Molecular and Cellular Biochemistry

, Volume 359, Issue 1–2, pp 301–313 | Cite as

Thrombin and vascular inflammation

  • Milan PopovićEmail author
  • Katarina Smiljanić
  • Branislava Dobutović
  • Tatiana Syrovets
  • Thomas Simmet
  • Esma R. Isenović


Vascular endothelium is a key regulator of homeostasis. In physiological conditions it mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. However, endothelial dysfunction caused by physical injury of the vascular wall, for example during balloon angioplasty, acute or chronic inflammation, such as in atherothrombosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites. At the same time, the dysfunction promotes thrombin generation, fibrin deposition, and coagulation. The serine protease thrombin plays a pivotal role in the coagulation cascade. However, thrombin is not only the key effector of coagulation cascade; it also plays a significant role in inflammatory diseases. It shows an array of effects on endothelial cells, vascular smooth muscle cells, monocytes, and platelets, all of which participate in the vascular pathophysiology such as atherothrombosis. Therefore, thrombin can be considered as an important modulatory molecule of vascular homeostasis. This review summarizes the existing evidence on the role of thrombin in vascular inflammation.


Thrombin Endothelium Vascular inflammation Atherosclerosis 





Activating protein C


Chemokine (C–C motif) ligand


Cytosolic phospholipase A2


Chemokine (C-X-C motif) ligand


Cysteinyl leukotrienes


Dendritic cells


Endothelial cells


Endothelium-derived hyperpolarizing factor


Extracellular signal regulated kinase


Epidermal growth factor receptor


Glycoprotein Ib/IIb/IIIa


Human leukocyte antigen


Intercellular adhesion molecule-1






Inducible protein-10






Mitogen activated protein kinase


Macrophage colony-stimulating factor


Nitric oxide


Plasminogen activator inhibitor-1


Protease-activated receptors


Platelet-derived growth factor receptor


Platelet factor 4


Prostaglandin E2


Prostacyclin I2


Polymorphonuclear leukocytes


P-selectin glycoprotein ligand-1


Regulated on activation, normal T expressed and secreted


Tissue factor


Transforming growth factor-β


Tissue factor pathway inhibitor


Tumor necrosis factor-α


Thromboxane A2


Vascular cell adhesion molecule-1


Vascular endothelial growth factor


Vascular smooth muscle cells


von Willebrand factor



This study was supported by grants: Deutsche Forschungsgemeinschaft, Si 285/7-1 (to Tatiana Syrovets and Thomas Simmet), and Serbian Government Research Grants, No. 173033 (to Esma R. Isenović) and No. 175085 (to Milan Popović).


