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

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

Jean Guy G. Gilles
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Renaud Lavend’homme
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Kathelijne Peerlinck
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Marc G. Jacquemin
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Marc Hoylaerts
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Sylvie Jorieux
1   Laboratoire Français de Fractionnement et des Biotechnologies, Lille, France
,
Claudine Mazurier
1   Laboratoire Français de Fractionnement et des Biotechnologies, Lille, France
,
Jos Vermylen
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Jean-Marie R. Saint-Remy
2   From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
› Author AffiliationsThis work was supported in part by research grant G.0292.98 of the Flemish Research Foundation. JV is holder of the “Dr. J. Choay Chair in Haemostasis Research”.
Further Information

Publication History

Received 01 December 1998

Accepted after resubmission 25 February 1999

Publication Date:
11 December 2017 (online)

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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.

 

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