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Thromb Haemost 2010; 104(01): 136-142
DOI: 10.1160/TH09-08-0582
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Anticoagulant therapy in critical organ ischaemia/reperfusion injury

Sarah T. B. G. Loubele
1   Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands
,
Hugo ten Cate
1   Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands
,
Henri M. H. Spronk
1   Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands
› Author Affiliations Financial support: Sarah T. B. G. Loubele is financially supported by the Netherlands Heart Foundation (Grant no. 2003-B065) and by Thrombosestichting Nederland.
Further Information

Publication History

Received: 20 August 2009

Accepted after major revision: 18 February 2010

Publication Date:
23 November 2017 (online)

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Summary

Ischaemia/reperfusion (I/R) injury is central to a number of pathologies including myocardial infarction and stroke. Several cellular processes are involved in the progress of I/R injury, involving complex interactions between coagulation and inflammatory or apoptotic processes. Besides for their anti-coagulant function, anticoagulant proteins such as activated protein C (APC), active site inhibited factor VIIa (ASIS), tissue factor pathway inhibitor (TFPI), and antithrombin (AT) are also known for their anti-inflammatory or cell protective effects. This review gives an overview of the application of these anti-coagulants in several animal models of I/R injury in critical organs and describes the effects of these proteins on cellular processes including inflammation and apoptosis. The future testing of mutant forms of some of these inhibitors including APC in a clinical setting should be actively explored.

Keywords

Ischaemia/reperfusion injury - anti-coagulant therapy - animal models - inflammation - apoptosis
 