  1. 1.
    Bombeli T, Mueller M, Haeberli A (1997) Anticoagulant properties of the vascular endothelium. Thromb Haemost 77:408–423PubMedGoogle Scholar
  2. 2.
    Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  3. 3.
    Rosenberg RD, Rosenberg JS (1984) Natural anticoagulant mechanisms. J Clin Invest 76:1–5CrossRefGoogle Scholar
  4. 4.
    Stamler JS, Singel DJ, Loscalzo J (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902PubMedCrossRefGoogle Scholar
  5. 5.
    Zimmerman GA, Whatley RE, Benson DE, Prescott SM (1990) Endothelial cells for studies of platelet-activating factor and arachidonate metabolites. Methods Enzymol 187:520–535PubMedCrossRefGoogle Scholar
  6. 6.
    Roth GJ (1992) Platelets and blood vessels: the adhesion event. Immunol Today 13:100–105PubMedCrossRefGoogle Scholar
  7. 7.
    Coughlin SR (1999) How the protease thrombin talks to cells. Proc Natl Acad Sci USA 96:11023–11027PubMedCrossRefGoogle Scholar
  8. 8.
    Butcher EC (1991) Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67:1033–1036PubMedCrossRefGoogle Scholar
  9. 9.
    Ebnet K, Vestweber D (1999) Molecular mechanism that control leukocyte extravasation: the selectins and chemokines. Histochem Cell Biol 112:1–23PubMedCrossRefGoogle Scholar
  10. 10.
    Fantone CJ, Ward PA (1982) Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107:395–418PubMedGoogle Scholar
  11. 11.
    Touyz RM (2003) Reactive oxygen species in vascular biology: role in arterial hypertension. Expert Rev Cardiovasc Ther 1:91–106PubMedCrossRefGoogle Scholar
  12. 12.
    Lubrano V, Di Cecco P, Zucchelli GC (2006) Role of superoxide dismutase in vascular inflammation and in coronary artery disease. Clin Exp Med 6:84–88PubMedCrossRefGoogle Scholar
  13. 13.
    Nawroth PP, Stern DM (1985) An endothelial cell procogaulant pathway. J Cell Biochem 28:253–264PubMedCrossRefGoogle Scholar
  14. 14.
    Stern DM, Carpenter B, Nawroth PP (1986) Endothelium and the regulation of coagulation. Pathol Immunopathol Res 5:29–36PubMedCrossRefGoogle Scholar
  15. 15.
    Serhan CN (2007) Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 25:101–137PubMedCrossRefGoogle Scholar
  16. 16.
    Bevilacqua MP, Nelson RM, Mannori G, Cecconi O (1994) Endothelial-leukocyte adhesion molecules in human disease. Annu Rev Med 45:361–378PubMedCrossRefGoogle Scholar
  17. 17.
    Springer TA (1990) Adhesion receptors of the immune system. Nature 346:425–434PubMedCrossRefGoogle Scholar
  18. 18.
    Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1176PubMedCrossRefGoogle Scholar
  19. 19.
    Flower RJ (2006) Prostaglandins, bioassay and inflammation. Br J Pharmacol 147(Suppl 1):S182–S192PubMedGoogle Scholar
  20. 20.
    Levin EG, Marzec U, Anderson J, Harker LA (1984) Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest 74:1988–1995PubMedCrossRefGoogle Scholar
  21. 21.
    Levin ER (1995) Endothelins. N Engl J Med 333:356–363PubMedCrossRefGoogle Scholar
  22. 22.
    Zwick E, Wallasch C, Daub H, Ullrich A (1999) Distinct calcium-dependent pathways of epidermal growth factor receptor transactivation and PYK2 tyrosine phosphorylation in PC12 cells. J Biol Chem 274:20989–20996PubMedCrossRefGoogle Scholar
  23. 23.
    Isenovic ER, Trpkovic A, Zakula Z, Koricanac G, Marche P (2008) Role of ERK1/2 activation in thrombin-induced vascular smooth muscle cell hypertrophy. Curr Hypertens Rev 4:190–196CrossRefGoogle Scholar
  24. 24.
    Isenovic ER, Soskic S, Trpkovic A, Dobutovic B, Popovic M, Gluvic Z, Putnikovic B, Marche P (2010) Insulin, thrombine, ERK1/2 kinase and vascular smooth muscle cells proliferation. Curr Pharm Des 16:3895–3902PubMedCrossRefGoogle Scholar
  25. 25.
    Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814PubMedCrossRefGoogle Scholar
  26. 26.
    Hou L, Howells GL, Kapas S, Macey MG (1998) The protease-activated receptors and their cellular expression and function in blood-related cells. Br J Haematol 101:1–9PubMedCrossRefGoogle Scholar
  27. 27.
