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Semin Vasc Med 2003; 03(2): 205-214
DOI: 10.1055/s-2003-40679
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Targeting Tissue Factor as an Antithrombotic Strategy

Paolo Golino, Giovanni Cimmino
  • Division of Cardiology, Seconda Università di Napoli, Naples, Italy
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Publication History

Publication Date:
18 July 2003 (online)

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ABSTRACT

It is generally accepted that the initial event in coagulation and intravascular thrombus formation is the exposure of cell-surface protein, such as tissue factor (TF). TF is exposed to the flowing blood as a consequence of vascular injury induced, for instance, by PTCA, or by spontaneous rupture of an atherosclerotic plaque. Expression of TF may also be induced in monocytes and endothelial cells in several conditions such as sepsis and cancer, causing a more generalized activation of clotting. In addition to its essential role in hemostasis, TF may be also implicated in several pathophysiological processes, such as intracellular signaling, cell proliferation, and inflammation. For all these reasons, TF has been the subject of intense research focus. Many experimental studies have demonstrated that inhibition of TF:factor VIIa procoagulant activity is a powerful inhibitor of in vivo thrombosis and that this approach usually results in a less-pronounced bleeding tendency compared with other “more classical” antithrombotic interventions. Alternative approaches may be represented by antibodies directed against TF, by transfection of the arterial wall with natural inhibitors of the TF:factor VIIa complex, such as the TF pathway inhibitor, or with catalytic RNA (ribozyme), which could inhibit the expression of the TF protein by the disruption of cellular TF mRNA. All these approches seem particulary attractive because they may result in complete inhibition of local thrombosis without incurring potentially harmful systemic effects. Further studies are warranted to determine the efficacy and safety of such approaches in patients.

KEYWORDS

Tissue factor - coagulation - intracellular signaling - tissue factor pathway inhibitor - inactivated factor VII

REFERENCES

  • 1 Dahlbäch B. Blood coagulation.  Lancet . 2000;  355 1627-1632
    CrossrefPubMedGoogle Scholar
  • 2 Morrissey J H, Macik B G, Neuenschwander P F, Comp P C. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.  Blood . 1993;  81 734-744
    Google Scholar
  • 3 Nemerson V, Repke D. Tissue factor accelerates the activation of coagulation factor VII: the role of a high functional coagulation cofactor.  Thromb Res . 1985;  40 351-358
    Google Scholar
  • 4 Rao L V, Rapaport S I. Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation.  Proc Natl Acad Sci USA . 1988;  85 6687-6691
    PubMedGoogle Scholar
  • 5 Radcliffe R, Nemerson V. Activation and control of factor VII by activated factor X and thrombin: isolation and characterization of a single chain form of factor VII.  J Biol Chem . 1975;  250 388-395
    PubMedGoogle Scholar
  • 6 Kisiel W, Fujikawa K, Davie E W. Activation of bovine factor VII (proconverlin) by factor XIIa (activated Hageman factor).  Biochemistry . 1977;  16 4189-4194
    CrossrefPubMedGoogle Scholar
  • 7 Seligsohn U, Osterud B, Brown S F, Griffin J H, Rapaport S I. Activation of human factor VII in plasma and in purified systems: roles of activated factor IX, kallikrein, and activated factor XII.  J Clin Invest . 1979;  64 1056
    PubMedGoogle Scholar
