aPC resistance of fV Leiden modifies responsiveness to aPC therapy. (A) Survival of wild-type mice after intraperitoneal inoculation of live bacteria. Within 30 minutes of infection, mice received 150 μg/kg of IV 5A-aPC together with intraperitoneal 200 U/kg of unfractionated heparin, 30 mg/kg of mouse 14E11 monoclonal antibody, or 30 mg/kg of nonimmune mouse immunoglobulin G (IgG). (B) Homozygous fV Leiden mice (fV QQ) were infected with live S aureus and, within 30 minutes, received an IV injection of wild-type aPC (wt), 5A-aPC (5A), or E149A-aPC (E149A; 150 μg/kg body weight) dissolved in 200 μL of PBS, or vehicle alone. Homozygous fV Leiden mice (fVQQ) (C), fVQQ mice with superimposed hemophilia A (fVQQ fVIII⁻) (D), and fVQQ mice with superimposed PAR4 deficiency (fVQQ Par4^−/−) (E) received intraperitoneal LPS (40 mg/kg) and, within 30 minutes, received an IV injection of 5A-aPC (150 μg/kg body weight) dissolved in 200 μL of PBS, or vehicle alone. (F) Survival of LPS-treated fVQQ mice infused within 30 minutes after LPS challenge with mouse 5A-aPC dissolved in 200 μL of plasma from wt or fVQQ mice, or with 200 μL of wild-type plasma alone. Significance of differences in cumulative 7-day survival was determined by Mantel-Cox log-rank analysis of Kaplan-Meyer survival plots.