Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis

Thrombosis and Haemostasis

Volumn 90, Issue 4, 2003, Pages 642-653

  Dhainaut, Jean François ^a   Yan, S Betty ^b   Margolis, Benjamin D ^c   Lorente, José A ^d   Russell, James A ^e   Freebairn, Ross C ^f   Spapen, Herbert D ^g   Riess, Hanno ^h   Basson, Bruce ^b   Johnson III, Gerald ^b   Kinasewitz, Gary T ⁱ  

^a Universitaire Cochin Port Royal ^*  (France)

^b ELI LILLY AND COMPANY   (United States)

^c West Suburban Medical Center   (United States)

^d HOSPITAL UNIVERSITARIO DE GETAFE   (Spain)

^e ST PAUL S HOSPITAL   (Canada)

^f HAWKE S BAY HOSPITAL   (New Zealand)

^g UNIVERSITY HOSPITAL BRUSSELS   (Belgium)

^h CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

ⁱ UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

Author keywords

Activated protein C; Biomarkers; Coagulopathy; Drotrecogin alfa (activated); Randomized controlled trial

Indexed keywords

ACTIVATED PROTEIN C; ANTICOAGULANT PROTEIN; BIOLOGICAL MARKER; DROTRECOGIN; FIBRINOLYTIC FACTOR; INTERLEUKIN 6; PLACEBO; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEIN C; THROMBIN;

ADULT; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BLOOD CLOTTING DISORDER; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; ENDOTHELIUM INJURY; FIBRINOLYSIS; HEMOSTASIS; HUMAN; IMMUNE RESPONSE; INFLAMMATION; MAJOR CLINICAL STUDY; PARTIAL THROMBOPLASTIN TIME; PHARMACODYNAMICS; PRIORITY JOURNAL; PROSPECTIVE STUDY; PROTEIN BLOOD LEVEL; PROTHROMBIN TIME; RANDOMIZED CONTROLLED TRIAL; SEPSIS; STATISTICAL ANALYSIS; SURVIVAL;

EID: 12444249948     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/th02-11-0270     Document Type: Article

References (47)

