Although the development of inhibitors represents a serious danger for all patients with haemophilia A, there is a sub-population of haemophiliacs that is particularly vulnerable to this threat: PUPs (Previously Untreated Patients) suffering from severe haemophilia A, i.e. those patients with the most severe forms of factor VIII mutation and who are faced with the prospect of replacement therapy for the first time. These are often very young children, on average about 1 year of age, who are forced to resort to replacement therapy very early to reduce the risk of haemorrhages and hemarthrosis, which in the most serious forms of the disease tend to appear from the very early months of life.
Factor VIII is either completely absent or present in extremely small quantities in the blood of PUPs with severe haemophilia A. The immune system is therefore unaccustomed to recognising it as a normal component of the body and it is therefore possible that, when the first few infusions are administered, factor VIII is recognised as a potential threat. This triggers an immune reaction that leads to the production of specific antibodies, known as inhibitors, which attack the infused factor VIII and neutralise it. The most recent studies have shown that 25% to 35% of PUPs suffering from severe haemophilia A have inhibitors and that they appear in the first 75 days of treatment. However, in 50% of cases, inhibitors can appear as early as the first 14 to 15 days of treatment.
When treating PUPs with severe haemophilia A, knowing the time-points most at risk for the development of inhibitors brings a particularly important advantage in terms of their prevention, as it allows both the doctors and the families of young patients to adopt certain measures that limit the exposure to risk factors. For example, it is possible to reduce exposure to high doses of factor VIII during critical periods, or to choose factor VIII concentrates with a lower immunogenicity, i.e. a lower tendency to trigger an immune system reaction.
- Carcao M. et al. Inhibitors in hemophilia: a primer. Fifth edition, 2018. World Federation of Hemophilia (WFH)
- Giangrande P. L. F. et al. European principles of inhibitor management in patients with haemophilia. Orphanet Journal of Rare Diseases, 2018. 13(1):66
- Marijke van den Berg H. et al. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood, 2019. 134:317-320