Submitted January 14, 2008
Accepted April 16, 2008
Non-classical anti-C2 domain antibodies are present in patients with factor VIII inhibitors
Shannon L Meeks, John F. Healey, Ernest T. Parker, Rachel T. Barrow, and Pete Lollar*
Aflac Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, United States
* Corresponding author; email: jlollar{at}emory.edu.
The anti-human factor VIII (fVIII) C2 domain immune response in hemophilia A mice consists of antibodies that can be divided into 5 groups of structural epitopes and 2 groups of functional epitopes. Groups A, AB, and B consist of classical C2 antibodies that inhibit the binding of fVIII to phospholipid and von Willebrand factor. Groups BC and C contain non-classical C2 antibodies that block the activation of fVIII by thrombin or factor Xa. Group BC antibodies are the most common and display high specific inhibitory activity and type II kinetics. The C2 epitope groups recognized by 26 polyclonal human anti-fVIII inhibitor plasmas were identified by a novel competition ELISA using group-specific murine monoclonal antibodies. Most of the anti-C2 inhibitor plasmas inhibited the binding of both classical and non-classical antibodies. These results suggest that non-classical anti-C2 antibodies contribute significantly to the pathogenicity of fVIII inhibitors.
