Challenges in immune tolerance induction in an adult patient with non-severe hemophilia A.

P. Kuta1, S. Achenbach1, T. Zöller2, R. Zimmermann1 (1Erlangen, Germany, 2Coburg, Germany)

Bleeding disorders, coagulation and fibrinolytic factors
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Haemophilia A is a bleeding disorder caused by deficiency of clotting factor VIII (factor eight), which may result both in spontaneous haemorrhage or prolonged bleeding following injuries. Therefore, patients with haemophilia A are usually identified in early childhood. Treatment is based on prophylactic or on-demand administration of factor concentrates. Development of inhibitors neutralizes the effect of administrated factor VIII and is one of the most challenging complications in the treatment for haemophilia today.

Methods: We present here the case of a 42-year-old patient with frequent haematuria of initially unknown origin. In another hospital, digital subtraction angiography was performed to determine the cause of the haematuria and resulted in major retroperitoneal bleeding. The developing haematoma compressed the left femoral nerve leading to paraesthesia and to impairment in mobility. Clotting analyses detected a low level of factor VIII activity and initially no inhibitor suggesting a non-severe haemophilia A.

Results: A factor VIII concentrate (turoctocog alfa) was administered twice daily to control bleeding and resorb haematoma. To improve the outcome and to obtain functionality of the femoral nerve the treatment was continued in lower doses at the rehabilitation clinic. On the second day at home after factor VIII administration was stopped a new soft tissue bleeding appeared and treatment was resumed. This time higher doses and more frequent administration were necessary to control bleeding. Pharmacokinetic (PK) analysis revealed diminished recovery and half-life indicating the development of an inhibitor, which was confirmed by a positive Bethesda assay with an inhibitor titre level of 2 BU. According to the latest German Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives we started immune tolerance induction (ITI) by continuous factor VIII replacement with 50 IE/kg body weight three times per week.

Conclusion: After six months of low dose ITI no breakthrough bleeding occurred, but recovery kept to be diminished with inhibitor titre levels of 6 BU. Therefore we decided to increase frequency and doses of administration adjusted to the Bonn protocol. Despite normalized recovery factor VIII on day 13 half-life kept to be low. High dose ITI was continued for several months till inhibitor did not reappear and half-life normalized.