Session B1.2

14 S 355
Patient-determined risk factors
J OLDENBURG
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany
Alloantibodies (inhibitors) against factor VIII (FVIII) or factor IX (FIX) represent a major complication in patient care because they render
classical substitution therapy ineffective. Inhibitors occur at a frequency of 20–30% in severe haemophilia A and 3% in haemophilia B,
respectively. Several studies suggest that predisposing genetic factors, environmental factors and their interactions contribute to the inhibitor
phenotype. In particular, genetic factors, such as factor VIII gene mutations and immune response genes, e.g. the major histocompatibility
complex, have been shown to constitute decisive risk factors for the development of inhibitors. In severe hemophilia A and B, those mutations
that result in the absence or severe truncation of the factor VIII/IX proteins are associated with the highest risk for inhibitor formation,
indicating that a major driving force in inhibitor development is the presentation of a novel antigen to the patient’s immune system. Most
recently, a strong association betweenCArepeat polymorphism of the IL-10 gene and the development of inhibitors has been shown and more
immune gene markers are on the way to be published. An alternative pathomechanism may underlie inhibitor development in patients with
mild hemophilia A. Certain missense mutations may alter the immunogenicity of the FVIII protein, eliciting an inhibitor response against the
mutated epitope. In some patients with hemophilia B, especially those with large deletions to the FIX gene, a severe allergic reaction occurs
simultaneously with inhibitor onset.

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