    Hamilton JR, Cocks TM (2000) Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol 130:181–188PubMedCrossRefGoogle Scholar
  28. 28.
    Mizuno O, Hirano K, Nishimura J, Kubo C, Kanaide H (1998) Mechanism of endothelium-dependent relaxation induced by thrombin in the pig coronary artery. Eur J Pharmacol 351:67–77PubMedCrossRefGoogle Scholar
  29. 29.
    Ku DD, Zaleski JK (1993) Receptor mechanism of thrombin-induced endothelium-dependent and endothelium-independent coronary vascular effects in dogs. J Cardiovasc Pharmacol 22:609–616PubMedCrossRefGoogle Scholar
  30. 30.
    Gudmundsdottir IJ, Lang NN, Boon NA, Ludlam CA, Webb DJ, Fox KA, Newby DE (2008) Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans. J Am Coll Cardiol 51:1749–1756PubMedCrossRefGoogle Scholar
  31. 31.
    Rabausch K, Bretschneider E, Sarbia M, Meyer-Kirchrath J, Censarek P, Pape R, Fischer JW, Schror K, Weber AA (2005) Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ Res 96:e1–e6PubMedCrossRefGoogle Scholar
  32. 32.
    Rosenkranz AC, Rauch BH, Freidel K, Schror K (2009) Regulation of protease-activated receptor-1 by vasodilatory prostaglandins via NFAT. Cardiovasc Res 83:778–784PubMedCrossRefGoogle Scholar
  33. 33.
    Pape R, Rauch BH, Rosenkranz AC, Kaber G, Schror K (2008) Transcriptional inhibition of protease-activated receptor-1 expression by prostacyclin in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 28:534–540PubMedCrossRefGoogle Scholar
  34. 34.
    Takaki A, Morikawa K, Tsutsui M, Murayama Y, Tekes E, Yamagishi H, Ohashi J, Yada T, Yanagihara N, Shimokawa H (2008) Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 205:2053–2063PubMedCrossRefGoogle Scholar
  35. 35.
    Hirano K (2007) The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 27:27–36PubMedCrossRefGoogle Scholar
  36. 36.
    Motley ED, Eguchi K, Patterson MM, Palmer PD, Suzuki H, Eguchi S (2007) Mechanism of endothelial nitric oxide synthase phosphorylation and activation by thrombin. Hypertension 49:577–583PubMedCrossRefGoogle Scholar
  37. 37.
    Church FC, Pratt CW, Noyes CN, Kalayanamit T, Sherrill JB, Tobin RB, Meade JB (1989) Structural and functional properties of human alpha-thrombin, phosphopyridoxylated alpha-thrombin, and gamma T-thrombin. Identification of lysyl residues in alpha-thrombin that are critical for heparin and fibrin(ogen) interactions. J Biol Chem 264:18419–18425PubMedGoogle Scholar
  38. 38.
    Coughlin SR (2000) Thrombin signaling and protease-activated receptors. Nature 407:258–264PubMedCrossRefGoogle Scholar
  39. 39.
    Esmon CT (1999) Inflammation, sepsis, and coagulation. Haematologica 84:254–259PubMedGoogle Scholar
  40. 40.
    Davey MG, Luscher EF (1967) Actions of thrombin and other coagulant and proteolytic enzymes on blood platelets. Nature 216:857–858PubMedCrossRefGoogle Scholar
  41. 41.
    Li X, Syrovets T, Paskas S, Laumonnier Y, Simmet T (2008) Mature dendritic cells express functional thrombin receptors triggering chemotaxis and CCL18/pulmonary and activation-regulated chemokine induction. J Immunol 181:1215–1223PubMedGoogle Scholar
  42. 42.
    Abdallah RT, Keum JS, Lee MH, Wang B, Gooz M, Luttrell DK, Luttrell LM, Jaffa AA (2010) Plasma kallikrein promotes epidermal growth factor receptor transactivation and signaling in vascular smooth muscle through direct activation of protease-activated receptors. J Biol Chem 285:35206–35215PubMedCrossRefGoogle Scholar
  43. 43.
    Schmaier AH (2008) Assembly, activation, and physiologic influence of the plasma kallikrein/kinin system. Int Immunopharmacol 8:161–165PubMedCrossRefGoogle Scholar
  44. 44.
    Ahn HS, Chackalamannil S, Boykow G, Graziano MP, Foster C (2003) Development of proteinase-activated receptor 1 antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. Curr Pharm Des 9:2349–2365PubMedCrossRefGoogle Scholar
  45. 45.
    McLaughlin JN, Patterson MM, Malik AB (2007) Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. Proc Natl Acad Sci USA 104:5662–5667PubMedCrossRefGoogle Scholar
