Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII

In order to determine the difference in reactivity of factor (F) VIII inhib itors against the FVIII/von Willebrand factor (vWF) complex and against vWF -deficient FVIII, we investigated a panel of 10 antibodies to FVIII from mu ltitransfused individuals with severe haemophilia A and other pathologies. Immunoblotting of purified FVIII and purified thrombin-cleaved FVIII reveal ed that in all cases inhibitor epitopes could be localized in the heavy cha in (A2 subunit) while in four cases they were also present in the light cha in. One of the FVIII inhibitors remained unclassified. The effect on FVIII: C of purified IgG from inhibitor plasmas was tested against a high purity F VIII/vWF concentrate and a monoclonally purified FVIII concentrate with onl y trace contents of vWF, by two different functional assays. Our results su ggest that for those inhibitors showing A2 plus light chain (LC) reactivity , the IgG concentration required to inhibit 50% of FVIII activity in vitro is higher for the FVIII/vWF complex than for the vWF-deficient FVIII. We co nclude that there might be a protective role of vWF (at least in vitro) aga inst FVIII inhibitors with A2 and LC subunit specificity.