Role of Coagulation Inhibitors in Inflammation

Charles T. Esmon

doi:10.1055/s-0037-1616200

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(01): 51-56
DOI: 10.1055/s-0037-1616200

Research Article

Schattauer GmbH

Role of Coagulation Inhibitors in Inflammation

Authors

Charles T. Esmon

¹Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Departments of Pathology, and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, and Howard Hughes Medical Institute, Oklahoma City, OK, USA

Abstract

Summary

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response.

The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFκB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. colimediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.

Key words

Thrombin - natural anticoagulants - inflammation - sepsis - endothelium

Full Text

References

References
1 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
2 Smith D. Report of the international meeting on Intensive Care Medicine, Rome, Italy, October 1-4, 2000. Critical Care 2000; 4: 255-62.
3 Schaub RG, Simmons CA, Koets MH, Romano PJ, Stewart GJ. Early events in the formation of a venous thrombus following local trauma and stasis. Lab Invest 1984; 51: 218-24.
4 Yang J, Furie BC, Furie B. The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction. Thromb Haemost 1999; 81: 1-7.
5 Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
6 Wakefield TW, Strieter RM, Schaub R, Myers DD, Prince MR, Wrobleski SK. et al. Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy. J Vasc Surg 2000; 31: 309-24.
7 Coughlin SR. Thrombin receptor function and cardiovascular disease. Trends Cardiovasc Med 1994; 4: 77-83.
8 Lorant DE, Patel KD, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: A juxtacrine system for adhesion and activation of neutrophils. J Cell Biol 1991; 115: 223-34.
9 Creasey AA. New potential therapeutic modalities: tissue factor pathway inhibitor. Sepsis 1999; 3: 173-82.
10 Opal SM. Therapeutic rationale for antithrombin III in sepsis. Crit Care Med 2000; 28: S34-S37.
11 Esmon CT, Taylor Jr FB, Snow TR. Inflammation and coagulation: Linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 1991; 66: 160-5.
12 Taylor Jr FB, Peer GT, Lockhart MS, Ferrell G, Esmon CT. EPCR plays an important role in protein C activation in vivo. Blood 2001; 97: 1685-8.
13 White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000; 96: 3719-24.
14 Yamauchi T, Umeda F, Inoguchi T, Nawata H. Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells. Biochem Biophys Res Commun 1989; 163: 1404-11.
15 Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999; 93: 157-64.
16 Ostrovsky L, Woodman RC, Payne D, Teoh D, Kubes P. Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion. Circulation 1997; 96: 2302-10.
17 Uchiba M, Okajima K. Antithrombin III (AT III) prevents LPS-induced vascular injury: novel biological activity of AT III. Thromb Haemost 1997; 23: 583-90.
18 Duensing TD, Wing JS, van Putten JPM. Sulfated polysaccharide-directed recruitment of mammalian host proteins: a novel strategy in microbial pathogenesis. Infect Immun 1999; 67: 4463-8.
19 Minnema MC, Chang ACK, Jansen PM, Lubbers YTP, Pratt BM, Whittaker BG. et al. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli . Blood 2000; 95: 1117-23.
20 Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 1996; 88: 881-6.
21 Broze Jr GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990; 29: 7539-46.
22 Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci (USA) 2000; 97: 5255-60.
23 Camerer E, Rottingen J-A, Iversen J-G, Prydz H. Coagulation factors VII and X induce Ca²⁺ oscillations in Madin-Darby canine kidney cells only when proteolytically active. J Biol Chem 1996; 271: 29034-42.
24 Camerer E, Rottingen JA, Gjernes E, Larsen K, Skartlien AH, Iversen JG. et al. Coagulation factors VIIa and Xa induce cell signaling leading to upregulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
25 Sørensen BB, Freskgård P-O, Nielsen LS, Rao LVM, Ezban M, Petersen LC. Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. J Biol Chem 1999; 274: 21349-54.
26 Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 1999; 94: 3413-20.
27 St Pierre J, Yang L-Y, Tamirisa K, Scherrer D, De Ciechi P, Eisenberg P. et al. Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs. Arterioscler Thromb Vasc Biol 1999; 19: 2263-8.
28 Sevinsky JR, Rao LVM, Ruf W. Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway. J Cell Biol 1996; 133: 293-304.
29 Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem 1998; 273: 5419-22.
30 Creasey AA, Chang AC, Fiegen L, Wun T-C, Taylor Jr FB, Hinshaw LB. Tissue factor pathway inhibitor (TFPI) reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-60.
31 Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood 2000; 95: 1113-6.
32 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 9 suppl S31-S33.
33 Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planché C, Dehan M. et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. New Engl J Med 1991; 325: 565-8.
34 Dreyfus M, Masterson M, David M, Rivard GE, Muller F-M, Kreuz W. et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Sem Thromb Hemost 1995; 21: 371-81.
35 Busch C, Cancilla P, DeBault L, Goldsmith J, Owen W. Use of endothelium cultured on microcarriers as a model for the microcirculation. Lab Invest 1982; 47: 498-504.
