Journal of Thrombosis and Thrombolysis

, Volume 37, Issue 1, pp 4–11 | Cite as

Emerging paradigms in arterial thrombosis

  • James W. WislerEmail author
  • Richard C. Becker


A traditional perspective of arterial thrombosis begins with vessel wall injury and exposure of subendothelial proteins, including collagen and tissue factor, to circulating cellular and non-cellular components. Adhesion and activation of platelets, mediated by their interaction with von Willebrand protein and collagen, respectively, coupled with tissue factor-mediated activation of coagulation proteins, results in thrombin generation and fibrin formation. While this time-honored paradigm remains firm and soundly based, emerging evidence suggests that arterial thrombosis is much more complex and dynamic than originally believed. Several novel triggers, templates and facilitators, such as cell-free nucleic acids, histones, DNA-histone complexes, polyphosphates, and microvesicles have recently been identified and require inclusion in the expanding universe of thrombosis as a dominant phenotype of human disease. Because these mediators appear to have modest if any effect on physiologic hemostasis, they likely represent acquired and disease or condition-dependent processes that are highly attractive targets for pharmacologic intervention.


Thrombosis Cell-free DNA Histones NETs Polyphosphates Microvesicles 


  1. 1.
    Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451(7181):914–918. doi: 10.1038/nature06797 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Hoffman M, Monroe DM 3rd (2001) A cell-based model of hemostasis. Thromb Haemost 85(6):958–965PubMedGoogle Scholar
  3. 3.
    Furie B, Furie BC (2008) Mechanisms of thrombus formation. N Engl J Med 359(9):938–949. doi: 10.1056/NEJMra0801082 PubMedCrossRefGoogle Scholar
  4. 4.
    Dubois C, Panicot-Dubois L, Merrill-Skoloff G, Furie B, Furie BC (2006) Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. Blood 107(10):3902–3906. doi: 10.1182/blood-2005-09-3687 PubMedCrossRefGoogle Scholar
  5. 5.
    Massberg S, Gawaz M, Gruner S, Schulte V, Konrad I, Zohlnhofer D, Heinzmann U, Nieswandt B (2003) A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 197(1):41–49PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Bergmeier W, Piffath CL, Goerge T, Cifuni SM, Ruggeri ZM, Ware J, Wagner DD (2006) The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci USA 103(45):16900–16905. doi: 10.1073/pnas.0608207103 PubMedCrossRefGoogle Scholar
  7. 7.
    Morrissey JH, Macik BG, Neuenschwander PF, Comp PC (1993) Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 81(3):734–744PubMedGoogle Scholar
  8. 8.
    Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64(6):1057–1068PubMedCrossRefGoogle Scholar
  9. 9.
    Roque M, Reis ED, Fuster V, Padurean A, Fallon JT, Taubman MB, Chesebro JH, Badimon JJ (2000) Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 36(7):2303–2310PubMedCrossRefGoogle Scholar
  10. 10.
    Marmur JD, Thiruvikraman SV, Fyfe BS, Guha A, Sharma SK, Ambrose JA, Fallon JT, Nemerson Y, Taubman MB (1996) Identification of active tissue factor in human coronary atheroma. Circulation 94(6):1226–1232PubMedCrossRefGoogle Scholar
  11. 11.
    Hathcock JJ, Nemerson Y (2004) Platelet deposition inhibits tissue factor activity: in vitro clots are impermeable to factor Xa. Blood 104(1):123–127. doi: 10.1182/blood-2003-12-4352 PubMedCrossRefGoogle Scholar
  12. 12.
    Mandel P, Metais P (1948) C R Seances Soc Biol Fil 142(3–4):241–243PubMedGoogle Scholar
  13. 13.
    Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL (1994) Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev 3(1):67–71PubMedGoogle Scholar
  14. 14.
    Vasioukhin V, Anker P, Maurice P, Lyautey J, Lederrey C, Stroun M (1994) Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. Br J Haematol 86(4):774–779PubMedCrossRefGoogle Scholar
  15. 15.
    Lo YM, Chan LY, Lo KW, Leung SF, Zhang J, Chan AT, Lee JC, Hjelm NM, Johnson PJ, Huang DP (1999) Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59(6):1188–1191PubMedGoogle Scholar
  16. 16.
    Pornthanakasem W, Shotelersuk K, Termrungruanglert W, Voravud N, Niruthisard S, Mutirangura A (2001) Human papillomavirus DNA in plasma of patients with cervical cancer. BMC Cancer 1:2PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Tan EM, Schur PH, Carr RI, Kunkel HG (1966) Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 45(11):1732–1740. doi: 10.1172/JCI105479 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lo YM, Rainer TH, Chan LY, Hjelm NM, Cocks RA (2000) Plasma DNA as a prognostic marker in trauma patients. Clin Chem 46(3):319–323PubMedGoogle Scholar
