Characterization of FVIII Pharmacokinetics in Hemophilia A Patients with or without Nonneutralizing FVIII Antibodies

Inhibitor development is still the most severe complication in modern hemophilia A treatment and the eradication of inhibitors during immune tolerance induction (ITI) is the treatment of choice and a great challenge. After successful ITI, lower factor VIII (FVIII) levels have been observed in some patients.

A total of 73 patients with severe hemophilia A were included in this analysis. Thirteen patients had undergone a successful ITI. Data on treatment, FVIII trough levels, incremental recovery, THL (WAPPS PK), Bethesda units were collected, and residual plasma was analyzed for FVIII-specific antibodies.

All patients received prophylactic treatment with recombinant or plasma-derived FVIII. Incremental recoveries ranged from 1 to 3. Recoveries and THL increased with age. Bethesda titers of all patients were constantly negative.

Nonneutralizing FVIII antibodies (NNAs) were detected in 10% of all patients. Importantly, exclusively all patients with NNAs had a history of inhibitors and a successful ITI. These antibodies included the IgG subclasses 1 or 4. Cognate epitopes on FVIII were located in both, the heavy and the light chain of FVIII including the A2, C1, and/or C2 domain.

We could not find a significant difference in FVIII pharmacokinetics in patients with nonneutralizing antibodies in this study, although nonneutralizing antibodies against FVIII could exclusively be detected in patients with a history of successful ITI and not in patients who had never developed an inhibitor.

Publication History

Article published online:
13 November 2020