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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2267-2273
Antifactor VIII Antibody Inhibiting Allogeneic but not Autologous
Factor VIII in Patients With Mild Hemophilia A
Kathelijne Peerlinck,
Marc G. Jacquemin,
Jef Arnout,
Marc F. Hoylaerts,
Jean Guy G. Gilles,
Renaud Lavend'homme,
Karen M. Johnson,
Kathleen Freson,
Dorothea Scandella,
Jean-Marie R. Saint-Remy, and
Jos Vermylen
From the Center for Molecular and Vascular Biology, Katholieke
Universiteit Leuven, Leuven, Belgium; the Haemostasis Research Group,
MRC Clinical Sciences Centre, ICSM, London, UK; and the American Red
Cross, Holland Laboratory, Rockville, MD.
Two unrelated patients with the same Arg2150His mutation in the
factor VIII (FVIII) C1 domain, a residual FVIII activity of 0.09 IU/mL,
and inhibitor titres of 300 and 6 Bethesda Units, respectively, were
studied. Further analysis of patient LE, with the highest inhibitor
titer, showed that (1) plasma or polyclonal IgG antibodies prepared
from LE plasma inhibited the activity of allogeneic (wild-type) but not
of self FVIII; (2) the presence of von Willebrand factor (vWF)
increased by over 10-fold the inhibitory activity on wild-type FVIII;
(3) the kinetics of FVIII inhibition followed a type II pattern, but in
contrast to previously described type II inhibitors, LE IgG was
potentiated by the presence of vWF instead of being in competition with
it; (4) polyclonal LE IgG recognized the FVIII light chain in
enzyme-linked immunosorbent assay and the recombinant A3-C1 domains in
an immunoprecipitation assay, indicating that at least part of LE
antibodies reacted with the FVIII domain encompassing the mutation
site; and (5) LE IgG inhibited FVIII activity by decreasing the rate of
FVIIIa release from vWF, but LE IgG recognized an epitope distinct from ESH8, a murine monoclonal antibody exhibiting the same property. We
conclude that the present inhibitors are unique in that they clearly
distinguish wild-type from self, mutated FVIII. The inhibition of
wild-type FVIII by LE antibody is enhanced by vWF and is associated with an antibody-dependent reduced rate of FVIIIa release from vWF.
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