Semin Vasc Med 2003; 03(2): 193-198
DOI: 10.1055/s-2003-40677
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Role of the Tissue Factor-Thrombin Pathway in Cardiac Ischemia-Reperfusion Injury

Nigel Mackman
  • Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, CA
Further Information

Publication History

Publication Date:
18 July 2003 (online)


This article focuses on the role of the tissue factor (TF)-thrombin pathway in cardiac ischemia-reperfusion (I/R) injury. We and others have used rabbit models of cardiac I/R injury to show that anti-TF therapy prevents the transient decrease in regional myocardial blood flow, reduces platelet and fibrin(ogen) accumulation, and reduces infarct size. At present, the mechanism by which TF-initiated coagulation contributes to myocardial injury is not established. Inhibition of TF may decrease intravascular fibrin deposition and thrombosis. However, immunohistochemical studies demonstrated that fibrin deposition was predominantly within the myocardium and depletion of fibrinogen did not reduce infarct size. In contrast, inhibition of thrombin reduced infarct size to a similar extent as anti-TF therapy. We propose that the TF-thrombin pathway may contribute to myocardial injury by an additional mechanism that is not dependent on fibrin deposition but involves activation of protease activated receptor 1 (PAR-1) on vascular endothelial cells and cardiac myocytes. Anti-TF therapy would inhibit both thrombin-dependent fibrin deposition and thrombin-dependent PAR-1 signaling.