36 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-6.
37 Fukudome K, Esmon CT. Identification, cloning and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 994 269: 26486-91.
38 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci (USA) 1996; 93: 10212-6.
39 Xu J, Esmon NL, Esmon CT. Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation. J Biol Chem 1999; 274: 6704-10.
40 Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H. et al. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 1998; 187: 1029-35.
41 Gu J-M, Ferrell G, Esmon CT. Targeted disruption of the endothelial protein C receptor (EPCR) causes early embryonic lethality in mice. Blood. (In Press).
42 Healy AM, Rayburn HB, Rosenberg RD, Weiler H. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci (USA) 1995; 92: 850-4.
43 Regan LM, Stearns-Kurosawa DJ, Kurosawa S, Mollica J, Fukudome K, Esmon CT. The endothelial cell protein C receptor: Inhibition of activated protein C anticoagulant function without modulation of reaction with proteinase inhibitors. J Biol Chem 1996; 271: 17499-503.
44 Liaw PCY, Neuenschwander PF, Smirnov MD, Esmon CT. Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J Biol Chem 2000; 275: 5447-52.
45 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-8.
46 Murphy TL, Walker FJ, Taylor Jr FB, Beller-Todd BK, Archer LT, Sofer SS. et al. Endogenous anticoagulation during extracorporeal perfusion: Generation of a heparin-like inhibitor. Am J Physiol 1980; 239: H742-H750.
47 Hinshaw LB, Chang ACK, Beller-Todd BK, Archer LT, Taylor Jr FB. Extracorporeal perfusion without exogenous anticoagulation: Its protective role in endotoxin shock. Circ Shock 1982; 9: 281-95.
48 Comp PC, Jacocks RM, Ferrell GL, Esmon CT. Activation of protein C in vivo. J Clin Invest 1982; 70: 127-34.
49 Taylor Jr FB, Chang A, Hinshaw LB, Esmon CT, Archer LT, Beller BK. A model for thrombin protection against endotoxin. Thromb Res 1984; 36: 177-85.
50 Taylor Jr FB, Stern DM, Nawroth PP, Esmon CT, Hinshaw LB, Blick KE. Activated protein C prevents E. coli induced coagulopathy and shock in he primate. Circulation 1986; 74: 65a (abstr.).
51 Taylor F, Chang A, Ferrell G, Mather T, Catlett R, Blick K. et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood 1991; 78: 357-63.
52 Taylor Jr FB, Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang ACK, Laszik Z. et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-6.
53 Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. J Immunol 1994; 153: 3664-72.
54 Hirose K, Okajima K, Taoka Y, Uchiba M, Tagami H, Nakano K-Y. et al. Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Annals of Surgery 2000; 232: 272-80.
55 Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H. et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272: L197-L202.
56 Taoka Y, Okajima K, Uchiba M, Murakami K, Harada N, Johno M. et al. Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes. J Neurosci 1998; 18: 1393-8.
57 Hancock WW, Grey ST, Hau L, Akalin E, Orthner C, Sayegh MH, Salem HH. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte dependent proliferative responses. Transplantation 1995; 60: 1525-32.
58 White B, Schmidt M, Murphy C, Livingstone W, O’Toole D, Lawler M. et al. Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 2000; 110: 130-4.
59 Xu J, Esmon CT. Endothelial cell protein C receptor (EPCR) constitutively translocates into the nucleus and also mediates activated protein C, but not protein C, nuclear translocation. Thromb Haemost. 1999 suppl Aug 1999; 206a (abstr.).
60 Esmon CT, Xu J, Gu JM, Qu D, Laszik Z, Ferrell G. et al. Endothelial protein C receptor. Thromb Haemost 1999; 82: 251-8.
61 Shu F, Kobayashi H, Fukudome K, Tsuneyoshi N, Kimoto M, Terao T. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner. FEBS Lett 2000; 477: 208-12.
62 Fisher CJ, Yan SB. Protein C levels as a prognostic indicator of outcome in sepsis and related diseases. Crit Care Med 2000; 28: S49-S56.
63 Powars DR, Rogers ZR, Patch MJ, McGehee WG, Francis RB. Purpura fulminans in meningococcemia: Association with acquired deficiencies of proteins C and S [Letter]. New Engl J Med 1987; 317: 571-4.
64 Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993; 91: 418-22.
65 Rintala E, Seppala O-P, Kotilainen P, Pettila V, Rasi V. Protein C in the treatment of coagulopathy in meningococcal disease. Crit Care Med 1998; 26: 965-8.
66 Smith OP, White B. Infectious pupura fulminans: diagnosis and treatment. Br J Haematol 1999; 104: 202-7.
67 Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B. et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997; 350: 1590-3.
68 Rivard GE, David M, Farrell C, Schwarz HP. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 1995; 126 (Suppl. 04) 646-52.
69 Faust SN, Heyderman RS, Harrison O, Goldin RD, Laszik Z, Esmon CT. et al. Molecular mechanisms of thrombosis in meningococcal septicaemia: the role of the protein C pathway in vivo. Proceedings of the 2nd Annual Meeting of the British Infection Society, London, April 23, 1999.
70 Hartman DL, Bernard GR, Helterbrand JD, Yan SB, Fisher CJ. Recombinant human activated protein C (rhAPC) improves coagulation abnormalities associated with severe sepsis. Intensive Care Medicine 1998; 24: S77a (abstr.).