Successful factor VIII re-exposure after long-term aPCC prophylaxis in two hemophilia A patients with inhibitors
C. Königs1, A. Siegemund2, D. Stichel1, A. Orlowski1, C. Heller1, J. Kahle1, D. Schwabe1, U. Scholz2 (1Frankfurt, Germany, 2Leipzig, Germany)
Bleeding disorders, coagulation and fibrinolytic factors
Time: 17:15 - 18:15
Objective: Inhibitor development is still the most severe complication in modern hemophilia A treatment and the eradication of inhibitors during immune tolerance induction (ITI) is a great challenge. After failed ITI, patients are treated on demand or by prophylaxis with bypassing agents including aPCCs. We report on two patients that were successfully re-exposed to factor VIII (FVIII) after failed ITI and aPCC treatment.
Methods: Two patients aged 24 and 66 years with a longstanding history of inhibitors were closely monitored for coagulation, pharmacokinetic and immunological parameters during reexposure to FVIII.
Results: Both patients had been positive for FVIII inhibitors for years. Earlier ITI had failed. The younger patient was on prophylaxis with aPCC (FEIBA®), the older was treated on demand. Thus both patients had a minimal dose FVIII exposure during aPCC treatment over years. Both patients were negative for FVIII inhibitors at the time of re-exposure, but they were discordant for FVIII non-neutralizing antibodies. The patients were re-exposed with either pdFVIII with high vWF-content or rFVIII-Fc. The patient negative for FVIII antibodies before re-exposure never developed any neutralizing or non-neutralizing antibodies during the first 100 re-exposure days. Of note, after 10 days of re-exposure the FVIII recovery and half-life decreased dramatically and only recovered to initial values after another 8 days of rFVIII-Fc treatment. The patient positive for FVIII non-neutralizing antibodies at re-exposure also did not develop any inhibitors so far: non-neutralizing FVIII inhibitors remained detectable. The anti-FVIII IgG titre increased after re-exposure with antibodies mainly directed against the light chain and without any detectable anti-A2 antibodies, but with a change in the IgG-subclass distributionfrom IgG1 to IgG2 and 4.
Conclusion: After long-term aPCC exposure in patients with inhibitors FVIII re-exposure appears feasible for effective FVIII treatment. Monitoring of immunological and coagulation parameters is essential as anamnestic or d novo immune responses may occur and as the mechanisms of tolerance are poorly understood.