  46. 46.
    Ostrowska E, Reiser G (2008) The protease-activated receptor-3 (PAR-3) can signal autonomously to induce interleukin-8 release. Cell Mol Life Sci 65:970–981PubMedCrossRefGoogle Scholar
  47. 47.
    Vidwan P, Pathak A, Sheth S, Huang J, Monroe DM, Stouffer GA (2010) Activation of protease-activated receptors 3 and 4 accelerates tissue factor-induced thrombin generation on the surface of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 30:2587–2596PubMedCrossRefGoogle Scholar
  48. 48.
    Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JE (2008) Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling. J Pharmacol Exp Ther 324:1045–1054PubMedCrossRefGoogle Scholar
  49. 49.
    Ritchie E, Saka M, Mackenzie C, Drummond R, Wheeler-Jones C, Kanke T, Plevin R (2007) Cytokine upregulation of proteinase-activated-receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase beta in human endothelial cells. Br J Pharmacol 150:1044–1054PubMedCrossRefGoogle Scholar
  50. 50.
    Dangwal S, Rauch BH, Gensch T, Dai L, Bretschneider E, Vogelaar CF, Schror K, Rosenkranz AC (2011) High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:624–633PubMedCrossRefGoogle Scholar
  51. 51.
    Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, Farese RV Jr, Tam C, Coughlin SR (1998) A dual thrombin receptor system for platelet activation. Nature 394:690–694PubMedCrossRefGoogle Scholar
  52. 52.
    Shah R (2009) Protease-activated receptors in cardiovascular health and diseases. Am Heart J 157:253–262PubMedCrossRefGoogle Scholar
  53. 53.
    Covic L, Gresser AL, Kuliopulos A (2000) Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39:5458–5467PubMedCrossRefGoogle Scholar
  54. 54.
    Wu CC, Wu SY, Liao CY, Teng CM, Wu YC, Kuo SC (2010) The roles and mechanisms of PAR4 and P2Y12/phosphatidylinositol 3-kinase pathway in maintaining thrombin-induced platelet aggregation. Br J Pharmacol 161:643–658PubMedCrossRefGoogle Scholar
  55. 55.
    Italiano JE Jr, Shivdasani RA (2003) Megakaryocytes and beyond: the birth of platelets. J Thromb Haemost 1:1174–1182PubMedCrossRefGoogle Scholar
  56. 56.
    Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494PubMedCrossRefGoogle Scholar
  57. 57.
    Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111:1227–1233PubMedCrossRefGoogle Scholar
  58. 58.
    Bath PM, Hassall DG, Gladwin AM, Palmer RM, Martin JF (1991) Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb 11:254–260PubMedCrossRefGoogle Scholar
  59. 59.
    De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68PubMedCrossRefGoogle Scholar
  60. 60.
    Moncada S, Vane JR (1978) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 30:293–331PubMedGoogle Scholar
  61. 61.
    Frenette PS, Johnson RC, Hynes RO, Wagner DD (1995) Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA 92:7450–7454PubMedCrossRefGoogle Scholar
  62. 62.
    Frenette PS, Moyna C, Hartwell DW, Lowe JB, Hynes RO, Wagner DD (1998) Platelet-endothelial interactions in inflamed mesenteric venules. Blood 91:1318–1324PubMedGoogle Scholar
  63. 63.
    Rendu F, Brohard-Bohn B (2001) The platelet release reaction: granules’ constituents, secretion and functions. Platelets 12:261–273PubMedCrossRefGoogle Scholar
  64. 64.
    Garcia JG, Pavalko FM, Patterson CE (1995) Vascular endothelial cell activation and permeability responses to thrombin. Blood Coagul Fibrinolysis 6:609–626PubMedCrossRefGoogle Scholar
  65. 65.
    Bavendiek U, Libby P, Kilbride M, Reynolds R, Mackman N, Schonbeck U (2002) Induction of tissue factor expression in human endothelial cells by CD40 ligand is mediated via activator protein 1, nuclear factor kappa B, and Egr-1. J Biol Chem 277:25032–25039PubMedCrossRefGoogle Scholar
  66. 66.
    Wilcox JN, Smith KM, Schwartz SM, Gordon D (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 86:2839–2843PubMedCrossRefGoogle Scholar
  67. 67.
    Mackman N (2004) Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol 24:1015–1022PubMedCrossRefGoogle Scholar