  • 8 Masys D R, Bajaj S P, Rapaport S I. Activation of human factor VII by activated factors IX and X.  Blood . 1982;  60 1143-1150
    PubMedGoogle Scholar
  • 9 Tsujioka H, Suehiro A, Kakishita E. Activation of coagulation factor VII by tissue-type plasminogen activator.  Am J Hematol . 1999;  61 34-39
    CrossrefPubMedGoogle Scholar
  • 10 Nakagaki T, Foster D C, Berkner K L, Kisiel W. Initiation of the extrinsic pathway of blood coagulation: evidence for the tissue factor dependent autoactivation of human coagulation factor VII.  Biochemistry . 1991;  30 10819-10824
    CrossrefPubMedGoogle Scholar
  • 11 Neuenschwander P F, Fiore M M, Morrissey J H. Factor VII autoactivation proceeds via interaction of distinct protease-cofactor and zymogen-cofactor complexes. Implications of a two-dimensional enzyme kinetic mechanism.  J Biol Chem . 1993;  268 21489-21492
    PubMedGoogle Scholar
  • 12 Sato Y, Asada Y, Marutsuka K. Tissue factor induces migration of cultured aortic smooth muscle cells.  Thromb Haemost . 1996;  75 389-392
    PubMedGoogle Scholar
  • 13 McNamara C A, Sarembock I J, Backhuber B G. Thrombin and vascular smooth muscle cells proliferation: implication for atherosclerosis and restenosis.  Semin Thromb Hemost . 1996;  22 139-144
    PubMedGoogle Scholar
  • 14 Broze Jr J G, Leykam J E, Schwartz B D, Miletich J P. Purification of human brain tissue factor.  J Biol Chem . 1985;  260 10917-10920
    PubMedGoogle Scholar
  • 15 Paborsky L R, Tate K M, Harris R J. Purification of recombinant human tissue factor.  Biochemistry . 1989;  28 8072-8077
    CrossrefPubMedGoogle Scholar
  • 16 Bazan J F. Structural design and molecular evolution of a cytokine receptor superfamily.  Proc Natl Acad Sci USA . 1990;  87 6934-6938
    PubMedGoogle Scholar
  • 17 Paborsky L R, Caras L W, Fisher K L, Gorman C M. Lipid association, but not the transmembrane domain, is required for tissue factor activity. Substitution of the transmembrane domain with a phosphatidylinositol anchor.  J Biol Chem . 1991;  266 21911-21916
    PubMedGoogle Scholar
  • 18 Pedersen A H, Nordfang O, Norris F, Willbeig F C, Christensen P M, Mueller K B. Recombinant human extrinsic pathway inhibitor. Production, isolation, and characterization of its inhibitory activity on tissue factor-initiated coagulation reactions.  J Biol Chem . 1990;  265 16786-16793
    PubMedGoogle Scholar
  • 19 Ruf W, Rehemtulla A, Morrissey J H, Edgington T S. Phospholipid-independent and -dependent interactions required for tissue factor receptor and cofactor function.  J Biol Chem . 1991;  266 2158-2166
    PubMedGoogle Scholar
  • 20 Payne M A, Neuenschwander P F, Johnson A E, Morrissey J H. Effect of soluble tissue factor on the kinetic mechanism of factor VIIa: enhancement of p-guanidinobenzoate substrate hydrolysis.  Biochemistry . 1996;  35 7100-7106
    CrossrefPubMedGoogle Scholar
  • 21 Huang Q L, Neuenschwander P F, Rezaie A R, Monrissey J H. Substrate recognition by tissue factor-factor VIta-evidence for interaction of residues Lys 165 and Lys 166 of tissue factor with the 4-carboxyglutamate-rich domain of factor X.  J Biol Chem . 1996;  271 21752-21757
    CrossrefPubMedGoogle Scholar
  • 22 Maynard J R, Dreyer B E, Stemerman M B, Pitlick F A. Tissue-factor coagulant activity of cultured human endothelial and smooth muscle cells and fibroblasts.  Blood . 1977;  50 387-396
    PubMedGoogle Scholar
  • 23 Drake T A, Rut W, Morrissey J H, Edgingtun T S. Functional tissue factor is entirely cell surface expressed on LPS stimulated human blood monocytes and a constitutively tissue factor producing neoplastic cell line.  J Cell Biol . 1989;  109 389-395