  • References

  • 1 Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword?. J Clin Invest 1985; 76: 1713-1719.
    CrossrefPubMedGoogle Scholar
  • 2 Jennings RB, Murry CE, Steenbergen Jr C. et al Development of cell injury in sustained acute ischemia. Circulation 1990; 82 (Suppl. 03) (Suppl) II2-12.
    PubMedGoogle Scholar
  • 3 Bolli R. Oxygen-derived free radicals and postischemic myocardial dysfunction (′stunned myocardium′). J Am Coll Cardiol 1988; 12: 239-249.
    CrossrefPubMedGoogle Scholar
  • 4 Dhalla NS, Elmoselhi AB, Hata T. et al Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res 2000; 47: 446-456.
    CrossrefPubMedGoogle Scholar
  • 5 Sellak H, Franzini E, Hakim J. et al Reactive oxygen species rapidly increase endothelial ICAM-1 ability to bind neutrophils without detectable upregulation. Blood 1994; 83: 2669-2677.
    PubMedGoogle Scholar
  • 6 Krijnen PA, Nijmeijer R, Meijer CJ. et al Apoptosis in myocardial ischaemia and infarction. J Clin Pathol 2002; 55: 801-811.
    CrossrefPubMedGoogle Scholar
  • 7 Hill JH, Ward PA. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med 1971; 133: 885-900.
    CrossrefPubMedGoogle Scholar
  • 8 Vakeva AP, Agah A, Rollins SA. et al Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 1998; 97: 2259-2267.
    CrossrefPubMedGoogle Scholar
  • 9 Birdsall HH, Green DM, Trial J. et al Complement C5a, TGF-beta 1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation 1997; 95: 684-692.
    CrossrefPubMedGoogle Scholar
  • 10 Gottlieb RA, Burleson KO, Kloner RA. et al Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994; 94: 1621-1628.
    CrossrefPubMedGoogle Scholar
  • 11 Kajstura J, Cheng W, Reiss K. et al Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 1996; 74: 86-107.
    PubMedGoogle Scholar
  • 12 Garg S, Hofstra L, Reutelingsperger C. et al Apoptosis as a therapeutic target in acutely ischemic myocardium. Curr Opin Cardiol 2003; 18: 372-377.
    CrossrefPubMedGoogle Scholar
  • 13 Olivetti G, Quaini F, Sala R. et al Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 1996; 28: 2005-2016.
    CrossrefPubMedGoogle Scholar
  • 14 Zak R. Cell proliferation during cardiac growth. Am J Cardiol 1973; 31: 211-219.
    CrossrefPubMedGoogle Scholar
  • 15 Buja LM, Vela D. Cardiomyocyte death and renewal in the normal and diseased heart. Cardiovasc Pathol 2008; 17: 349-374.
    CrossrefPubMedGoogle Scholar
  • 16 Kuroda S, Siesjo BK. Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci 1997; 04: 199-212.
    PubMedGoogle Scholar
  • 17 D'Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med 2001; 07: 367-382.
    PubMedGoogle Scholar
  • 18 Arumugam TV, Shiels IA, Woodruff TM. et al The role of the complement system in ischemia-reperfusion injury. Shock 2004; 21: 401-409.
    CrossrefPubMedGoogle Scholar
  • 19 Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40: e331-339.
    CrossrefPubMedGoogle Scholar
  • 20 Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55: 310-318.
    CrossrefPubMedGoogle Scholar
  • 21 Takano T, Oberheim N, Cotrina ML. et al Astrocytes and ischemic injury. Stroke 2009; 40 (Suppl. 03) (Suppl) S8-12.
    CrossrefPubMedGoogle Scholar
  • 22 Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996; 334: 1448-1460.
    CrossrefPubMedGoogle Scholar
  • 23 Molitoris BA, Dahl R, Geerdes A. Cytoskeleton disruption and apical redistribution of proximal tubule Na(+)-K(+)-ATPase during ischemia. Am J Physiol 1992; 263: F488-495.
    PubMedGoogle Scholar
  • 24 Bayati A. A study in the maintenance phase of ischaemic acute renal failure in the rat. Acta Physiol Scand 1990; 138: 349-357.
    CrossrefPubMedGoogle Scholar
  • 25 Arendshorst WJ, Finn WF, Gottschalk CW. Pathogenesis of acute renal failure following temporary renal ischemia in the rat. Circ Res 1975; 37: 558-568.
    CrossrefPubMedGoogle Scholar
  • 26 Alejandro V, Scandling Jr JD, Sibley RK. et al Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft. J Clin Invest 1995; 95: 820-831.
    CrossrefPubMedGoogle Scholar
  • 27 Flores J, DiBona DR, Beck CH. et al The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute. J Clin Invest 1972; 51: 118-126.
    CrossrefPubMedGoogle Scholar
  • 28 Kaushal GP, Basnakian AG, Shah SV. Apoptotic pathways in ischemic acute renal failure. Kidney Int 2004; 66: 500-506.
