Tissue factor in atherosclerosis and atherothrombosis

  • Steven P. Grover
    UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Search for articles by this author
  • Nigel Mackman
    Corresponding author. Department of Medicine, 116 Manning Drive 8004B Mary Ellen Jones Building, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
    UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Search for articles by this author


      • Tissue Factor (TF) is highly expressed in human atherosclerotic plaques.
      • TF pathway inhibitor regulates atherosclerotic plaque development.
      • TF driven activation of coagulation is critical for atherothrombosis.


      Atherosclerosis is a chronic inflammatory disease that is characterized by the formation of lipid rich plaques in the wall of medium to large sized arteries. Atherothrombosis represents the terminal manifestation of this pathology in which atherosclerotic plaque rupture or erosion triggers the formation of occlusive thrombi. Occlusion of arteries and resultant tissue ischemia in the heart and brain causes myocardial infarction and stroke, respectively. Tissue factor (TF) is the receptor for the coagulation protease factor VIIa, and formation of the TF:factor VIIa complex triggers blood coagulation. TF is expressed at high levels in atherosclerotic plaques by both macrophage-derived foam cells and vascular smooth muscle cells, as well as extracellular vesicles derived from these cells. Importantly, TF mediated activation of coagulation is critically important for arterial thrombosis in the setting of atherosclerotic disease. The major endogenous inhibitor of the TF:factor VIIa complex is TF pathway inhibitor 1 (TFPI-1), which is also present in atherosclerotic plaques. In mouse models, increased or decreased expression of TFPI-1 has been found to alter atherosclerosis. This review highlights the contribution of TF-dependent activation of coagulation to atherthrombotic disease.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Grover S.P.
        • Mackman N.
        Tissue factor: an essential mediator of hemostasis and trigger of thrombosis.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 709-725
        • Schecter A.D.
        • Giesen P.L.
        • Taby O.
        • et al.
        Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation.
        J. Clin. Invest. 1997; 100: 2276-2285
        • 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
        • Lupu C.
        • Westmuckett A.D.
        • Peer G.
        • et al.
        Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis.
        Am. J. Pathol. 2005; 167: 1161-1172
        • Hoffman M.
        • Colina C.M.
        • McDonald A.G.
        • et al.
        Tissue factor around dermal vessels has bound factor VII in the absence of injury.
        J. Thromb. Haemostasis. 2007; 5: 1403-1408
        • Egorina E.M.
        • Sovershaev M.A.
        • Bjørkøy G.
        • et al.
        Intracellular and surface distribution of monocyte tissue factor: application to intersubject variability.
        Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1493-1498
        • Butenas S.
        • Mann K.G.
        Active tissue factor in blood?.
        Nat. Med. 2004; 10: 1155-1156
        • Butenas S.
        • Bouchard B.A.
        • Brummel-Ziedins K.E.
        • et al.
        Tissue factor activity in whole blood.
        Blood. 2005; 105: 2764-2770
        • Mackman N.
        • Brand K.
        • Edgington T.S.
        Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites.
        J. Exp. Med. 1991; 174: 1517-1526
        • Parry G.C.
        • Mackman N.
        NF-κB mediated transcription in human monocytic cells and endothelial cells.
        Trends Cardiovasc. Med. 1998; 8: 138-142
        • Wilcox J.N.
        • Smith K.M.
        • Schwartz S.M.
        • et al.
        Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.
        Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2839-2843
        • Cimmino G.
        • D'Amico C.
        • Vaccaro V.
        • et al.
        The missing link between atherosclerosis, inflammation and thrombosis: is it tissue factor?.
        Expert Rev. Cardiovasc Ther. 2011; 9: 517-523
        • Annex B.H.
        • Denning S.M.
        • Channon K.M.
        • et al.
        Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes.
        Circulation. 1995; 91: 619-622
        • Marmur J.D.
        • Thiruvikraman S.V.
        • Fyfe B.S.
        • et al.
        Identification of active tissue factor in human coronary atheroma.
        Circulation. 1996; 94: 1226-1232
        • Ardissino D.
        • Merlini P.A.
        • Ariëns R.
        • et al.
        Tissue-factor antigen and activity in human coronary atherosclerotic plaques.
        Lancet. 1997; 349: 769-771
        • Hatakeyama K.
        • Asada Y.
        • Marutsuka K.
        • et al.
        Localization and activity of tissue factor in human aortic atherosclerotic lesions.
        Atherosclerosis. 1997; 133: 213-219
        • Kaikita K.
        • Ogawa H.
