A low concentration of rFVIIa, 0.25 mg/kg, restores hemostasis in FVIII antibody-induced hemophilia mice administered with proteolytically inactive FVIIa or EPCR blocking antibodies (BL. Ab). (A,B) Wild-type C57BL/6J mice were administered intravenously with saline (Con) or FVIII mAb (1 mg/kg) to induce hemophilia. Two hours after administering FVIII antibody, the mice were injected with saline (0), 0.25, 1.0, or 4.0 mg/kg rFVIIa or FVII_AI, or 0.25 mg/kg rFVIIa plus FVII_AI (0.25 or 1.0 mg/kg) via the tail vein. Five minutes following rFVIIa administration, the bleeding was initiated by the saphenous vein incision and average time to achieve hemostasis (A) and blood loss (B) were determined. (C-D) FVIII antibody-induced hemophilia mice were injected with EPCR blocking or non-blocking antibodies (4 mg/kg) ± 0.25 mg/kg rFVIIa. Following the saphenous vein injury, the average time to achieve hemostasis (C) and blood loss (D) were determined as described in “Materials and methods” (n = 5-10 mice/group). *P < .05; **P < .01 ***P < .001. Note: The data shown for Con and Ab-induced hemophilia with 0, 0.25, and 1.0 mg/kg of rFVIIa (C-D) were the same as that of shown in panels A and B, respectively, except for minor differences in the number of animals in some groups.