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.