    CrossrefPubMedGoogle Scholar
  • 24 Bach R, Rifkin D B. Expression of tissue factor procoagulant activity: regulation by cytosolic calcium.  Proc Natl Acad Sci USA . 1990;  87 6995-6999
    PubMedGoogle Scholar
  • 25 Balasubramanian V, Grabowsky E, Bini A, Nemerson Y. Platelets, circulating tissue factor, and fibrin colocalize ex vivo thrombi: real time fluorescence images of thrombus formation and propagation under defined flow conditions.  Blood . 2002;  100(8) 2787-2792
    CrossrefPubMedGoogle Scholar
  • 26 Giesen P L, Rauch U, Bohrmann B. Blood-born tissue factor: another view of thrombosis.  Proc Natl Acad Sci USA . 1999;  96 2311-2315
    Google Scholar
  • 27 Wilcox J N, Smith K M, Schwartz S, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.  Proc Natl Acad Sci USA . 1989;  86 2839-2843
    PubMedGoogle Scholar
  • 28 Jander S, Sitzer M, Wendt A. Expression of tissue factor in high-grade carotid stenosis: association with plaque destabilization.  Stroke . 2001;  32 850-854
    PubMedGoogle Scholar
  • 29 Toschi V, Gallo R, Lettino M. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.  Circulation . 1997;  95 594-599
    CrossrefPubMedGoogle Scholar
  • 30 Annex B H, Denning S M, Channon K M, Sketch M H, Stack R S, Morrisey J H, Peters K G. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes.  Circulation . 1995;  91 619-622
    PubMedGoogle Scholar
  • 31 Ardissino D, Merlini P A, Ariens R, Coppola R, Bramucci E, Mannucci P M. Tissue-factor antigen and activity in human coronary atherosclerotic plaques.  Lancet . 1997;  349 769-771
    CrossrefPubMedGoogle Scholar
  • 32 Ragni M, Golino P, Cirillo P. Endogenous tissue factor pathway inhibitor modulates thrombus formation in an in vivo model of rabbit carotid artery stenosis and endothelial injury.  Circulation . 2000;  102 113-117
    CrossrefPubMedGoogle Scholar
  • 33 Ravera A, Golino P, Piscione F. Activation of tissue factor-dependent coagulation pathway in patients with acute myocardial infarction.  J Am Coll Cardiol . 2000;  35 (suppl A) 406
    PubMedGoogle Scholar
  • 34 Soejima H, Ogawa H, Yasue H. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina.  Circulation . 1999;  99 2908-2913
    CrossrefPubMedGoogle Scholar
  • 35 Soejima H, Ogawa H, Yasue H. Plasma tissue factor pathway inhibitor and tissue factor antigen levels after administration of heparin in patients with angina pectoris.  Thromb Res . 1999;  93 17-25
    CrossrefPubMedGoogle Scholar
  • 36 Asakura H, Kamikubo Y, Goto A. Role of tissue factor in disseminated intravascular coagulation.  Thromb Res . 1995;  80 217-224
    CrossrefPubMedGoogle Scholar
  • 37 Amengual O, Atsumi T, Khamashta M A, Hughes G R. The role of tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome.  Thromb Haemost . 1998;  79 276-281
    PubMedGoogle Scholar
  • 38 Key N S, Slungaard A, Dandelet L. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease.  Blood . 1998;  91 4216-4223
    PubMedGoogle Scholar
  • 39 Levi M, ten Cate H, van der Poll T, Van Deventer J S. Pathogenesis of disseminated intravascular coagulation in sepsis.  JAMA . 1993;  270 975-979
    CrossrefPubMedGoogle Scholar
  • 40 Fernandez P M, Rickles F R. Tissue factor and angiogenesis in cancer.  Curr Opin Hematol . 2002;  9(5) 401-406
    CrossrefPubMedGoogle Scholar
  • 41 Bokawera M I, Morrissey J H, Tarkowski A. Tissue factor as a proinflammatory agent.  Arthritis Res . 2002;  4(3) 190-195
    CrossrefPubMedGoogle Scholar
