Inhibitor development and management in three non-severe haemophilia A patients with T295A variant.

Missense mutations are the most common F8 gene defects among the patients with non-severe haemophilia A. This type of mutation is typically associated with low (5%) inhibitor risk. In the present retrospective study we analysed the clinical data of 16 haemophiliacs with the T295A missense mutation treated at Bonn Haemophilia Centre. In total, three patients developed inhibitors: two patients experienced low-titer and one high-titer inhibitors. Both patients with low titer inhibitors underwent successful ITI. The third patient, at the age of 81, developed initially low-titer inhibitors (3 BU/ml) after rFVIII therapy because of knee surgery. He experienced spontaneous multiple large skin haematomas and haemarthrosis. Immunosuppressive therapy was not applicable because of the infectious origin of discitis (Th3-Th4). Immunoadsorption was performed, but the inhibitor titer increased up to 42 BU/ml nine weeks after termination. A successful treatment of discitis with antibiotics finally allowed a weekly therapy (four times) with rituximab (375 mg/m(2)). This resulted in a decrease of inhibitor titre to 0.7 BU/ml eight weeks after the fourth rituximab application. Patient had endogenous FVIII levels of 3-5%. Twelve months after rituximab therapy (after B cells recovery) he relapsed with low-titer inhibitors and therefore was treated with single rituximab dose (375 mg/m(2)) again. This resulted in his depletion of B cells, measurable endogenous FVIII levels and non measurable inhibitors. This study demonstrated T295A variant to be associated with significantly increased (3/16 patients, 17%) inhibitor development.