La survenue d’un anticorps inhibiteur, évènement iatrogène fréquent, est actuellement la complication la plus grave du traitement par facteur VIII chez les jeunes enfants atteints d’hémophilie A sévère. L’inhibiteur, habituellement détecté au cours des premières dizaines de journées de traitement, peut compromettre gravement son efficacité. Les PUPs (previously untreated patients) représentent la population la plus appropriée pour étudier ce risque. Parmi les différents facteurs de risque d’inhibiteur, les plus anciennement documentés sont d’ordre génétique. Ces facteurs de risque directement liés au patient lui-même sont non modifiables. On a aussi identifié des facteurs environnementaux liés aux modalités et circonstances de mise en œuvre du traitement. Les traitements intensifs initiaux représentent un facteur de risque fort alors que les études récentes suggèrent un rôle protecteur de la prophylaxie. Enfin, des facteurs spécifiquement liés au concentré de facteur VIII restent discutés. Les publications font état d’un risque différentiel d’inhibiteur, soit favorable aux concentrés plasmatiques, soit non significativement différent entre produits plasmatiques et recombinants. De manière inattendue, trois larges études PUPs contemporaines (cohortes internationales RODIN, nationales FranceCoag et UKHCDO) ont récemment montré un risque d’inhibiteur différent selon le type de facteur VIII recombinant utilisé chez les PUPss atteints d’hémophilie A sévère. La prise en compte des facteurs de risque d’inhibiteur lors de l’initiation du traitement par facteur VIII chez ces enfants représente un enjeu majeur pour leur état de santé, leur qualité de vie et aussi d’un point de vue économique. Les études récentes soulignent l’intérêt des cohortes pour la connaissance épidémiologique.

Inhibitor development is a frequent adverse event that nowadays stands for the most serious complication of replacement therapy in children treated by factor VIII concentrates for severe haemophilia A. The incidence of inhibitors varies among the series, most often between 15 and 35% of cases. Their occurrence is usually documented during the first twenty days of replacement therapy. The population of so-called “previously untreated patients” represents the most relevant one to investigate risk factor for inhibitor occurrence. Several groups of inhibitor risk factors have been stratified. The first documented risk factors, directly related to the patient's characteristics, concern genetics. Such risk factors cannot be modified by any preventive approach. Another group is linked to conditions that may influence the effects of treatment such as the regimen of replacement therapy or environmental situation. In this field, it has been demonstrated that intensive treatment as first replacement therapy has to be considered as a highly risky condition whereas recent studies suggest that early prophylactic regimen may have a protective role for inhibitor formation. Finally, the factor VIII concentrate itself has to be taken into account as a potential risk with possible differences according to the product. Among many studies, mostly retrospective and often with some important risk factors, such as treatment intensity, missing in the multivariate analysis, no decisive result has been assessed until now to demonstrate a differential risk between plasma derived and recombinant concentrates. In the majority of cases, the difference appears either in favour of plasma derived concentrates or not significant. The recent results of three independent studies (RODIN, FranceCoag and UKHCDO Cohorts) suggest that the risk may be different among recombinant products that had been considered as one single class product in the former studies. The results of an ongoing randomised study might be helpful to complete these somewhat unexpected results. Current knowledge can be used to give some advices in the management of young children with severe haemophilia A. In that way, we should recommend to prevent the neonatal trauma if possible and to prevent serious bleeding in noticeable obstetrical trauma, to make replacement therapy as short as possible when required; to postpone elective surgery, including central venous device insertion or circumcision, until a sufficient amount of days with treatment has occurred; to be aware that the amount of product in a vial usually exceeds the required dose for a neonate and to discard the excess; to favour preventive infusion of FVIII in basal circumstances aiming to decrease the number of infusions in situations with danger signal at the beginning of treatment; to select the first factor VIII concentrate according to updated knowledge in this evolving domain. A better definition and comprehension of inhibitor risk factors in children with severe haemophilia represents a major therapeutic challenge for the future. In haemophilia that stands for a rare disease, large cohort studies have to be promoted to reach this goal.