A Hemophilia Patient with C1 Domain Arg2150His Mutation Developed a High Titer Inhibitor Not Inhibiting Autologous Factor VIII after Switching to Third Generation Recombinant Product.

In mild hemophilia A the development of inhibitors is a serious but infrequently reported complication (3–13%) occurring more commonly later in life, often following intensive factor VIII replacement for surgery or trauma. Due to cross-reactivity with endogenous factor VIII:C, the development of inhibitors in most patients with mild hemophilia A results in a fall in the endogenous level of factor VIII:C, converting patients to severe phenotype (FVIII:C<1%). Antibodies inhibiting allogenic (wild-type) but not autologous factor VIII are exceptional. In contrast to severe hemophilia A, little is known regarding risk factors for inhibitor development in mild hemophilia A and specifically regarding factor exposure (amount and intensity of factor VIII, episodic bolus injections versus continuous infusion, type of factor VIII, and context in which exposure occurs).

We report on a 61-year-old patient with mild hemophilia A associated with a Arg2150His mutation in the C1 domain of factor VIII. The baseline factor VIII:C level is 5.2%. Age at initial exposure to allogenic factor VIII (cryoprecipitate) in 1975 was 31 years, age at initial exposure to recombinant factor VIII (first generation product) in 1996 was 51 years. In 1996 coronary-artery bypass grafting was performed because of coronary heart disease. The procedure was covered by factor VIII replacement therapy with episodic bolus injections. From 1996 to 2004 the patient was on demand treatment and received a total of 160 bolus injections of factor VIII (first generation product). At this time, there was no inhibitor development. In 2004 the patient was switched from first to third generation recombinant product (same cell line). Until April 2005 he received 25 factor VIII bolus injections without inhibitor development. In April 2005 a femoro-popliteal bypass using autogenous long saphenous vein graft was performed for treatment of peripheral arterial disease (Fontaine stage IIb). Again, the procedure was covered by factor VIII replacement therapy with episodic bolus injections. The patient never received continuous factor VIII infusions. On day 4 a high titer inhibitor (23 Bethesda-Units) developed. Since the patient showed a stable factor VIII activity of ~ 5% due to a missing inhibitor cross-reactivity with endogenous factor VIII, he had only a mild bleeding tendency without the need for application of factor VIII bypassing products.

This case report describes a patient who developed a high titer factor VIII antibody inhibiting allogeneic but not autologous factor VIII after switching from a first to a third generation recombinant factor VIII product. The inhibitor development may be triggered by a more intense bolus infusion due to surgery. Mild hemophilia patients with a C1 domain Arg2150His mutation maintain significant factor VIII activity despite the development of high titer anti-factor VIII antibody. This immune response to factor VIII might represent a unique opportunity to study mechanisms of alloimmunization and autoimmunization.