Some Factor VIII (FVIII) Inhibitors Recognise a FVIII Epitope(s) that Is Present only on FVIII-vWF Complexes

Jean Guy G. Gilles; Renaud Lavend’homme; Kathelijne Peerlinck; Marc G. Jacquemin; Marc Hoylaerts; Sylvie Jorieux; Claudine Mazurier; Jos Vermylen; Jean-Marie R. Saint-Remy

doi:10.1055/s-0037-1614627

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(01): 40-45
DOI: 10.1055/s-0037-1614627

Rapid Communication

Schattauer GmbH

Some Factor VIII (FVIII) Inhibitors Recognise a FVIII Epitope(s) that Is Present only on FVIII-vWF Complexes

Authors

Jean Guy G. Gilles

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Renaud Lavend’homme

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Kathelijne Peerlinck

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Marc G. Jacquemin

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Marc Hoylaerts

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Sylvie Jorieux

¹Laboratoire Français de Fractionnement et des Biotechnologies, Lille, France
Claudine Mazurier

¹Laboratoire Français de Fractionnement et des Biotechnologies, Lille, France
Jos Vermylen

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Jean-Marie R. Saint-Remy

²From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

Abstract

Summary

A mild haemophilia A patient (LE) with an Arg2150His mutation in the C1 domain of the factor VIII (FVIII) light chain was shown to have anti-FVIII antibodies inhibiting wild type but not self FVIII. Polyclonal anti-FVIII antibodies of this patient were purified by affinity adsorption using recombinant FVIII (rFVIII) and/or plasma-derived FVIII-von Willebrand factor (vWF) complexes. A distinct population of antibodies was obtained that bound to FVIII-vWF complexes but not to rFVIII, indicating that an epitope was created by the association of FVIII to vWF. Such antibodies belonged to the IgG₂ isotype, but the FVIII epitopes to which they bind could not be mapped with precision due to vWF dependency. Depletion experiments showed that anti-FVIII antibodies recognising FVIII-vWF complex also distinguished wild-type from mutated self FVIII, indicating that the Arg2150His mutation alters the B cell epitope formed by the association of FVIII to vWF. To determine whether the Arg2150His substitution also alters the formation of the FVIII-vWF complex, the interaction between mutated or normal FVIII with vWF was evaluated in plasma. The dissociation rate of mutated FVIII from vWF was found to be significantly increased. The presence of an Arg2150His mutation therefore results in the disappearance of a FVIII B cell epitope generated by the association of FVIII with vWF. Patients carrying such an Arg2150His mutation and receiving infusion of wild-type FVIII may therefore be at risk of developing inhibitors to allogeneic FVIII only.

Full Text

References

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