1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for treatment of patients with severe sepsis. N Engl J Med 2001; 344: 699-709.
2. Kinasewitz GT, Margolis BD, Freebairn RC, et al. Changes in markers of coagulation and inflammation in patients were severe sepsis treated with recombinant activated protein C. SCCM 2001 (abstract).
3. Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345: 408-16.
4. Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 1995; 9: 946-55.
5. Esmon CT. The endothelial cell protein C receptor. Thromb Haemost 2000; 83: 639-43.
6. Sakata Y, Loskutoff DJ, Gladson CL, et al. Mechanism of protein C-dependent clot lysis: Role of plasminogen activator inhibitor. Blood 1986; 68: 1218-23.
7. Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-72.
8. Murakami K, Okajima K, Uchiba M, et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272 (part 1): L197-L202.
9. Shu F, Kobayashi H, Fukudome K, et al. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner. FEBS Lett 2000; 477: 208-12.
10. Grinnell BW, Hermann RB, Yan SB. Human protein C inhibits selectin-mediated cell adhesion: Role of unique fucosylated oligosaccharide. Glycobiology 1994; 4: 221-5.
11. Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 2001; 29: S48-S52.
12. Taylor FB, Chank A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of E. coli infusion in the baboon. J Clin Invest 1987; 79: 918-25.
13. Taylor FB, Chang A, Ferrell G, et al. C4b-binding Protein exacerbates the host response to E. coli. Blood 1991; 78: 357-63.
14. Taylor FB, Stearns-Kurosawa DJ, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-6.
15. Dhainaut JF, Marin N, Mignon A, et al. Hepatic response to sepsis: Interaction between coagulation and inflammatory processes. Crit Care Med 2001; 29: S42-S47.
16. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure and disseminated intravascular coagulation: Compare patterns of antithrombin III, Protein C and Protein S deficiencies. Chest 1992; 101: 816-23.
17. Hesselvik JF, Blomback M, Brodin B, et al. Coagulation, fibrinolysis, and kallikrein systems in sepsis: Relation to outcome. Crit. Care Med. 1989; 17: 724-33.
18. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-42.
19. Roback MG, Stack AM, Thompson C, et al. Activated protein C concentrate for the treatment of meningococcal endotoxin shock in rabbits. Shock 1998; 9: 138-42.
20. Fourrier F, Jourdain M, Tournoys A, et al. Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock. Shock 1998; 10: 364-70.
21. Yan SB, Dhainaut JF. Activated protein C versus protein C in severe sepsis. Crit. Care Med. 2001; 29 (Suppl.): S69-S74.
22. Abraham E. Why immunomodulatory therapies have not worked in sepsis. Intens. Care Med. 1999; 25: 556-66.
23. Fulton R, McDade R, Smith P, et al. Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 1997; 43: 1749-56.
24. FDA Anti-infective Drugs Advisory Committee Briefing Document, Xigris ™ drotrecogin alfa (activated), Biologic License application 125029, Eli Lilly and Company, T0955 Department of health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, October 16, 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_01_Sponsor.pdf.
25. Macias WL, Dhainaut JF, Yan SB, et al.. Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis. Clin Pharmacol Ther 2002; 72: 391-401.
26. Dahlback B. Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986; 261: 12022-7.
27. Dahlback B, Lundwall A, Stenflo J. Localization of thrombin cleavage sites in the amino-terminal region of bovine protein S. J Biol Chem 1986; 261: 5111-5.
28. Bajzar L, Nesheim M, Tracy PB. The profibrinolytic effect of activated Protein C in clots formed from plasma is TAFI-dependent. Blood 1996; 88(6): 2093-100.
29. Nesheim M, Wang W, Boffa M, et al.. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78(1): 386-91.
30. Krishnamurti C, Young GD, Barr CF, et al.. Enhancement of tissue plasminogen activator-induced fibrinolysis by activated Protein C in endotoxin-treated rabbits. J Lab Clin Med 1991; 118: 523-30.
31. Boffa MB, Hamill JD, Bastajian N, et al.. A role for CCAAT/Enhancer-binding protein in hepatic expression of thrombin-activable fibrinolysis inhibitor. J Biol Chem 2002; 277: 25329-36.
32. Bernard GR, Ely EW, Wright TJ, et al.. Safety and dose-relationship of recombinant human activated protein C (rhAPC) on coagulopathy in severe sepsis. Crit Care Med 2001; 29: 2051-9.
33. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Haemost 1998; 24: 33-44.
34. Kalil AC, Turlo MA, Um J, et al.. Drotrecogin alfa (activated) in a human endotoxin model. Crit Care Med 2002; 30(12 (Suppl.)): A105 (Abstract 440).
35. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-64.
36. Riewald M, Petrovan RJ, Donner A, et al.. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-2.
37. Hooper WC, Phillips DJ, Renshaw MA, et al.. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. J Immunol 1998; 161: 2567-73.
38. Abraham E, Arcaroli J, Carmody A, et al.. HMG-1 as a mediator of acute lung inflammation. J Immunol 2000; 165: 2950-4.
39. Boffa MC, Karmochkine M. Thrombomodulin: An overview and potential implications in vascular disorders. Lupus 1998; 7 (Suppl. 2): S120-S125.
40. Iba T, Yagi Y, Kidokoro A, et al.. Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure. Jpn J Surg 1995; 25: 585-90.
41. Ikegami K, Suzuki Y, Yukioka T, et al.. Endothelial cell injury, as quantified by the soluble thrombomodulin levels, predicts sepsis/multiple organ dysfunction syndrome after blunt trauma. J Trauma 1998; 44: 789-94.
42. Gando S, Kameue T, Nanzaki S, et al.. Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Thromb Res 1995; 80: 519-26.
43. Ileri M, Hisar I, Yekin E, et al. Increased levels of plasma thrombomodulin in patients with acute myocardial infarction who had thrombolytic therapy and achieved successful reperfusion. Clin Cardiol 2001; 24: 377-9.
44. Conway EM, Van De Wouwer M, Pollefeyt S, et al.. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappa B and mitogen-activated protein kinase pathways. J Exp Med 2002; 196: 565-77.
45. Warren BL, Eid A, Singer P, et al.. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001; 286: 1869-78.
46. Joyce DE, Gelbert L, Ciaccia A, et al. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-203.
47. Cheng T, Liu D, Griffin JH, et al.. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nature Med 2003; 9(3): 338-42.