    CrossrefPubMedGoogle Scholar
  • 29 Rabb H, O'Meara YM, Maderna P. et al Leukocytes, cell adhesion molecules and ischemic acute renal failure. Kidney Int 1997; 51: 1463-1468.
    CrossrefPubMedGoogle Scholar
  • 30 Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002; 62: 1539-1549.
    CrossrefPubMedGoogle Scholar
  • 31 Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury--a fresh look. Exp Mol Pathol 2003; 74: 86-93.
    CrossrefPubMedGoogle Scholar
  • 32 Meesters EW, Hansen H, Spronk HM. et al The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus. Blood Coagul Fibrinolysis 2007; 18: 21-28.
    CrossrefPubMedGoogle Scholar
  • 33 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592.
    CrossrefPubMedGoogle Scholar
  • 34 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007; 27: 1687-1693.
    CrossrefPubMedGoogle Scholar
  • 35 Girard TJ, Warren LA, Novotny WF. et al Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989; 338: 518-520.
    CrossrefPubMedGoogle Scholar
  • 36 Baugh RJ, Broze Jr GJ, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem 1998; 273: 4378-4386.
    CrossrefPubMedGoogle Scholar
  • 37 Spronk HM, Govers-Riemslag JW, ten Cate H. The blood coagulation system as a molecular machine. Bioessays 2003; 25: 1220-1228.
    CrossrefPubMedGoogle Scholar
  • 38 Beresford CH. Antithrombin III deficiency. Blood Rev 1988; 02: 239-250.
    CrossrefPubMedGoogle Scholar
  • 39 Barnes JA, Singh S, Gomes AV. Protease activated receptors in cardiovascular function and disease. Mol Cell Biochem 2004; 263: 227-239.
    CrossrefPubMedGoogle Scholar
  • 40 Vu TK, Hung DT, Wheaton I V. et al Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-1068.
    CrossrefPubMedGoogle Scholar
  • 41 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-264.
    CrossrefPubMedGoogle Scholar
  • 42 Junge CE, Sugawara T, Mannaioni G. et al The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci USA 2003; 100: 13019-13024.
    CrossrefPubMedGoogle Scholar
  • 43 Pawlinski R, Tencati M, Hampton CR. et al Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 2007; 116: 2298-2306.
    CrossrefPubMedGoogle Scholar
  • 44 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: 5255-5260.
    CrossrefPubMedGoogle Scholar
  • 45 Riewald M, Petrovan RJ, Donner A. et al Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
    CrossrefPubMedGoogle Scholar
  • 46 Cunningham MA, Romas P, Hutchinson P. et al Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 1999; 94: 3413-3420.
    PubMedGoogle Scholar
  • 47 Napoli C, Cicala C, Wallace JL. et al Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart. Proc Natl Acad Sci USA 2000; 97: 3678-3683.
    CrossrefPubMedGoogle Scholar
  • 48 Ollivier V, Parry GC, Cobb RR. et al Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem 1996; 271: 20828-20835.
    CrossrefPubMedGoogle Scholar
  • 49 Uchiba M, Okajima K, Murakami K. Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats. Thromb Res 1998; 89: 233-241.
    CrossrefPubMedGoogle Scholar
  • 50 Ostrovsky L, Woodman RC, Payne D. et al Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion. Circulation 1997; 96: 2302-23010.
    CrossrefPubMedGoogle Scholar
  • 51 White B, Schmidt M, Murphy C. et al Activated protein C inhibits lipopolysac-charide-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: 130-134.
    CrossrefPubMedGoogle Scholar
  • 52 Yuksel M, Okajima K, Uchiba M. et al Activated protein C inhibits lipopolysac-charide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb Haemost 2002; 88: 267-273.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Shua F, Kobayashia H, Fukudomeb 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: 208-212.
    CrossrefPubMedGoogle Scholar
  • 54 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 kappaB and mitogen-activated protein kinase pathways. J Exp Med 2002; 196: 565-577.
    CrossrefPubMedGoogle Scholar
  • 55 Campbell W, Okada N, Okada H. Carboxypeptidase R is an inactivator of complement-derived inflammatory peptides and an inhibitor of fibrinolysis. Immunol Rev 2001; 180: 162-167.
    CrossrefPubMedGoogle Scholar
  • 56 Black SC, Gralinski MR, Friedrichs GS. et al Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury. Cardiovasc Res 1995; 29: 629-636.
    CrossrefPubMedGoogle Scholar
