In previously untreated patients with severe hemophilia A, nearly all inhibitory antibodies (inhibitors) against factor VIII develop within 75 days of exposure, according to research published in Blood.

Researchers followed 1038 previously untreated pediatric patients with severe hemophilia A who received treatment with factor VIII. Median age of the cohort at first exposure was 1.1 years. Development of an inhibitor was the primary outcome.

Patients who reached 75 exposure days had a median age of 2.3 years. Of the 300 inhibitors that developed, 298 (99.3%) developed within the first 75 exposure days, with 236 (79%) developing within 20 exposure days, 53 (18%) developing between 21 and 50 exposure days, and 9 (3%) developing between 51 and 75 exposure days. The remaining inhibitors developed at 249 and 262 exposure days, respectively.

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Cumulative incidence of inhibitors in the whole cohort was 28.9% at 50 exposure days, 29.9% at 75 exposure days, and 30.2% at 1000 exposure days. The calculated risk of developing inhibitors after 75 exposure days was 0.5 per 1000 person-years.

The researchers noted that clinical trials in previously untreated patients have typically followed patients for only 50 exposure days, although the results of the current study demonstrate that inhibitors continue to develop until 75 exposure days. The researchers recommended frequently testing for inhibitors until 75 exposure days.

In addition, previously treated patients have typically been defined as patients with more than 150 exposure days who are “considered tolerant to exogenous factor VIII.” Instead, the authors suggested that “75 exposure days should be the cutoff to distinguish previously untreated patients from previously treated patients.”


1.     Van den Berg H, Fischer K, Carcao M, et al. Timing of inhibitor development in >1000 previously untreated patients with severe hemophilia A [published online June 11, 2019]. Blood. doi:10.1182/blood.2019000658