Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation.

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Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia by Ulla Derhaschnig, Rosemarie Reiter, Paul Knöbl, Magdalena Baumgartner, Priska Keen, and Bernd Jilma Blood Volume 102(6):2093-2098 September 15, 2003 ©2003 by American Society of Hematology

Pharmacokinetics of recombinant human activated protein C (rhAPC) in the human endotoxin (LPS) model. Pharmacokinetics of recombinant human activated protein C (rhAPC) in the human endotoxin (LPS) model. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪), which increased APC levels 70-fold (top graph), or placebo (○) intravenously starting 2 hours before LPS bolus infusion (2 ng/kg), which enhanced endogenous protein C activation (2.3-fold; 95% CI, 1.4-3.1). Friedman ANOVA for PC:Ag and PC:Act in both groups: P < .001; P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Recombinant human activated protein C (rhAPC) prolongs activated partial thromboplastin time (aPTT) but decreases tissue factor (TF)–mRNA before LPS infusion. Recombinant human activated protein C (rhAPC) prolongs activated partial thromboplastin time (aPTT) but decreases tissue factor (TF)–mRNA before LPS infusion. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS bolus infusion (2 ng/kg). rhAPC increased aPTT levels (top graph) by 20% (P < .001 between groups). rhAPC decreased only basal TF-mRNA (bottom graph) by – 32% (CI, – 49 to – 14%; *P < .05 between groups at 0 hour). P < .001 versus baseline in both groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced coagulation. Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced coagulation. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). rhAPC slightly reduced thrombin formation and action during the first 3 hours of infusion (indicated by asterisk), but LPS-induced thrombin generation was not blunted: thrombin antithrombin complexes (TAT; top graph), prothrombin fragment (F1 + 2; middle graph), or d-dimer (bottom graph). *P < .005 versus baseline in the rhAPC groups and for relative change between groups, P < .001 for Friedman ANOVA for both groups, and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced cytokine release. Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced cytokine release. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). rhAPC did not significantly reduce LPS-induced inflammation: tumor necrosis factor alpha (TNF-α; top graph) or interleukin-6 (IL-6; bottom graph) levels. P < .001 versus baseline for both groups, and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Activation and subsequent inhibition of fibrinolysis by endotoxin. Activation and subsequent inhibition of fibrinolysis by endotoxin. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). Plasmin antiplasmin complexes (PAP; top graph), tissue plasminogen activator (tPA; middle graph), or plasminogen activator inhibitor (PAI-1; bottom graph). P < .001 versus baseline for both groups, and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced endothelial, platelet, or neutrophil activation. Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced endothelial, platelet, or neutrophil activation. (A) E-selectin. (B) P-selectin. (C) Elastase. (D) Platelet counts. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). P < .001 versus baseline for both groups, and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced changes in white blood cell counts. Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced changes in white blood cell counts. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours; ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). rhAPC did not alter white blood counts of neutrophils (top graph), monocytes (middle graph), or lymphocytes (bottom graph). P < .001 versus baseline for both groups; and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology

Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced changes in vital parameters. Effects of recombinant human activated protein C (rhAPC) on endotoxin (LPS)–induced changes in vital parameters. Healthy male volunteers received rhAPC (24 μg/kg per hour for 8 hours, ▪) or placebo (○) intravenously starting 2 hours before LPS challenge (2 ng/kg). rhAPC did not significantly alter vital parameters: heart rate (HR; top graph), systolic blood pressure (SBP; middle graph), and diastolic blood pressure (DBP; bottom graph). P < .001 for Friedman ANOVA for both groups, and P = ns between groups; mean ± SEM. Ulla Derhaschnig et al. Blood 2003;102:2093-2098 ©2003 by American Society of Hematology