  • 57 Friedrichs GS, Kilgore KS, Manley PJ. et al Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart. Circ Res 1994; 75: 701-710.
    CrossrefPubMedGoogle Scholar
  • 58 Habazettl H, Lindert J, Baeter S. et al Effects of unfractionated heparin, low molecular weight heparin and r-hirudin on leukocyte adhesion in ischemia/reperfusion. Blood Coagul Fibrinolysis 2004; 15: 375-381.
    CrossrefPubMedGoogle Scholar
  • 59 Karabiyikoglu M, Hua Y, Keep RF. et al Intracerebral hirudin injection attenuates ischemic damage and neurologic deficits without altering local cerebral blood flow. J Cereb Blood Flow Metab 2004; 24: 159-166.
    CrossrefPubMedGoogle Scholar
  • 60 Weinstein RE, Walker FJ. Species specificity of the fibrinolytic effects of activated protein C. Thromb Res 1991; 63: 123-131.
    CrossrefPubMedGoogle Scholar
  • 61 He X, Dahlback B. Rabbit plasma, unlike its human counterpart, contains no complex between protein S and C4b-binding protein. Thromb Haemost 1994; 71: 446-451.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Maroney SA, Ferrel JP, Collins ML. et al Tissue factor pathway inhibitor-gamma is an active alternatively spliced form of tissue factor pathway inhibitor present in mice but not in humans. J Thromb Haemost 2008; 06: 1344-1351.
    CrossrefPubMedGoogle Scholar
  • 63 Hisaka T, Lardeux B, Lamireau T. et al Expression of tissue factor pathway inhibitor-2 in murine and human liver regulation during inflammation. Thromb Haemost 2004; 91: 569-575.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Petersen LC, Norby PL, Branner S. et al Characterization of recombinant murine factor VIIa and recombinant murine tissue factor: a human-murine species compatibility study. Thromb Res 2005; 116: 75-85.
    CrossrefPubMedGoogle Scholar
  • 65 Taylor Jr FB, Peer GT, Lockhart MS. et al Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 2001; 97: 1685-1688.
    CrossrefPubMedGoogle Scholar
  • 66 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS. et al The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
    CrossrefPubMedGoogle Scholar
  • 67 Esmon CT. Coagulation and inflammation. J Endotoxin Res 2003; 09: 192-198.
    CrossrefPubMedGoogle Scholar
  • 68 Riewald M, Petrovan RJ, Donner A. et al Activated protein C signals through the thrombin receptor PAR1 in endothelial cells. J Endotoxin Res 2003; 09: 317-321.
    CrossrefPubMedGoogle Scholar
  • 69 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: 11199-11203.
    CrossrefPubMedGoogle Scholar
  • 70 Cheng T, Liu D, Griffin JH. et al Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 09: 338-342.
    CrossrefPubMedGoogle Scholar
  • 71 Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med 2002; 30 (Suppl. 05) (Suppl) S288-293.
    CrossrefPubMedGoogle Scholar
  • 72 Franscini N, Bachli EB, Blau N. et al Gene expression profiling of inflamed human endothelial cells and influence of activated protein C. Circulation 2004; 110: 2903-2909.
    CrossrefPubMedGoogle Scholar
  • 73 Shibata M, Kumar SR, Amar A. et al Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103: 1799-1805.
    CrossrefPubMedGoogle Scholar
  • 74 Zlokovic BV, Zhang C, Liu D. et al Functional recovery after embolic stroke in rodents by activated protein C. Ann Neurol 2005; 58: 474-477.
    CrossrefPubMedGoogle Scholar
  • 75 Hirose K, Okajima K, Taoka Y. et al Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann Surg 2000; 232: 272-280.
    CrossrefPubMedGoogle Scholar
  • 76 Dillon JP, Laing AJ, Cahill RA. et al Activated protein C attenuates acute ischaemia reperfusion injury in skeletal muscle. J Orthop Res 2005; 23: 1454-1459.
    CrossrefPubMedGoogle Scholar
  • 77 Mizutani A, Okajima K, Uchiba M. et al Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 2000; 95: 3781-3787.
    PubMedGoogle Scholar
  • 78 Kuriyama N, Isaji S, Hamada T. et al Activated protein C prevents hepatic ischaemia-reperfusion injury in rats. Liver Int 2009; 29: 299-307.
    CrossrefPubMedGoogle Scholar
  • 79 Loubele ST, Spek CA, Leenders P. et al Activated protein C protects against myocardial ischemia/ reperfusion injury via inhibition of apoptosis and inflammation. Arterioscler Thromb Vasc Biol 2009; 29: 1087-1092.
    CrossrefPubMedGoogle Scholar
  • 80 Kerschen EJ, Fernandez JA, Cooley BC. et al Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 2007; 204: 2439-2448.