  19. 19.
    Rainer TH, Wong LK, Lam W, Yuen E, Lam NY, Metreweli C, Lo YM (2003) Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke. Clin Chem 49(4):562–569PubMedCrossRefGoogle Scholar
  20. 20.
    Chang CP, Chia RH, Wu TL, Tsao KC, Sun CF, Wu JT (2003) Elevated cell-free serum DNA detected in patients with myocardial infarction. Clin Chim Acta 327(1–2):95–101PubMedCrossRefGoogle Scholar
  21. 21.
    Giacona MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD (1998) Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas 17(1):89–97PubMedCrossRefGoogle Scholar
  22. 22.
    Suzuki N, Kamataki A, Yamaki J, Homma Y (2008) Characterization of circulating DNA in healthy human plasma. Clin Chim Acta 387(1–2):55–58. doi: 10.1016/j.cca.2007.09.001 PubMedCrossRefGoogle Scholar
  23. 23.
    Swarup V, Rajeswari MR (2007) Circulating (cell-free) nucleic acids—a promising, non-invasive tool for early detection of several human diseases. FEBS Lett 581(5):795–799. doi: 10.1016/j.febslet.2007.01.051 PubMedCrossRefGoogle Scholar
  24. 24.
    Nakazawa F, Kannemeier C, Shibamiya A, Song Y, Tzima E, Schubert U, Koyama T, Niepmann M, Trusheim H, Engelmann B, Preissner KT (2005) Extracellular RNA is a natural cofactor for the (auto-)activation of Factor VII-activating protease (FSAP). Biochem J 385(Pt 3):831–838. doi: 10.1042/BJ20041021 PubMedGoogle Scholar
  25. 25.
    Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, Song Y, Tzima E, Kennerknecht E, Niepmann M, von Bruehl ML, Sedding D, Massberg S, Gunther A, Engelmann B, Preissner KT (2007) Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 104(15):6388–6393. doi: 10.1073/pnas.0608647104 PubMedCrossRefGoogle Scholar
  26. 26.
    Swystun LL, Mukherjee S, Liaw PC (2011) Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost 9(11):2313–2321. doi: 10.1111/j.1538-7836.2011.04465.x PubMedCrossRefGoogle Scholar
  27. 27.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61(4):1659–1665PubMedGoogle Scholar
  28. 28.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535. doi: 10.1126/science.1092385 PubMedCrossRefGoogle Scholar
  29. 29.
    Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J, Vandenabeele P (2011) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 21(2):290–304. doi: 10.1038/cr.2010.150 PubMedCrossRefGoogle Scholar
  30. 30.
    Steinberg BE, Grinstein S (2007) Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE 379:pe11. doi: 10.1126/stke.3792007pe11 Google Scholar
  31. 31.
    Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT (2009) Extracellular histones are major mediators of death in sepsis. Nat Med 15(11):1318–1321. doi: 10.1038/nm.2053 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Holdenrieder S, Stieber P (2009) Clinical use of circulating nucleosomes. Crit Rev Clin Lab Sci 46(1):1–24. doi: 10.1080/10408360802485875 PubMedCrossRefGoogle Scholar
  33. 33.
    Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, Esmon CT (2011) Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118(7):1952–1961. doi: 10.1182/blood-2011-03-343061 PubMedCrossRefGoogle Scholar
  34. 34.
    Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13(4):463–469. doi: 10.1038/nm1565 PubMedCrossRefGoogle Scholar
  35. 35.
    Gupta AK, Joshi MB, Philippova M, Erne P, Hasler P, Hahn S, Resink TJ (2010) Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 584(14):3193–3197. doi: 10.1016/j.febslet.2010.06.006 PubMedCrossRefGoogle Scholar
  36. 36.
    Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 107(36):15880–15885. doi: 10.1073/pnas.1005743107 PubMedCrossRefGoogle Scholar
  37. 37.
    von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209(4):819–835. doi: 10.1084/jem.20112322 CrossRefGoogle Scholar
  38. 38.
    Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16(8):887–896. doi: 10.1038/nm.2184 PubMedCrossRefGoogle Scholar
  39. 39.
    Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, Lohmeyer J, Preissner KT (2012) Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 7(2):e32366. doi: 10.1371/journal.pone.0032366 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Okrent DG, Lichtenstein AK, Ganz T (1990) Direct cytotoxicity of polymorphonuclear leukocyte granule proteins to human lung-derived cells and endothelial cells. Am Rev Respir Dis 141(1):179–185PubMedCrossRefGoogle Scholar