  • 42 Coughlin S R. Sol Sherry lecture in thrombosis: how thrombin `talks' to cells: molecular mechanisms and roles in vivo.  Arterioscler Thromb Vase Biol . 1998;  18 514-518
    PubMedGoogle Scholar
  • 43 Camerer E, Huang W, Coughlm S R. 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
  • 44 Petersen L C, Thastrup O, Hagel G. Exclusion of known protease activated receptors in factor VIIa-induced signal transduction.  Thromb Haemost . 2000;  83 571-576
    PubMedGoogle Scholar
  • 45 Camerer E, Rottingen J A, Gjernes E, Larsen K, Skartlien A H, Iversen J G. Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-l gene.  J Biol Chem . 1999;  274 32225-32233
    CrossrefPubMedGoogle Scholar
  • 46 Taniguchi T, Kakkar A K, Tuddenham E GD, Williamson R CN, Leinoine N R. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.  Cancer Res . 1998;  58 4461-4467
    PubMedGoogle Scholar
  • 47 Prydz H. A new paradigm for blood coagulation research.  Thromb Haemost . 2000;  83 520-522
    PubMedGoogle Scholar
  • 48 Broze Jr J G. Tissue factor pathway inhibitor.  Thromb Haemost . 1995;  74 90-93
    PubMedGoogle Scholar
  • 49 Broze Jr J G. Tissue factor pathway inhibitor and the current concept of blood coagulation.  Blood Coagul Fibrinolysis . 1995;  6 S7-S13
    PubMedGoogle Scholar
  • 50 Hamik A, Setiadi H, Bo G J, McEver R P, Morrissey J H. Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein.  J Biol Chem . 1999;  274 4962-4969
    CrossrefPubMedGoogle Scholar
  • 51 Sevinsky J R, Rao L VM, Rut 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
    Google Scholar
  • 52 Ott I, Miyagi Y, Miyazaki K, Heeb M J, Mueller B M, Rao L VM. Reversible regulation of tissue factor-induced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor.  Arterioscler Thromb Vase Biol . 2000;  20 874-882
    CrossrefPubMedGoogle Scholar
  • 53 Haskel E J, Torr S R, Day K C. Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor.  Circulation . 1991;  84 821-827
    CrossrefPubMedGoogle Scholar
  • 54 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 3041-3050
    PubMedGoogle Scholar
  • 55 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
    CrossrefPubMedGoogle Scholar
  • 56 St Pierre J, Yang L Y, Tamirisa K. 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 2263-2268
    Google Scholar
  • 57 Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis.  Crit Care Med . 2000;  28 831-833
    PubMedGoogle Scholar
  • 58 Golino P, Cirillo P, Calabrò P, Ragni M, D'Andrea D, Chiariello P. Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries.  J Am Coll Cardiol . 2001;  38 569-576
    CrossrefPubMedGoogle Scholar
  • 59 Zoldhelyi P, Chen Z Q, Shelat H S, McNatt J M, Willereson J T. Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries.  Proc Natl Acad Sci USA . 2000;  98 4078-4083
    PubMedGoogle Scholar
  • 60 Atsuchi N, Nishida T, Marutsuka K, Asada Y, Kamikubo Y, Takeshita A, Ueno H. Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries.  Circulation . 2001;  103 570-575
    PubMedGoogle Scholar
  • 61 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
    PubMedGoogle Scholar
  • 62 Ragni M, Cirillo P, Pascucci I. A 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 1913-1920
    PubMedGoogle Scholar
  • 63 Petersen L C, Sprecher C A, Foster D C, Blumberg H, Hamamoto T, Kisiel W. Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor.  Biochemistry . 1996;  35 266-272
    Google Scholar
  • 64 Kondo S, Kisiel W. Regulation of factor VIIa in plasma: evidence that antithrombin III is the sole plasma proteinase inhibitor of human factor VIIa.  Thromb Res . 1987;  46 325-331
