PB1301 - Low-titer inhibitor and decreased FVIII activity to 1.1% with increased bleeding in a 4 year old patient with congenital mild hemophilia A

Background: The inhibitor development in mild hemophilia A is rare. Due to cross-reactivity of the inhibitor to the endogenous FVIII, plasma FVIII activity is typically decreasing (to 1-2%) and bleeding complication are increasing. The INSIGHT Study reported a cumulative incidence of 5.3% after a median of 28 exposure days. Among 214 different missense mutation, 19 were associated with inhibitor development. The inhibitors disappeared in around 70% of patients after a median of 45 weeks and in 70% of them without a specific eradication treatment.

Aims: We report the clinical and immunological course of a 4 year old boy with mild hemophilia A (FVIII 20%) caused by a missense mutation (M2164V).

Methods: We analysed the inhibitor and immune response.

Results: He developed low titer inhibitor (4.6BU) following tonsillectomy with rFVIII substitution (50IU/kgBW) for 10 days. Routine inhibitor monitoring revealed an FVIII level of 1.1% and an inhibitor of 4.6 BU with clinically increased bleeding.
The FVIII mutation was not described as high-risk mutation for inhibitor development in mild hemophilia A. The immunological diagnostic showed IgG1, IgG3 and IgG4, but with IgG3 highest, and a binding to FVIII domain HC, A2, LC, C1 and C2. The profile seems comparable with that of severe hemophilia with inhibitor.
After diagnosis of inhibitor and change to moderate/severe hemophilia, we started a treatment with emicizumab as bleeding prophylaxis. Bleeding symptoms disappeared.

Conclusion(s): Although no high-risk mutation was present, the patient with mild hemophilia A developed low-titer inhibitor after FVIII substitution for surgery, changing mild Hemophilia to moderate/severe and increasing bleeding tendency. This indicates the importance of regular inhibitor analysis following FVIII substitution also in patients with mild hemophilia. The profile of immune response seems comparable to patients with severe hemophilia. At ISTH 2023, we will be able to show the 6-month course of the immune response with a treatment with emicizumab.