Abstract
The term “vulnerable plaque” identifies atherosclerotic lesions prone to rupture. Plaque disruption facilitates the interaction of the inner components of the lesion, tissue factor (TF) among them, with the flowing blood. This results in activation of the coagulation cascade, ultimately leading to thrombus formation, and abrupt vascular occlusion. Despite the central role of vulnerable plaques in the onset of acute coronary syndromes (ACS), there are certain conditions (e.g., eroded plaques) where a hyperactive, “vulnerable” blood, may play a predominant pathophysiological role. Recently, two distinct pools of circulating TF have been identified. One, associated with cell-derived microparticles probably originating from apoptotic cells, such as macrophages, smooth muscle cells, and endothelium. The most recent, blood-borne TF, circulates in an “inactive” form (encryption) and has to be activated (decryption) to exert its thrombogenic activity. Certain pathological conditions associated with an increased rate of thrombotic complications have been associated with high levels of circulating TF. It is thought that the blood-borne TF perpetuates the initial thrombogenic stimulus, leading to the formation of larger or more stable thrombus, and thus, more severe ACS. Thus, the concept of vulnerable blood could represent a new link between the vulnerable lesion and the high-risk patient. Therefore, the assessment of selected biomarkers associated with “vulnerable or hyperreactive blood”, e.g., blood-borne tissue factor, may represent a useful tool to identify patients with a high-risk profile of developing major cardiovascular events.
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Aikawa M, Libby P (2004) The vulnerable atherosclerotic plaque: pathogenesis, therapeutic approach. Cardiovasc Pathol 13:125–138
Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernández-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ (1997) Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95(3):594–599
Hutter R, Valdiviezo C, Sauter BV, Savontaus M, Chereshnev I, Carrick FE, Bauriedel G, Lüderitz B, Fallon JT, Fuster V, Badimon JJ (2004) Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis. Circulation 109(16):2001–2008
Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y (2003) Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 9:458
Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM (2000) Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler ThrombVasc Biol 20(5):1262–1275
Nemerson Y (2002) A simple experiment and a weakening paradigm: the contribution of blood to propensity for thrombus formation. Arterioscler Thromb Vasc Biol 22(9):1369
Yusuf S, Reddy S, Ounpuu S, Anand S (2001) Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104(22):2746–2753
Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ (2003) Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 107(7):973–977
Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH (2001) Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 134(3):224–238
Giesen PL, Rauch U, Bohrmann B, Kling D, Roqué M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y (1999) Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 96(5):2311–2315
Tutar E, Ozcan M, Kilickap M, Gülec S, Aras O, Pamir G, Oral D, Dandelet L, Key NS (2003) Elevated whole-blood tissue factor procoagulant activity as a marker of restenosis after percutaneous transluminal coronary angioplasty and stent implantation. Circulation 108(13):1581–1584
Suefuji H, Ogawa H, Yasue H, Kaikita K, Soejima H, Motoyama T, Mizuno Y, Oshima S, Saito T, Tsuji I, Kumeda K, Kamikubo Y, Nakamura S (1997) Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J 134(2 pt 1):253–259
Østerud B, Bjørklid E (2006) Sources of tissue factor. Semin Thromb Hemost 32(1):11–23
Lechner D, Weltermann A (2008) Circulating tissue factor-exposing microparticles. Thromb Res 122(Suppl 1):S47–S54
Rivers RP, Hathaway WE, Weston WL (1975) The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 30(3):311–316
Maugeri N, Brambilla M, Camera M, Carbone A, Tremoli E, Donati MB, de Gaetano G, Cerletti C (2006) Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J Thromb Haemost 4(6):1323–1330
Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, Rafail S, Kartalis G, Sideras P, Lambris JD (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 177(7):4794–4802
Moosbauer C, Morgenstern E, Cuvelier SL, Manukyan D, Bidzhekov K, Albrecht S, Lohse P, Patel KD, Engelmann B (2007) Eosinophils are a major intravascular location for tissue factor storage and exposure. Blood 109(3):995–1002
Sovershaev MA, Lind KF, Devold H, Jørgensen TØ, Hansen JB, Østerud B, Egorina EM (2008) No evidence for the presence of tissue factor in high-purity preparations of immunologically isolated eosinophils. J Thromb Haemost 6(10):1742–1749
Egorina EM, Sovershaev MA, Olsen JO, Østerud B (2008) Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer. Blood 111(3):1208–1216 (Epub 2007)
Zillmann A, Luther T, Muller I, Kotzsch M, Spannagl M, Kauke T, Oelschlägel U, Zahler S, Engelmann B (2001) Platelet-associated tissue factor contributes to the collagen-triggered activation of blood coagulation. Biochem Biophys Res Commun 281:603–609
Weyrich AS, Lindemann S, Tolley ND, Kraiss LW, Dixon DA, Mahoney TM, Prescott SP, McIntyre TM, Zimmerman GA (2004) Change in protein phenotype without a nucleus: translational control in platelets. Semin Thromb Hemost 30:493–500
