Haemophilia A and development of “Inhibitors”

Haemophilia A is a recessive X-linked bleeding disorder caused by a deficiency or a functional abnormality of coagulation co-factor, factor VIII (FVIII).   This disorder affects 1 in 5000 males resulting in bleeding in joints, muscles and soft tissues, and is usually treated by prophylactic infusions of FVIII therapeutic products.  However, one of the major complications of such substitutive treatment is the development of an immune response towards FVIII. Antibodies inhibiting FVIII activity, so-called inhibitors, preclude further use of FVIII, therefore leaving patients in a precarious life-threatening situation. Such antibodies are observed in 10 to 40% of the patients.  FVIII autoantibodies can also develop in non-haemophiliacs, in a variety of clinical settings, such as the postpartum period and chronic lymphocytic leukaemia.  Use of recombinant FVIII has not reduced the incidence of inhibitors, which unfortunately suggests that the forthcoming gene therapy for haemophilia will not reduce this high incidence either.  In addition, the very methods used to prepare FVIII or reduce viral transmission carry the risk of altering the immunogenicity of the molecule.  Present treatments to eradicate FVIII inhibitors are unsatisfactory. They rely on methods such as infusion of large doses of FVIII, alone or in combination with non-specific immunosuppressive agents. The cost of such treatments is prohibitively high, and their efficiency is limited to patients having recent, low titre inhibitors.  Inhibitor development in up to 20% of patients is related with gene defect (intron 22 inversion of the FVIII gene).  Preventing the development of inhibitors is presently not feasible, as criteria to identify patients at risk are not yet fully defined. Alternative, more efficient therapies are therefore needed, which would be both specific and cost-effective; however before this can happen a precise understanding of the mechanisms of inhibitor development needs to be attained.

Areas of Research

• New approaches to the quantitation of inhibitory antibodies to FVIII

• Sensitive assays for monitoring FVIII expression in gene and cell

    therapy for haemophilia A.

• stability of novel liquid formulations for factor VIII and factor VIIa

• diagnosis and treatment strategies for von Willebrand disease