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Factor VIII products are used to manage acute bleeding or to prevent excessive bleeding as a treatment for patients with hemophilia A and/or von Willebrand disease. However, the development of neutralizing anti-factor VIII (FVIII) antibodies is a serious complication that may be encountered when FVIII replacement therapy is administered to patients with hemophilia A (HA). It affects 25% to 30% of the treated HA population, with a peak occurrence after ∼14 FVIII infusions.<br /><br />The most common epitopes recognized by hemophilic inhibitors are on the FVIII A2 and C2 domains. The FVIII C2 domain (FVIII-C2) mediates numerous functions that are essential for the full procoagulant cofactor activity of FVIII, including membrane binding and assembly of the intrinsic tenase complex.