        • Yasue H.
        • et al.
        Tissue factor expression on macrophages in coronary plaques in patients with unstable angina.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2232-2237
        • Landers S.C.
        • Gupta M.
        • Lewis J.C.
        Ultrastructural localization of tissue factor on monocyte-derived macrophages and macrophage foam cells associated with atherosclerotic lesions.
        Virchows Arch. 1994; 425: 49-54
        • Colli S.
        • Lalli M.
        • Risè P.
        • et al.
        Increased thrombogenic potential of human monocyte-derived macrophages spontaneously transformed into foam cells.
        Thromb. Haemostasis. 1999; 81: 576-581
        • Lesnik P.
        • Rouis M.
        • Skarlatos S.
        • et al.
        Uptake of exogenous free cholesterol induces upregulation of tissue factor expression in human monocyte-derived macrophages.
        Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10370-10374
        • Schwartz B.S.
        • Levy G.A.
        • Curtiss L.K.
        • et al.
        Plasma lipoprotein induction and suppression of the generation of cellular procoagulant activity in vitro: two procoagulant activities are produced by peripheral blood mononuclear cells.
        J. Clin. Invest. 1981; 67: 1650-1658
        • Wada H.
        • Kaneko T.
        • Wakita Y.
        • et al.
        Effect of lipoproteins on tissue factor activity and PAI-II antigen in human monocytes and macrophages.
        Int. J. Cardiol. 1994; 47: S21-S25
        • Lewis J.C.
        • Bennett-Cain A.L.
        • DeMars C.S.
        • et al.
        Procoagulant activity after exposure of monocyte-derived macrophages to minimally oxidized low density lipoprotein. Co-localization of tissue factor antigen and nascent fibrin fibers at the cell surface.
        Am. J. Pathol. 1995; 147: 1029-1040
        • Meisel S.R.
        • Xu X.P.
        • Edgington T.S.
        • et al.
        Dose-dependent modulation of tissue factor protein and procoagulant activity in human monocyte-derived macrophages by oxidized low density lipoprotein.
        J. Atherosclerosis Thromb. 2011; 18: 596-603
        • Brand K.
        • Eisele T.
        • Kreusel U.
        • et al.
        Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1901-1909
        • Drake T.A.
        • Hannani K.
        • Fei H.H.
        • et al.
        Minimally oxidized low-density lipoprotein induces tissue factor expression in cultured human endothelial cells.
        Am. J. Pathol. 1991; 138: 601-607
        • Cimmino G.
        • Cirillo P.
        • Conte S.
        • et al.
        Oxidized low-density lipoproteins induce tissue factor expression in T-lymphocytes via activation of lectin-like oxidized low-density lipoprotein receptor-1.
        Cardiovasc. Res. 2019; 116 (In Press): 1125-1135
        • Ferro D.
        • Basili S.
        • Alessandri C.
        • et al.
        Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia.
        Lancet. 1997; 350: 1222
        • Sanguigni V.
        • Ferro D.
        • Pignatelli P.
        • et al.
        CD40 ligand enhances monocyte tissue factor expression and thrombin generation via oxidative stress in patients with hypercholesterolemia.
        J. Am. Coll. Cardiol. 2005; 45: 35-42
        • Owens A.P.
        • Passam F.H.
        • Antoniak S.
        • et al.
        Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.
        J. Clin. Invest. 2012; 122: 558-568
        • Bruni F.
        • Puccetti L.
        • Pasqui A.L.
        • et al.
        Different effect induced by treatment with several statins on monocyte tissue factor expression in hypercholesterolemic subjects.
        Clin. Exp. Med. 2003; 3: 45-53
        • Hisada Y.
        • Alexander W.
        • Kasthuri R.
        • et al.
        Measurement of microparticle tissue factor activity in clinical samples: a summary of two tissue factor-dependent FXa generation assays.
        Thromb. Res. 2016; 139: 90-97
        • Mallat Z.
        • Hugel B.
        • Ohan J.
        • et al.
        Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity.
        Circulation. 1999; 99: 348-353
        • Leroyer A.S.
        • Isobe H.
        • Lesèche G.
        • et al.
        Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques.
        J. Am. Coll. Cardiol. 2007; 49: 772-777
        • Caplice N.M.
        • Mueske C.S.
        • Kleppe L.S.
        • et al.
        Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity.
        Circulation. 1998; 98: 1051-1057
        • Crawley J.
        • Lupu F.
        • Westmuckett A.D.
        • et al.
        Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1362-1373
        • Basavaraj M.G.