  68. 68.
    Mann KG, van’t Veer C, Cawthern K, Butenas S (1998) The role of the tissue factor pathway in initiation of coagulation. Blood Coagul Fibrinolysis 9(Suppl 1):S3–S7PubMedGoogle Scholar
  69. 69.
    Nemerson Y (1988) Tissue factor and hemostasis. Blood 71:1–8PubMedGoogle Scholar
  70. 70.
    Mann KG, Lawson JH (1992) The role of the membrane in the expression of the vitamin K-dependent enzymes. Arch Pathol Lab Med 116:1330–1336PubMedGoogle Scholar
  71. 71.
    Tracy PB, Nesheim ME, Mann KG (1992) Platelet factor Xa receptor. Methods Enzymol 215:329–360PubMedCrossRefGoogle Scholar
  72. 72.
    Esmon CT (1979) The subunit structure of thrombin-activated factor V. Isolation of activated factor V, separation of subunits, and reconstitution of biological activity. J Biol Chem 254:964–973PubMedGoogle Scholar
  73. 73.
    Nesheim ME, Mann KG (1979) Thrombin-catalyzed activation of single chain bovine factor V. J Biol Chem 254:1326–1334PubMedGoogle Scholar
  74. 74.
    Fay PJ (1988) Subunit structure of thrombin-activated human factor VIIIa. Biochim Biophys Acta 952:181–190PubMedCrossRefGoogle Scholar
  75. 75.
    Fay PJ, Anderson MT, Chavin SI, Marder VJ (1986) The size of human factor VIII heterodimers and the effects produced by thrombin. Biochim Biophys Acta 871:268–278PubMedCrossRefGoogle Scholar
  76. 76.
    Di Scipio RG, Kurachi K, Davie EW (1978) Activation of human factor IX (Christmas factor). J Clin Invest 61:1528–1538PubMedCrossRefGoogle Scholar
  77. 77.
    Osterud B, Bouma BN, Griffin JH (1978) Human blood coagulation factor IX. Purification, properties, and mechanism of activation by activated factor XI. J Biol Chem 253:5946–5951PubMedGoogle Scholar
  78. 78.
    Broze GJ Jr, Girard TJ, Novotny WF (1991) The lipoprotein-associated coagulation inhibitor. Prog Hemost Thromb 10:243–268PubMedGoogle Scholar
  79. 79.
    Broze GJ Jr, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP (1988) The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood 71:335–343PubMedGoogle Scholar
  80. 80.
    Rauch U, Nemerson Y (2000) Tissue factor, the blood, and the arterial wall. Trends Cardiovasc Med 10:139–143PubMedCrossRefGoogle Scholar
  81. 81.
    Engelmann B, Luther T, Muller I (2003) Intravascular tissue factor pathway: a model for rapid initiation of coagulation within the blood vessel. Thromb Haemost 89:3–8PubMedGoogle Scholar
  82. 82.
    Soejima H, Ogawa H, Yasue H, Kaikita K, Nishiyama K, Misumi K, Takazoe K, Miyao Y, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I, Kumeda K (1999) Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 99:2908–2913PubMedGoogle Scholar
  83. 83.
    Misumi K, Ogawa H, Yasue H, Soejima H, Suefuji H, Nishiyama K, Takazoe K, Kugiyama K, Tsuji I, Kumeda K, Nakamura S (1998) Comparison of plasma tissue factor levels in unstable and stable angina pectoris. Am J Cardiol 81:22–26PubMedCrossRefGoogle Scholar
  84. 84.
    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 134:253–259PubMedCrossRefGoogle Scholar
  85. 85.
    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 96:2311–2315PubMedCrossRefGoogle Scholar
  86. 86.
    Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B (1992) Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 359:848–851PubMedCrossRefGoogle Scholar
  87. 87.
    Zillmann A, Luther T, Muller I, Kotzsch M, Spannagl M, Kauke T, Oelschlagel U, Zahler S, Engelmann B (2001) Platelet-associated tissue factor contributes to the collagen-triggered activation of blood coagulation. Biochem Biophys Res Commun 281:603–609PubMedCrossRefGoogle Scholar
  88. 88.
    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 105:192–198PubMedCrossRefGoogle Scholar
  89. 89.
    Sims PJ, Faioni EM, Wiedmer T, Shattil SJ (1988) Complement proteins C5b–9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 263:18205–18212PubMedGoogle Scholar
  90. 90.
    Esmon CT (2005) The interactions between inflammation and coagulation. Br J Haematol 131:417–430PubMedCrossRefGoogle Scholar