  • 1 Bolli R. Oxygen-derived free radicals and myocardial reperfusion injury: an overview.  Cardiovasc Drugs Ther . 1991;  5 249-268
  • 2 Homeister J W, Satoh P, Kilgore K S, Luchessi B R. Effects of complement activation in the isolated heart. Role of the terminal complement components.  Circ Res . 1992;  71 303-319
  • 3 Entman M L, Smith W C. Postreperfusion inflammation: a model for reaction to injury.  Cardiovasc Dis . 1994;  28 1301-1311
  • 4 Jordan J E, Zhao Z Q, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury.  Cardiovasc Res . 1999;  43 860-878
  • 5 Entman M L, Michael L, Rossen R D. Inflammation in the course of early myocardial ischemia.  FASEB J . 1991;  5 2529-2537
  • 6 Herskowitz A, Choi S, Ansari A A, Wesselingh S. Cytokine mRNA expression in postischemic/reperfused myocardium.  Am J Pathol . 1995;  146(2) 419-428
  • 7 Matsumura K, Jeremy R W, Schaper J, Becker L C. Progression of myocardial necrosis during reperfusion of ischemic myocardium.  Circulation . 1998;  97 795-804
  • 8 Ma X L, Lefer D J, Lefer A M, Rothlein R. Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion.  Circulation . 1992;  86(3) 937-946
  • 9 Ma X L, Tsao P S, Lefer A M. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion.  J Clin Invest . 1991;  88(4) 1237-1243
  • 10 Boyle Jr M E, Kovacich J C, Hébert C A. inhibition of interleukin-8 blocks myocardial ischemia-reperfusion injury.  J Thorac Cardiovasc Surg . 1998;  116 114-121
  • 11 Harlan J M, Winn R K. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy.  Crit Care Med . 2002;  30 S214-S219
  • 12 Edgington T S, Mackman N, Brand K, Ruf W. The structural biology of expression and function of tissue factor.  Thromb Haemost . 1991;  66 67-79
  • 13 Davie E W, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation.  Biochemistry . 1991;  30 10363-10370
  • 14 Drake T A, Morrissey J H, Edgington T S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis.  Am J Pathol . 1989;  134 1087-1097
  • 15 Fleck R A, Rao L VM, Rapaport S I, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody.  Thromb Res . 1990;  57 765-781
  • 16 Coughlin S R. Thrombin signalling and protease-activated receptors.  Nature . 2000;  407 258-264
  • 17 Déry O, Corvera C U, Steinhoff M, Bunnett N W. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases.  Am J Physiol . 1998;  274 C1429-C1452
  • 18 Golino P, Ragni M, Cirillo P. Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion.  Nature Med . 1996;  2 35-40
  • 19 Erlich J H, Boyle Jr M E, Labriola J. 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
  • 20 Mrak R E, Murphy M L, Peng C F, Straub K D. Microvasculature sparing with controlled reperfusion of ischemic myocardium.  Am J Cardiovasc Pathol . 1990;  3 253-258
  • 21 Hui K Y, Haber E, Matsueda G R. Monoclonal antibodies to a synthetic fibrin-like peptide bind to human fibrin but not fibrinogen.  Science . 1983;  222 1129-1132
  • 22 Armaganian L, Kam G, Eisenberg P R, Schechtman K B, Abendschein D R. Role of tissue factor-mediated coagulation in ischemia/reperfusion-induced injury of Langendorf-perfused rabbit hearts.  Coron Artery Dis . 2000;  11 481-487
  • 23 Golino P, Ragni M, Cirillo P. Recombinant human, active site-blocked factor VII reduces infarct size and the NO-reflow phenomenon in a rabbit model of myocardial ischemia and reperfusion.  Am J Physiol Heart Circ Physiol . 2000;  278 H1507-H1516
  • 24 Gertz S D, Fallon J T, Gallo R. Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries.  Circulation . 1998;  98 580-587
  • 25 Hatton M WC, Ross B, Soutward S MR, DeReske M, Richardson M. Pretreatment of rabbits with either hirudin, ancrod, or warfarin significantly reduces the immediate uptake of fibrinogen and platelets by the deendothelialized aorta wall after balloon-catheter injury in vivo.  Arterioscler Thromb Vasc Biol . 1998;  18 816-824
  • 26 Kupatt C, Habazettl H, Hanusch P. c7E3Fab reduces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury.  Arterioscler Thromb Vasc Biol . 2000;  20 2226-2232
  • 27 Cunningham M A, Rondeau E, Chen X, Coughlin S R, Holdsworth S R, Tipping P G. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis.  J Exp Med . 2000;  191 455-461
  • 28 Broze Jr J G. Tissue factor pathway inhibitor.  Thromb Haemost . 1995;  74(1) 90-93
  • 29 Presta L, Sims P, Meng Y G. Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic.  Thromb Haemost . 2001;  85 379-389
  • 30 Kelley R F, Refino C J, O'Connell M P. A soluble tissue factor mutant is a selective anticoagulant and antithrombotic agent.  Blood . 1997;  89 3219-3227
  • 31 Nicolaisen E M, Kristensen H, Kristensen A, Hedner U. Evaluation of potential antigenicity of active-site-inhibited recombinant human FVIIa (FFR-rFVIIa) in an immune-tolerant rat model.  Thromb Haemost . 2002;  87 836-839
  • 32 Lee A, Agnelli G, Buller H. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement.  Circulation . 2001;  104 74-78
  • 33 Jang I-K, Gold H K, Leinbach R C, Fallon J T, Collen D, Wilcox J N. Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.  Arterioscler Thromb . 1992;  12 948-954
  • 34 Pawashe A B, Golino P, Ambrosio G. A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.  Circ Res . 1994;  74 56-63
  • 35 Ragni M, Cirillo P, Pascucci I. Monoclonal antibody against tissue factor shortens tissue plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis.  Circulation . 1996;  93 1913-1918
  • 36 Jang Y, Guzman L A, Lincoff A M. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model.  Circulation . 1995;  92(10) 3041-3050
  • 37 Oltrona L, Speidel C M, Recchia D, Wickline S A, Eisenberg P R, Abendschein D R. Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury in minipigs.  Circulation . 1997;  96 646-652
  • 38 Abraham E, Reinhart K, Svoboda P. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.  Crit Care Med . 2001;  29 2081-2089