        • Sovershaev M.A.
        • Egorina E.M.
        • et al.
        Circulating monocytes mirror the imbalance in TF and TFPI expression in carotid atherosclerotic plaques with lipid-rich and calcified morphology.
        Thromb. Res. 2012; 129: e134-141
        • Petersen L.C.
        • Sprecher C.A.
        • Foster D.C.
        • et al.
        Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor.
        Biochemistry. 1996; 35: 266-272
        • Crawley J.T.
        • Goulding D.A.
        • Ferreira V.
        • et al.
        Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 218-224
        • Getz G.S.
        • Reardon C.A.
        Animal models of atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2012; 32: 1104-1115
        • Kato K.
        • Elsayed Y.A.
        • Namoto M.
        • et al.
        Enhanced expression of tissue factor activity in the atherosclerotic aortas of cholesterol-fed rabbits.
        Thromb. Res. 1996; 82: 335-347
        • Yamashita A.
        • Matsuda S.
        • Matsumoto T.
        • et al.
        Thrombin generation by intimal tissue factor contributes to thrombus formation on macrophage-rich neointima but not normal intima of hyperlipidemic rabbits.
        Atherosclerosis. 2009; 206: 418-426
        • Aikawa M.
        • Voglic S.J.
        • Sugiyama S.
        • et al.
        Dietary lipid lowering reduces tissue factor expression in rabbit atheroma.
        Circulation. 1999; 100: 1215-1222
        • Bea F.
        • Blessing E.
        • Shelley M.I.
        • et al.
        Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin-mediated inhibition of Egr-1 expression and activation.
        Atherosclerosis. 2003; 167: 187-194
        • Tilley R.E.
        • Pedersen B.
        • Pawlinski R.
        • et al.
        Atherosclerosis in mice is not affected by a reduction in tissue factor expression.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 555-562
        • Westrick R.J.
        • Bodary P.F.
        • Xu Z.
        • et al.
        Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice.
        Circulation. 2001; 103: 3044-3046
        • Xiao J.
        • Jin K.
        • Wang J.
        • et al.
        Conditional knockout of TFPI-1 in VSMCs of mice accelerates atherosclerosis by enhancing AMOT/YAP pathway.
        Int. J. Cardiol. 2017; 228: 605-614
        • Pan S.
        • White T.A.
        • Witt T.A.
        • et al.
        Vascular-directed tissue factor pathway inhibitor overexpression regulates plasma cholesterol and reduces atherosclerotic plaque development.
        Circ. Res. 2009; 105: 713-720
        • Chen D.
        • Xia M.
        • Hayford C.
        • et al.
        Expression of human tissue factor pathway inhibitor on vascular smooth muscle cells inhibits secretion of macrophage migration inhibitory factor and attenuates atherosclerosis in ApoE-/- mice.
        Circulation. 2015; 131: 1350-1360
        • Pan J.
        • Ma D.
        • Sun F.
        • et al.
        Over-expression of TFPI-2 promotes atherosclerotic plaque stability by inhibiting MMPs in apoE-/- mice.
        Int. J. Cardiol. 2013; 168: 1691-1697
        • Hong J.
        • Liu R.
        • Chen L.
        • et al.
        Conditional knockout of tissue factor pathway inhibitor 2 in vascular endothelial cells accelerates atherosclerotic plaque development in mice.
        Thromb. Res. 2016; 137: 148-156
        • Sato Y.
        • Asada Y.
        • Marutsuka K.
        • et al.
        Tissue factor induces migration of cultured aortic smooth muscle cells.
        Thromb. Haemostasis. 1996; 75: 389-392
        • Cirillo P.
        • Calì G.
        • Golino P.
        • et al.
        Tissue factor binding of activated factor VII triggers smooth muscle cell proliferation via extracellular signal-regulated kinase activation.
        Circulation. 2004; 109: 2911-2916
        • Ott I.
        • Weigand B.
        • Michl R.
        • et al.
        Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38.
        Circulation. 2005; 111: 349-355
        • Pyo R.T.
        • 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. Haemostasis. 2004; 92: 451-458
        • Marutsuka K.
        • Hatakeyama K.
        • Sato Y.
        • et al.
        Protease-activated receptor 2 (PAR2) mediates vascular smooth muscle cell migration induced by tissue factor/factor VIIa complex.
        Thromb. Res. 2002; 107: 271-276
        • Peña E.
        • Arderiu G.
        • Badimon L.
        Subcellular localization of tissue factor and human coronary artery smooth muscle cell migration.
