Thromb Haemost 2020; 120(08): 1166-1172
DOI: 10.1055/s-0040-1713097
Coagulation and Fibrinolysis

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study

H. Marijke van den Berg
1   PedNet Foundation, Baarn, The Netherlands
2   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy
Christoph Königs
3   Department of Paediatrics and Adolescent Medicine, University Hospital Frankfurt, Frankfurt, Germany
Roseline D'Oiron
4   Centre de Référence pour le Traitement des Maladies Hémorragiques, Hôpital Bicêtre, Paris, France
Helen Platokouki
5   Haemophilia Centre, Haemostasis Unit, “Aghia Sophia” Children's Hospital, Athens, Greece
Torben Stamm Mikkelsen
6   Division of Pediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
Jayashree Motwani
7   Haematology Department, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom
8   Our Lady's Children's Hospital Crumlin, Dublin, Ireland
Elena Santagostino
2   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy
on behalf of the European Pediatric Network for Haemophilia Management (PedNet) › Author Affiliations


Background Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype.

Methods The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test.

Results A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0–7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens.

Conclusion In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Publication History

Received: 14 March 2020

Accepted: 01 May 2020

Article published online:
22 June 2020

Georg Thieme Verlag KG
Stuttgart · New York