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The missense mutation Arg593 --> Cys is related to antibody formation in
a patient with mild hemophilia A
K Fijnvandraat, EA Turenhout, EN van den Brink, JW ten Cate, JA van Mourik, M Peters and J Voorberg
Department of Blood Coagulation, Central Laboratory of the Netherlands Red
Cross Blood Transfusion Service, Amsterdam.
The development of inhibitory antibodies to factor VIII in patients
affected by a mild form of hemophilia A (factor VIII > 0.05 IU/mL) is
considered a rare event. In this study, we evaluated the relationship
between genotype and anti-factor VIII antibody formation in a patient with
mild hemophilia A. Mutation analysis showed that a missense mutation in the
factor VIII gene leading to replacement of Arg593 by Cys in the A2 domain
of factor VIII was associated with hemophilia A in this patient. The
anti-factor VIII antibodies present in the patient's plasma were
characterized using metabolically labeled factor VIII fragments expressed
in insect cells. The anti-factor VIII antibodies, composed of subclasses
IgG2 and IgG4, reacted with both the fragment corresponding to the factor
VIII heavy chain and the A2 domain. The Arg593 --> Cys substitution was
introduced into the cDNA encoding the A2 domain of factor VIII and the
resulting construct was expressed in insect cells. Strikingly, the
metabolically labeled A2 domain carrying the Arg593 --> Cys mutation was
not recognized by the anti-factor VIII antibodies present in the plasma of
the patient. These data indicate that the anti-factor VIII antibodies are
exclusively directed against exogenous factor VIII. This strongly suggests
that the Arg593 --> Cys substitution results in recognition of wild-type
factor VIII as nonself and is thereby related to the formation of
anti-factor VIII antibodies after factor VIII replacement therapy in this
particular patient.
Volume 89,
Issue 12,
pp. 4371-4377,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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