        J. Thromb. Haemostasis. 2012; 10: 2373-2382
        • Demetz G.
        • Seitz I.
        • Stein A.
        • et al.
        Tissue Factor-Factor VIIa complex induces cytokine expression in coronary artery smooth muscle cells.
        Atherosclerosis. 2010; 212: 466-471
        • Akita K.
        • Isoda K.
        • Sato-Okabayashi Y.
        • et al.
        An interleukin-6 receptor antibody suppresses atherosclerosis in atherogenic mice.
        Front Cardiovasc. Med. 2017; 4: 84
        • Boisvert W.A.
        • Santiago R.
        • Curtiss L.K.
        • et al.
        A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice.
        J. Clin. Invest. 1998; 101: 353-363
        • Owens A.P.
        • Byrnes J.R.
        • Mackman N.
        Hyperlipidemia, tissue factor, coagulation, and simvastatin.
        Trends Cardiovasc. Med. 2014; 24: 95-98
        • Aikawa M.
        • Rabkin E.
        • Sugiyama S.
        • et al.
        An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro.
        Circulation. 2001; 103: 276-283
        • Sukhova G.K.
        • Williams J.K.
        • Libby P.
        Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1452-1458
        • Casani L.
        • Sanchez-Gomez S.
        • Vilahur G.
        • et al.
        Pravastatin reduces thrombogenicity by mechanisms beyond plasma cholesterol lowering.
        Thromb. Haemostasis. 2005; 94: 1035-1041
        • Posma J.J.
        • Grover S.P.
        • Hisada Y.
        • et al.
        Roles of coagulation proteases and PARs (Protease-Activated receptors) in mouse models of inflammatory diseases.
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: 13-24
        • Hara T.
        • Fukuda D.
        • Tanaka K.
        • et al.
        Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice.
        Atherosclerosis. 2015; 242: 639-646
        • Zhou Q.
        • Bea F.
        • Preusch M.
        • et al.
        Evaluation of plaque stability of advanced atherosclerotic lesions in apo E-deficient mice after treatment with the oral factor Xa inhibitor rivaroxaban.
        Mediat. Inflamm. 2011; 2011 (432080)
        • Samama M.M.
        • Contant G.
        • Spiro T.E.
        • et al.
        Laboratory assessment of rivaroxaban: a review.
        Thromb. J. 2013; 11: 11
        • Posthuma J.J.
        • Posma J.J.N.
        • van Oerle R.
        • et al.
        Targeting coagulation factor Xa promotes regression of advanced atherosclerosis in apolipoprotein-E deficient mice.
        Sci. Rep. 2019; 9: 3909
        • Pingel S.
        • Tiyerili V.
        • Mueller J.
        • et al.
        Thrombin inhibition by dabigatran attenuates atherosclerosis in ApoE deficient mice.
        Arch. Med. Sci. 2014; 10: 154-160
        • Lee I.O.
        • Kratz M.T.
        • Schirmer S.H.
        • et al.
        The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice.
        J. Pharmacol. Exp. Therapeut. 2012; 343: 253-257
        • Kadoglou N.P.
        • Moustardas P.
        • Katsimpoulas M.
        • et al.
        The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E-deficient mice : dabigatran etexilate and atherosclerosis.
        Cardiovasc. Drugs Ther. 2012; 26: 367-374
        • Preusch M.R.
        • Ieronimakis N.
        • Wijelath E.S.
        • et al.
        Dabigatran etexilate retards the initiation and progression of atherosclerotic lesions and inhibits the expression of oncostatin M in apolipoprotein E-deficient mice.
        Drug Des. Dev. Ther. 2015; 9: 5203-5211
        • Bea F.
        • Kreuzer J.
        • Preusch M.
        • et al.
        Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2787-2792
        • Borissoff J.I.
        • Otten J.J.
        • Heeneman S.
        • et al.
        Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner.
        PloS One. 2013; 8e55784
        • Wei H.J.
        • Li Y.H.
        • Shi G.Y.
        • et al.
        Thrombomodulin domains attenuate atherosclerosis by inhibiting thrombin-induced endothelial cell activation.
        Cardiovasc. Res. 2011; 92: 317-327
        • Zuo P.
        • Zuo Z.
        • Zheng Y.
        • et al.
        Protease-activated receptor-2 deficiency attenuates atherosclerotic lesion progression and instability in apolipoprotein E-deficient mice.
        Front. Pharmacol. 2017; 8: 647
        • Hara T.
        • Phuong P.T.
        • Fukuda D.
