Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophiliaA and in normal polyclonal human IgG

We have analyzed the properties of antifactor VIII (FVIII) immunoglobulin ( Ig) G recovered by affinity chromatography on FVIII-Sepharose from the IgG fraction of the plasma of healthy individuals and nonresponder patients wit h hemophilia A. Affinity-purified anti-FVIII antibodies were found to neutr alize FVIII activity and to bind to FVIII with an affinity similar to that of anti-FVIII IgG that had been affinity-purified from the plasma of inhibi tor-positive hemophilia patients and of patients with anti-FVIII autoimmune disease. The antibodies also exhibited patterns of reactivity with thrombi n-digested FVIII similar to those of FVIII inhibitors and preferentially re cognized epitopes located in the light chain of FVIII. These observations s uggest that FVIII inhibitors occurring in hemophilia A and in patients with anti-FVIII autoimmune disease originate from the expansion of preexisting natural anti-FVIII clones that exhibit FVIII-neutralizing properties. (C) 2 000 by The American Society of Hematology.