbH

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

H. Marijke van den Berg*
1   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
S. Mojtaba Hashemi*
1   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
Kathelijn Fischer
1   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
2   Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
Pia Petrini
3   Department of Pediatrics, Clinic of Coagulation Disorders, Karolinska Hospital, Stockholm, Sweden
Rolf Ljung
4   Department of Clinical Sciences, Lund University, Lund; Department of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skånes University Hospital, Malmö, Sweden
Anne Rafowicz
5   Centre de Référence pour le Traitement des Maladies Hémorragiques (CRTH), Hôpital Bicêtre, Paris, France
Manuel Carcao
6   Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
Günter Auerswald
7   Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany
Karin Kurnik
8   Dr. v. Haunersches Kinderspital, University of Munich, Munich, Germany
Gili Kenet
9   National Haemophilia Center, Ministry of Health, Sheba Medical Center, Tel Hashomer, Israel
Elena Santagostino
10   Haemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
for the PedNet Study group › Author Affiliations
Further Information

Publication History

Received: 31 August 2015

Accepted after major revision: 05 November 2015

Publication Date:
28 November 2017 (online)


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 five-year 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.

* These authors contributed equally.

# A complete list of the members of the PedNet Study Group appears in the Appendix.