        • et al.
        Protease-activated receptor-2 plays a critical role in vascular inflammation and atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2018; 138: 1706-1719
        • Jones S.M.
        • Mann A.
        • Conrad K.
        • et al.
        PAR2 (Protease-Activated receptor 2) deficiency attenuates atherosclerosis in mice.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 1271-1282
        • Raghavan S.
        • Singh N.K.
        • Mani A.M.
        • et al.
        Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3-mediated degradation of the ABCA1 transporter.
        J. Biol. Chem. 2018; 293: 10574-10589
        • Rana R.
        • Huang T.
        • Koukos G.
        • et al.
        Noncanonical matrix metalloprotease 1-protease-activated receptor 1 signaling drives progression of atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 1368-1380
        • Camerer E.
        • Barker A.
        • Duong D.N.
        • et al.
        Local protease signaling contributes to neural tube closure in the mouse embryo.
        Dev. Cell. 2010; 18: 25-38
        • Toschi V.
        • Gallo R.
        • Lettino M.
        • et al.
        Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.
        Circulation. 1997; 95: 594-599
        • Badimon J.J.
        • Lettino M.
        • Toschi V.
        • et al.
        Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions.
        Circulation. 1999; 99: 1780-1787
        • Reininger A.J.
        • Bernlochner I.
        • Penz S.M.
        • et al.
        A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques.
        J. Am. Coll. Cardiol. 2010; 55: 1147-1158
        • Chou J.
        • Mackman N.
        • Merrill-Skoloff G.
        • et al.
        Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation.
        Blood. 2004; 104: 3190-3197
        • Gross P.L.
        • Furie B.C.
        • Merrill-Skoloff G.
        • et al.
        Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development.
        J. Leukoc. Biol. 2005; 78: 1318-1326
        • Day S.M.
        • Reeve J.L.
        • Pedersen B.
        • et al.
        Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall.
        Blood. 2005; 105: 192-198
        • Pan S.
        • Kleppe L.S.
        • Witt T.A.
        • et al.
        The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis.
        Thromb. Haemostasis. 2004; 92: 495-502
        • Wang L.
        • Miller C.
        • Swarthout R.F.
        • et al.
        Vascular smooth muscle-derived tissue factor is critical for arterial thrombosis after ferric chloride-induced injury.
        Blood. 2009; 113: 705-713
        • Kuijpers M.J.
        • Munnix I.C.
        • Cosemans J.M.
        • et al.
        Key role of platelet procoagulant activity in tissue factor-and collagen-dependent thrombus formation in arterioles and venules in vivo differential sensitivity to thrombin inhibition.
        Microcirculation. 2008; 15: 269-282
        • Pawashe A.B.
        • Golino P.
        • Ambrosio G.
        • et al.
        A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.
        Circ. Res. 1994; 74: 56-63
        • Speidel C.M.
        • Thornton J.D.
        • Meng Y.Y.
        • et al.
        Procoagulant activity on injured arteries and associated thrombi is mediated primarily by the complex of tissue factor and factor VIIa.
        Coron. Artery Dis. 1996; 7: 57-62
        • Jiao J.A.
        • Kelly A.B.
        • Marzec U.M.
        • et al.
        Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site.
        Thromb. Haemostasis. 2010; 103: 224-233
        • Suleymanov O.D.
        • Szalony J.A.
        • Salyers A.K.
        • et al.
        Pharmacological interruption of acute thrombus formation with minimal hemorrhagic complications by a small molecule tissue factor/factor VIIa inhibitor: comparison to factor Xa and thrombin inhibition in a nonhuman primate thrombosis model.
        J. Pharmacol. Exp. Therapeut. 2003; 306: 1115-1121
        • Asada Y.
        • Hara S.
        • Tsuneyoshi A.
        • et al.
        Fibrin-rich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta.
        Thromb. Haemostasis. 1998; 80: 506-511
        • Roqué M.
        • Reis E.D.
        • Fuster V.
        • et al.
        Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty.
        J. Am. Coll. Cardiol. 2000; 36: 2303-2310
        • Chi L.
        • Gibson G.
        • Peng Y.W.
        • et al.
        Characterization of a tissue factor/factor VIIa-dependent model of thrombosis in hypercholesterolemic rabbits.
        J. Thromb. Haemostasis. 2004; 2: 85-92
        • Kuijpers M.J.
        • van der Meijden P.E.
        • Feijge M.A.
        • et al.
        Factor XII regulates the pathological process of thrombus formation on ruptured plaques.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34: 1674-1680