Longitudinal analysis of factor VIII inhibitors in a previously untreated mild haemophilia A patient with an Arg(593)-> Cys substitution

Recent studies suggest that certain missense mutations associated with mild to moderate haemophilia A predispose to inhibitor development. In this stu dy, we present a longitudinal analysis of the epitope specificity of an inh ibitor that developed in a mild haemophiliac with an Arg(593)-->Cys mutatio n. Immunoprecipitation studies revealed the presence of antibodies directed towards the light chain and A2 domain of factor VIII. Limited reactivity w as observed with metabolically labelled C2 domain. Almost complete inhibito r neutralization was achieved upon addition of A2 domain. Binding of the in hibitor was not affected by the presence of the Arg(593)-->Cys substitution in the recombinant A2 fragment. Evaluation of the epitope specificity of a nti-factor VIII antibodies in plasma samples obtained at different time-poi nts of inhibitor development revealed initial development of a low titre in hibitor directed towards the A2 domain and factor VIII light chain. A secon d period of factor VIII replacement therapy resulted in a dramatic rise in factor VIII inhibitor titre, which maintained their original epitope specif icity. Based on the results of this and previous studies (Fijnvandraat et a l., 1997; Thompson et al., 1997) it is argued that inhibitor development in patients with the Arg(593)-->Cys mutation may proceed via a similar mechan ism.