Schwertz H, Tolley ND, Foulks JM, Denis MM, Risenmay BW, Buerke M, Tilley RE, Rondina MT, Harris EM, Kraiss LW, Mackman N, Zimmerman GA, Weyrich AS (2006) Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 203:2433–2440
Chargaff E, West R (1946) The biological significance of the thromboplastic protein of blood. J Biol Chem 166:189–197
Davizon P, López JA (2009) Microparticles and thrombotic disease. Curr Opin Hematol 16(5):334–341
Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A (2009) Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 101(3):439–451
Schecter AD, Spirn B, Rossikhina M, Giesen PL, Bogdanov V, Fallon JT, Fisher EA, Schnapp LM, Nemerson Y, Taubman MB (2000) Release of active tissue factor by human arterial smooth muscle cells. Circ Res 87(2):126–132
Baroni M, Pizzirani C, Pinotti M, Ferrari D, Adinolfi E, Calzavarini S, Caruso P, Bernardi F, Di Virgilio F (2007) Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles. FASEB J 21(8):1926–1933
Antoniak S, Boltzen U, Eisenreich A, Stellbaum C, Poller W, Schultheiss HP, Rauch U (2009) Regulation of cardiomyocyte full-length tissue factor expression and microparticle release under inflammatory conditions in vitro. J Thromb Haemost 7(5):871–878
Hathcock J (2004) Vascular biology—the role of tissue factor. Semin Hematol 41(1 Suppl 1):30–34
Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U (2005) Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res 96:1233–1239
Bach RR (2006) Tissue factor encryption. Arterioscler Thromb Vasc Biol 26:456–461
Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet JM, Tedgui A (1999) Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99(3):348–353
Leroyer AS, Isobe H, Lesèche G, Castier Y, Wassef M, Mallat Z, Binder BR, Tedgui A, Boulanger CM (2007) Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. JACC 49:772–777
Berckmans RJ, Nieuwland R, Böing AN, Romijn FP, Hack CE, Sturk A (2001) Cell derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 85:639–646
Biró E, Sturk-Maquelin KN, Vogel GM, Meuleman DG, Smit MJ, Hack CE, Sturk A, Nieuwland R (2003) Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 1:2561–2568
Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie BC, Furie B (2004) Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 104:3190–3197
Hrachovinová I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP, Wagner DD (2003) Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9:1020–1025
Censarek P, Bobbe A, Grandoch M, Schrör K, Weber AA (2007) Alternatively spliced human tissue factor (asHTF) is not pro-coagulant. Thromb Haemost 97:11–14
Hobbs JE, Zakarija A, Cundiff DL, Doll JA, Hymen E, Cornwell M, Crawford SE, Liu N, Signaevsky M, Soff GA (2007) Alternatively spliced human tissue factor promotes tumor growth and angiogenesis in a pancreatic cancer tumor model. Thromb Res 120:S13–S21
Butenas S, Orfeo T, Mann KG (2009) Tissue factor in coagulation. Which? Where? When? Arterioscler Thromb Vasc Biol 29(12):1989–1996
Day SM, Reeve JL, Pedersen B, Farris DM, Myers DD, Im M, Wakefield TW, Mackman N, Fay WP (2005) Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 105:192–198
Butenas S, Bouchard BA, Brummel-Ziedins KE, Parhami-Seren B, Mann KG (2005) Tissue factor activity in whole blood. Blood 105:2764–2770
Balasubramanian V, Grabowski E, Bini A, Nemerson Y (2002) Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: real-time fluorescence images of thrombus formation and propagation under defined flow conditions. Blood 100(8):2787–2792
Campo G, Valgimigli M, Ferraresi P, Malagutti P, Baroni M, Arcozzi C, Gemmati D, Percoco G, Parrinello G, Ferrari R, Bernardi F (2006) Tissue factor and coagulation factor VII levels during acute myocardial infarction: association with genotype and adverse events. Arterioscler Thromb Vasc Biol 26(12):2800–2806
Morange PE, Blankenberg S, Alessi MC, Bickel C, Rupprecht HJ, Schnabel R, Lubos E, Münzel T, Peetz D, Nicaud V, Juhan-Vague I, Tiret L, Atherogene Investigators (2007) Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 5:475–482
Mälarstig A, Tenno T, Johnston N, Lagerqvist B, Axelsson T, Syvänen AC, Wallentin L, Siegbahn A (2005) Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes. Arterioscler Thromb Vasc Biol 25(12):2667–2672
Keller TT, Choi D, Nagel C, Te Velthuis H, Gerdes VE, Wareham NJ, Bingham SA, Luben R, Hack CE, Reitsma PH, Levi M, Khaw KT, Boekholdt SM (2006) Tissue factor serum levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. J Thromb Haemost 4(11):2391–2396
Bogdanov VY, Cimmino G, Tardos JG, Tunstead JR, Badimon JJ (2009) Assessment of plasma tissue factor activity in patients presenting with coronary artery disease: limitations of a commercial assay. J Thromb Haemost 7(5):894–897
Butenas S, Undas A, Gissel MT, Szuldrzynski K, Zmudka K, Mann KG (2008) Factor XIa and tissue factor activity in patients with coronary artery disease. Thromb Haemost 99:142–149
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Cimmino, G., Golino, P. & Badimon, J.J. Pathophysiological role of blood-borne tissue factor: should the old paradigm be revisited?. Intern Emerg Med 6, 29–34 (2011). https://doi.org/10.1007/s11739-010-0423-4
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DOI: https://doi.org/10.1007/s11739-010-0423-4