  41. 41.
    Pereira LF, Marco FM, Boimorto R, Caturla A, Bustos A, De la Concha EG, Subiza JL (1994) Histones interact with anionic phospholipids with high avidity; its relevance for the binding of histone–antihistone immune complexes. Clin Exp Immunol 97(2):175–180PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Kleine TJ, Gladfelter A, Lewis PN, Lewis SA (1995) Histone-induced damage of a mammalian epithelium: the conductive effect. Am J Physiol 268(5 Pt 1):C1114–C1125PubMedGoogle Scholar
  43. 43.
    Sporn LA, Marder VJ, Wagner DD (1986) Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 46(2):185–190PubMedCrossRefGoogle Scholar
  44. 44.
    Fuchs TA, Bhandari AA, Wagner DD (2011) Histones induce rapid and profound thrombocytopenia in mice. Blood 118(13):3708–3714. doi: 10.1182/blood-2011-01-332676 PubMedCrossRefGoogle Scholar
  45. 45.
    Watson K, Gooderham NJ, Davies DS, Edwards RJ (1999) Nucleosomes bind to cell surface proteoglycans. J Biol Chem 274(31):21707–21713PubMedCrossRefGoogle Scholar
  46. 46.
    Clejan L, Menahem H (1977) Binding of deoxyribonucleic acid to the surface of human platelets. Acta Haematol 58(2):84–88PubMedCrossRefGoogle Scholar
  47. 47.
    Dorsch CA (1981) Binding of single-strand DNA to human platelets. Thromb Res 24(1–2):119–129PubMedCrossRefGoogle Scholar
  48. 48.
    Higuchi DA, Wun TC, Likert KM, Broze GJ Jr (1992) The effect of leukocyte elastase on tissue factor pathway inhibitor. Blood 79(7):1712–1719PubMedGoogle Scholar
  49. 49.
    Ruiz FA, Lea CR, Oldfield E, Docampo R (2004) Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem 279(43):44250–44257. doi: 10.1074/jbc.M406261200M406261200 PubMedCrossRefGoogle Scholar
  50. 50.
    Muller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, Schmidbauer S, Gahl WA, Morrissey JH, Renne T (2009) Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139(6):1143–1156. doi: 10.1016/j.cell.2009.11.001 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH (2006) Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 103(4):903–908. doi: 10.1073/pnas.0507195103 PubMedCrossRefGoogle Scholar
  52. 52.
    Smith SA, Choi SH, Davis-Harrison R, Huyck J, Boettcher J, Rienstra CM, Morrissey JH (2010) Polyphosphate exerts differential effects on blood clotting, depending on polymer size. Blood 116(20):4353–4359. doi: 10.1182/blood-2010-01-266791 PubMedCrossRefGoogle Scholar
  53. 53.
    Mutch NJ, Myles T, Leung LL, Morrissey JH (2010) Polyphosphate binds with high affinity to exosite II of thrombin. J Thromb Haemost 8(3):548–555. doi: 10.1111/j.1538-7836.2009.03723.x PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Bae JS, Lee W, Rezaie AR (2012) Polyphosphate elicits pro-inflammatory responses that are counteracted by activated protein C in both cellular and animal models. J Thromb Haemost 10(6):1145–1151. doi: 10.1111/j.1538-7836.2012.04671.x PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107(9):1047–1057. doi: 10.1161/CIRCRESAHA.110.226456 PubMedCrossRefGoogle Scholar
  56. 56.
    Morel O, Jesel L, Freyssinet JM, Toti F (2011) Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 31(1):15–26. doi: 10.1161/ATVBAHA.109.200956 PubMedCrossRefGoogle Scholar
  57. 57.
    Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renne T, Ten Cate H, Spronk HM (2012) Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 10(7):1355–1362. doi: 10.1111/j.1538-7836.2012.04758.x CrossRefGoogle Scholar
  58. 58.
    Berckmans RJ, Nieuwland R, Boing AN, Romijn FP, Hack CE, Sturk A (2001) Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 85(4):639–646PubMedGoogle Scholar
  59. 59.
    Hron G, Kollars M, Weber H, Sagaster V, Quehenberger P, Eichinger S, Kyrle PA, Weltermann A (2007) Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 97(1):119–123PubMedGoogle Scholar
  60. 60.
    Kambas K, Markiewski MM, Pneumatikos IA, Rafail SS, Theodorou V, Konstantonis D, Kourtzelis I, Doumas MN, Magotti P, Deangelis RA, Lambris JD, Ritis KD (2008) C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol 180(11):7368–7375PubMedCentralPubMedGoogle Scholar
  61. 61.
    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):4794–4802PubMedGoogle Scholar
  62. 62.
    Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP (2003) Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood 102(7):2678–2683. doi: 10.1182/blood-2003-03-0693 PubMedCrossRefGoogle Scholar
  63. 63.
    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):126–132PubMedCrossRefGoogle Scholar
  64. 64.
    Owens AP 3rd, Mackman N (2011) Microparticles in hemostasis and thrombosis. Circ Res 108(10):1284–1297. doi: 10.1161/CIRCRESAHA.110.233056 PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Sinauridze EI, Kireev DA, Popenko NY, Pichugin AV, Panteleev MA, Krymskaya OV, Ataullakhanov FI (2007) Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 97(3):425–434PubMedGoogle Scholar
  66. 66.
    Giesen PL, Rauch U, Bohrmann B, Kling D, Roque 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):2311–2315PubMedCrossRefGoogle Scholar
  67. 67.
    Johnson GJ, Leis LA, Bach RR (2009) Tissue factor activity of blood mononuclear cells is increased after total knee arthroplasty. Thromb Haemost 102(4):728–734. doi: 10.1160/TH09-04-0261 PubMedGoogle Scholar
  68. 68.
    Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B (2003) Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 197(11):1585–1598. doi: 10.1084/jem.20021868 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Hoffman M, Whinna HC, Monroe DM (2006) Circulating tissue factor accumulates in thrombi, but not in hemostatic plugs. J Thromb Haemost 4(9):2092–2093. doi: 10.1111/j.1538-7836.2006.02085.x PubMedCrossRefGoogle Scholar
  70. 70.
    Mackman N, Tilley RE, Key NS (2007) Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 27(8):1687–1693. doi: 10.1161/ATVBAHA.107.141911 PubMedCrossRefGoogle Scholar
  71. 71.
    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(10):3190–3197. doi: 10.1182/blood-2004-03-0935 PubMedCrossRefGoogle Scholar
  72. 72.
    Falati S, Gross P, Merrill-Skoloff G, Furie BC, Furie B (2002) Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med 8(10):1175–1181. doi: 10.1038/nm782 PubMedCrossRefGoogle Scholar
  73. 73.
    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(1):192–198. doi: 10.1182/blood-2004-06-2225 PubMedCrossRefGoogle Scholar
  74. 74.
    Biro 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(12):2561–2568PubMedCrossRefGoogle Scholar
  75. 75.
    Ramacciotti E, Hawley AE, Farris DM, Ballard NE, Wrobleski SK, Myers DD Jr, Henke PK, Wakefield TW (2009) Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 101(4):748–754PubMedCentralPubMedGoogle Scholar
  76. 76.
    Wang JG, Manly D, Kirchhofer D, Pawlinski R, Mackman N (2009) Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice. J Thromb Haemost 7(7):1092–1098. doi: 10.1111/j.1538-7836.2009.03448.x PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM, Osanto S (2007) Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 5(3):520–527. doi: 10.1111/j.1538-7836.2007.02369.x PubMedCrossRefGoogle Scholar
  78. 78.
    Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC, Furie B (2009) Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 15(22):6830–6840. doi: 10.1158/1078-0432.CCR-09-0371 PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Morel O, Pereira B, Averous G, Faure A, Jesel L, Germain P, Grunebaum L, Ohlmann P, Freyssinet JM, Bareiss P, Toti F (2009) Increased levels of procoagulant tissue factor-bearing microparticles within the occluded coronary artery of patients with ST-segment elevation myocardial infarction: role of endothelial damage and leukocyte activation. Atherosclerosis 204(2):636–641. doi: 10.1016/j.atherosclerosis.2008.10.039 PubMedCrossRefGoogle Scholar
  80. 80.
    Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK (2002) Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 106(19):2442–2447PubMedCrossRefGoogle Scholar
  81. 81.
    Nieuwland R, Berckmans RJ, McGregor S, Boing AN, Romijn FP, Westendorp RG, Hack CE, Sturk A (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95(3):930–935PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of CardiologyDuke University Medical CenterDurhamUSA
  2. 2.Division of CardiologyDuke Clinical Research Institute, Duke University Medical CenterDurhamUSA
  3. 3.Division of HematologyDuke Clinical Research Institute, Duke University Medical CenterDurhamUSA
  4. 4.Cardiovascular Thrombosis CenterDuke Clinical Research Institute, Duke University Medical CenterDurhamUSA

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