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9) Ontachi Y, Asakura H, Nakao S, et al. No interplay between the pathways mediating coagulation and inflammation in tissue factor-induced disseminated intravascular coagulation in rats. Crit Care Med. 2006; 34: 2646-50
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10) Weiler H. Regulation of inflammation by the protein C system. Crit Care Med. 2010; 38 (2 Suppl): S18-25
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11) Sarangi PP, Lee HW, Kim M. Activated protein C action in inflammation. Br J Haematol. 2010; 148: 817-33
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12) Toltl LJ, Beaudin S, Liaw PC. Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes. J Immunol. 2008; 181: 2165-73
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13) Kerschen EJ, Fernandez JA, Cooley BC, et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med. 2007; 204: 2439-48
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14) van Veen SQ, Levi M, van Vliet AK, et al. Peritoneal lavage with activated protein C alters compartmentalized coagulation and fibrinolysis and improves survival in polymicrobial peritonitis. Crit Care Med. 2006; 34: 2799-805
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15) Choi G, Hofstra JJ, Roelofs JJ, et al. Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats. Crit Care Med. 2007; 35: 1362-8
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16) Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344: 699-709
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17) Fumagalli R, Mignini MA. The safety profile of drotrecogin alfa (activated). Crit Care. 2007; 11 Suppl 5: S6
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18) Ely EW, Laterre PF, Angus DC. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med. 2003; 31: 12-9
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19) Warren HS, Suffredini AF, Eichacker PQ, et al. Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med. 2002; 347: 1027-30
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20) Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa (activated) for the treatment of severe sepsis. Lancet Infect Dis. 2009; 9: 67-72
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22) Nadel S, Goldstein B, Williams MD. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007; 369: 836-43
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23) Carlet J. Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med. 2006; 34: 525-9
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24) Dellinger RP, Carlet JM, Masur H. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004; 30: 536-55
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25) Warren BL, Eid A, Singer P, Pillay SS, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001; 286: 1869-78
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26) Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003; 290: 238-47
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27) Toussaint S, Gerlach H. Activated protein C for sepsis. N Engl J Med. 2009; 361: 2646-52
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28) Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009; 15: 1318-21
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29) Mosnier LO, Zampolli A, Kerschen EJ, et al. Hyperantithrombotic, noncytoprotective Glu149 Ala-activated protein C mutant. Blood. 2009; 113: 5970-8
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30) Xu J, Ji Y, Zhang X, et al. Endogenous activated protein C signaling is critical to protection of mice from lipopolysaccaride-induced septic shock. J Thromb Haemost. 2009; 7: 851-6
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31) Niessen F, Furlan-Freguia C, Fernández JA, et al. Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality. Blood. 2009; 113: 2859-66
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32) Isobe H, Okajima K, Uchiba M, et al. Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation. 2001; 104: 1171-5
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33) Van Sluis GL, Niers TM, Esmon CT, et al. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood. 2009; 114: 1968-73
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34) Nick JA, Coldren CD, Geraci MW, et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood. 2004; 104: 3878-85
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35) Andonegui G, Bonder CS, Green F, et al. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest. 2003; 111: 1011-20
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36) Monnet X, Lamia B, Anguel N, et al. Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients. Intensive Care Med. 2005; 31: 1573-6
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37) Kalil AC, Coyle SM, Um JY, et al. Effects of drotrecogin alfa (activated) in human endotoxemia. Shock. 2004; 21: 222-9
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38) Sturn DH, Kaneider NC, Feistritzer C, et al. Expression and function of the endothelial protein C receptor in human neutrophils. Blood. 2003; 102: 1499-505
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39) Pereira C, Schaer DJ, Bachli EB, et al. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol. 2008; 28: 504-10
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40) Kerschen E, Hernandez I, Zogg M, et al. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest. 2010; 120: 3167-78
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41) Messaris E, Betrosian AP, Memos N, et al. Administration of human protein C improves survival in an experimental model of sepsis. Crit Care Med. 2010; 38: 209-16
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42) Danese S, Vetrano S, Zhang L, et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood. 2010; 115: 1121-30
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