    CrossrefPubMedGoogle Scholar
  • 81 Gupta A, Gerlitz B, Richardson MA. et al Distinct functions of activated protein C differentially attenuate acute kidney injury. J Am Soc Nephrol 2009; 20: 267-277.
    CrossrefPubMedGoogle Scholar
  • 82 Wang Y, Thiyagarajan M, Chow N. et al Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. Stroke 2009; 40: 1864-1869.
    CrossrefPubMedGoogle Scholar
  • 83 Mackman N. Role of tissue factor in hemostasis and thrombosis. Blood Cells Mol Dis 2006; 36: 104-107.
    CrossrefPubMedGoogle Scholar
  • 84 Pyo RT, Sato Y, Mackman N. et al Mice deficient in tissue factor demonstrate attenuated intimal hyperplasia in response to vascular injury and decreased smooth muscle cell migration. Thromb Haemost 2004; 92: 451-458.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 85 Carmeliet P, Mackman N, Moons L. et al Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75.
    CrossrefPubMedGoogle Scholar
  • 86 Ott I, Fischer EG, Miyagi Y. et al A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 1998; 140: 1241-1253.
    CrossrefPubMedGoogle Scholar
  • 87 Abe K, Shoji M, Chen J. et al Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA 1999; 96: 8663-8668.
    CrossrefPubMedGoogle Scholar
  • 88 Versteeg HH, Sorensen BB, Slofstra SH. et al VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J Biol Chem 2002; 277: 27065-27072.
    CrossrefPubMedGoogle Scholar
  • 89 Sorensen BB, Rao LV, Tornehave D. et al Antiapoptotic effect of coagulation factor VIIa. Blood 2003; 102: 1708-1715.
    CrossrefPubMedGoogle Scholar
  • 90 Hjortoe GM, Petersen LC, Albrektsen T. et al Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration. Blood 2004; 103: 3029-3037.
    CrossrefPubMedGoogle Scholar
  • 91 Golino P, Ragni M, Cirillo P. et al Recombinant human, active site-blocked factor VIIa reduces infarct size and no-reflow phenomenon in rabbits. Am J Physiol Heart Circ Physiol 2000; 278: H1507-1516.
    CrossrefPubMedGoogle Scholar
  • 92 Loubele ST, Spek CA, Leenders P. et al Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in mice. J Thromb Haemost 2009; 07: 290-298.
    CrossrefPubMedGoogle Scholar
  • 93 Olanders K, Borjesson A, Zhao X. et al Effects of anticoagulant treatment on intestinal ischaemia and reperfusion injury in rats. Acta Anaesthesiol Scand 2005; 49: 517-524.
    CrossrefPubMedGoogle Scholar
  • 94 Sevastos J, Kennedy SE, Davis DR. et al Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood 2007; 109: 577-583.
    CrossrefPubMedGoogle Scholar
  • 95 Erlich JH, Boyle EM, Labriola J. et al Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol 2000; 157: 1849-1862.
    CrossrefPubMedGoogle Scholar
  • 96 Koudsi B, Chatman DM, Ballinger BA. et al Tissue factor pathway inhibitor protects the ischemic spinal cord. J Surg Res 1996; 63: 174-178.
    CrossrefPubMedGoogle Scholar
  • 97 Ushigome H, Sano H, Okamoto M. et al The role of tissue factor in renal ischemic reperfusion injury of the rat. J Surg Res 2002; 102: 102-109.
    CrossrefPubMedGoogle Scholar
  • 98 Schoots IG, Levi M, van Vliet AK. et al Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats. Crit Care Med 2004; 32: 1375-1383.
    CrossrefPubMedGoogle Scholar
  • 99 Ozden A, Sarioglu A, Demirkan NC. et al Antithrombin III reduces renal ischemia-reperfusion injury in rats. Res Exp Med (Berl) 2001; 200: 195-203.
    PubMedGoogle Scholar
  • 100 Taylor Jr FB, Emerson Jr TE, Jordan R. et al Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988; 26: 227-235.
    PubMedGoogle Scholar
  • 101 Taylor Jr FB, Chang A, Esmon CT. et al Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925.
    CrossrefPubMedGoogle Scholar
  • 102 Taylor Jr FB. Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. Prog Clin Biol Res 1994; 388: 175-194.
    PubMedGoogle Scholar
  • 103 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.
    CrossrefPubMedGoogle Scholar
  • 104 Jilma B, Marsik C, Mayr F. et al Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans. Clin Pharmacol Ther 2002; 72: 403-410.
    CrossrefPubMedGoogle Scholar
  • 105 Warren BL, Eid A, Singer P. et al Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
    CrossrefPubMedGoogle Scholar
  • 106 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. J Am Med Assoc 2003; 290: 238-247.
    CrossrefPubMedGoogle Scholar