Blood, 1 July 2001, Vol. 98, No. 1, pp. 1-2
The fVIII inhibitor problem comes into focus
An outstanding problem in hemophilia A care concerns
the development of polyclonal inhibitory antibodies to transfused
fVIII. Frequently, this makes patients unresponsive to human fVIII and severely complicates clinical management. FVIII inhibitors also can
arise in nonhemophiliacs as an autoimmune phenomenon. In this issue,
Spiegel and colleagues (page 13), at the University of Washington and
Katholieke Universiteit Leuven, describe the x-ray structure of the
human factor VIII C2 domain in complex with a naturally occurring
inhibitory antibody at 2.0-Å resolution.
FVIII contains several domains, designated
A1-A2-B-A3-C1-C2. The C2 domain contains binding sites for
phospholipid and von Willebrand factor. The A2, C2, and, to a lesser
extent, A3 domains harbor most of the significant antibody epitopes.
Anti-C2 antibodies function primarily by blocking membrane binding.
Interestingly, although the immunologic settings in hemophilia A and
acquired hemophilia differ, the epitopes recognized by inhibitory
alloantibodies and autoantibodies appear to be similar.
Recently, the University of Washington group solved an x-ray structure
of the fVIII C2 domain (Pratt et al. Nature. 1999;402:439-442). They
proposed that the C2 domain binds phospholipid membranes by an
interaction involving insertion of 3 hydrophobic feet. Earlier, the
Leuven group had reported the properties of the first monoclonal antibody cloned from a hemophilia A inhibitor patient (Jacquemin et al.
Blood. 1998;92:496-506). This antibody, designated BO2C11, is a C2 inhibitor.
Now a collaborative effort between the 2 groups has produced an x-ray
structure of a fVIII C2-BO2C11 Fab complex. C2 residues that make up 2 of the putative hydrophobic feet (L2251, L2252, M2199, and F2200) are
buried in the complex, supporting the model of fVIII membrane binding
and the mechanism of action of anti-C2 inhibitors. This study
constitutes an important contribution toward our understanding of the
complex antigenic properties of fVIII.
Pete Lollar
Emory University School of Medicine