    CrossrefPubMedGoogle Scholar
  • 65 Girard T J, MacPhail L A, Likert K M, Novutny W F, Miletich J P, Bruze Jr J G. Inhibition of factor VIIa-tissue factor coagulation activity by a hybrid protein.  Science . 1990;  248 1421-1424
    PubMedGoogle Scholar
  • 66 Dennis M S, Lazarus R A. Kunitz domain inhibitors of tissue factor-factor VIIa. II. Potent and specific inhibitors by competitive phage selection.  J Biol Chem . 1994;  269 22137-22144
    PubMedGoogle Scholar
  • 67 Stassen J M, Lambeir A-M, Manhyssens G, Ripka W C, Nystrom A, Sixma J J. Characterisation of a novel series of aprotinin-derived anticoagulants. I. In vitro and pharmacological properties.  Thromb Haemost . 1995;  74 646-654
    PubMedGoogle Scholar
  • 68 Lee A, Agnelli G, Buller H. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in the prevention of post-operative venous thromboembolism in patients undergoing total knee replacement.  Circulation . 2000;  104 74-78
    PubMedGoogle Scholar
  • 69 Harker L A, Hanson S R, Wilcox J N, Kelly A B. Antithrombotic and anti-lesion benefits without hemorrhagic risks by inhibiting tissue factor pathway.  Haemostasis . 1996;  26 76-82
    PubMedGoogle Scholar
  • 70 Himber B, Kirebbofer D, Riederer M, Tschopp T B, Steiner B, Roux S P. Dissociation of antithrombotic effect and bleeding time prolongation in rabbits by inhibiting tissue factor function.  Thromb Haemost . 1997;  78 1142-1149
    PubMedGoogle Scholar
  • 71 Harker L A. Therapeutic inhibition of thrombin activities, receptors, and production.  Hematol Oncol Clin North Am . 1998;  12 1211-1230
    PubMedGoogle Scholar
  • 72 Golino P, Ragni M, Cirillo P. Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.  Circ Res . 1998;  82 39-46
    PubMedGoogle Scholar
  • 73 Golino P, Cirillo P, D'Andrea D. Long-term antithrombotic effects of human recombinant, active site-blocked factor VIIa in a chronic model of intravascular thrombosis (abstract).  Circulation . 1999;  98 I727
    PubMedGoogle Scholar
  • 74 Rao L VM, Ezban M. Active site-blocked activated factor VII as an effective antithrombotic agent: mechanism of action.  Blood Coagul Fibrinolysis . 2000;  11 S135-S143
    PubMedGoogle Scholar
  • 75 Marschall P, Thomson J B, Eckstein F. Inhibition of gene expression with ribozyme.  Cell Mol Neurobiol . 1994;  14 523-538
    PubMedGoogle Scholar
  • 76 Cech T R. Self-splicing of group I introns.  Annu Rev Biochem . 1990;  59 543-568
    CrossrefPubMedGoogle Scholar
  • 77 Symons R H. Small catalytic RNAs.  Annu Rev Biochem . 1992;  61 641-671
    CrossrefPubMedGoogle Scholar
  • 78 Kiehntopf M, Esquivel E L, Brach M A. Ribozyme: biology, biochemistry, and implication for clinical medicine.  J Mol Med . 1995;  73 65-71
    CrossrefPubMedGoogle Scholar
  • 79 Cavusoglu E, Chen I, Rappaport J, Marmur J D. Inhibition of tissue factor gene induction and activity using a hairpin ribozyme.  Circulation . 2002;  105(19) 2282-2287
    CrossrefPubMedGoogle Scholar
  • 80 Feldman L J, Steg G. Optimal techniques for arterial gene transfer.  Cardiovasc Res . 1997;  35 391-404
    CrossrefPubMedGoogle Scholar
  • 81 Brieger D, Topol E. Local drug delivery systems and prevention of restenosis.  Cardiovasc Res . 1997;  35 405-413
    CrossrefPubMedGoogle Scholar
  • 82 Nabel E G. Gene therapy for cardiovascular disease.  Circulation . 1995;  91 541-548
    CrossrefPubMedGoogle Scholar
  • 83 Miller D G, Adam M A, Miller A D. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection.  Mol Cell Biol . 1990;  10 4239-4242
    PubMedGoogle Scholar