  91. 91.
    Arita H, Nakano T, Hanasaki K (1989) Thromboxane A2: its generation and role in platelet activation. Prog Lipid Res 28:273–301PubMedCrossRefGoogle Scholar
  92. 92.
    Catella-Lawson F, FitzGerald GA (1995) Long-term aspirin in the prevention of cardiovascular disorders. Recent developments and variations on a theme. Drug Saf 13:69–75PubMedCrossRefGoogle Scholar
  93. 93.
    Atkinson BT, Stafford MJ, Pears CJ, Watson SP (2001) Signalling events underlying platelet aggregation induced by the glycoprotein VI agonist convulxin. Eur J Biochem 268:5242–5248PubMedCrossRefGoogle Scholar
  94. 94.
    Henriksen RA, Samokhin GP, Tracy PB (1997) Thrombin-induced thromboxane synthesis by human platelets. Properties of anion binding exosite I-independent receptor. Arterioscler Thromb Vasc Biol 17:3519–3526PubMedCrossRefGoogle Scholar
  95. 95.
    Wu CC, Hwang TL, Liao CH, Kuo SC, Lee FY, Teng CM (2003) The role of PAR4 in thrombin-induced thromboxane production in human platelets. Thromb Haemost 90:299–308PubMedGoogle Scholar
  96. 96.
    Borsch-Haubold AG, Bartoli F, Asselin J, Dudler T, Kramer RM, Apitz-Castro R, Watson SP, Gelb MH (1998) Identification of the phosphorylation sites of cytosolic phospholipase A2 in agonist-stimulated human platelets and HeLa cells. J Biol Chem 273:4449–4458PubMedCrossRefGoogle Scholar
  97. 97.
    Li Z, Xi X, Du X (2001) A mitogen-activated protein kinase-dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3. J Biol Chem 276:42226–42232PubMedCrossRefGoogle Scholar
  98. 98.
    Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts MF (2002) P2X(1)-mediated activation of extracellular signal-regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen. Blood 100:2499–2505PubMedCrossRefGoogle Scholar
  99. 99.
    Roger S, Pawlowski M, Habib A, Jandrot-Perrus M, Rosa JP, Bryckaert M (2004) Costimulation of the Gi-coupled ADP receptor and the Gq-coupled TXA2 receptor is required for ERK2 activation in collagen-induced platelet aggregation. FEBS Lett 556:227–235PubMedCrossRefGoogle Scholar
  100. 100.
    Sakurai K, Matsuo Y, Sudo T, Takuwa Y, Kimura S, Kasuya Y (2004) Role of p38 mitogen-activated protein kinase in thrombus formation. J Recept Signal Transduct Res 24:283–296PubMedCrossRefGoogle Scholar
  101. 101.
    Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72:269–278PubMedCrossRefGoogle Scholar
  102. 102.
    Borsch-Haubold AG, Kramer RM, Watson SP (1996) Inhibition of mitogen-activated protein kinase kinase does not impair primary activation of human platelets. Biochem J 318(Pt 1):207–212PubMedGoogle Scholar
  103. 103.
    Kuliopulos A, Mohanlal R, Covic L (2004) Effect of selective inhibition of the p38 MAP kinase pathway on platelet aggregation. Thromb Haemost 92:1387–1393PubMedGoogle Scholar
  104. 104.
    McNicol A, Jackson EC (2003) Inhibition of the MEK/ERK pathway has no effect on agonist-induced aggregation of human platelets. Biochem Pharmacol 65:1243–1250PubMedCrossRefGoogle Scholar
  105. 105.
    Garcia A, Quinton TM, Dorsam RT, Kunapuli SP (2005) Src family kinase-mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets. Blood 106:3410–3414PubMedCrossRefGoogle Scholar
  106. 106.
    Shankar H, Garcia A, Prabhakar J, Kim S, Kunapuli SP (2006) P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost 4:638–647PubMedCrossRefGoogle Scholar
  107. 107.
    Lundblad RL, White GC 2nd (2005) The interaction of thrombin with blood platelets. Platelets 16:373–385PubMedCrossRefGoogle Scholar
  108. 108.
    Canobbio I, Balduini C, Torti M (2004) Signalling through the platelet glycoprotein Ib-V-IX complex. Cell Signal 16:1329–1344PubMedCrossRefGoogle Scholar
  109. 109.
    De Candia E, Hall SW, Rutella S, Landolfi R, Andrews RK, De Cristofaro R (2001) Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. J Biol Chem 276:4692–4698PubMedCrossRefGoogle Scholar
  110. 110.
    Dubois C, Steiner B, Kieffer N, Reigner SC (2003) Thrombin binding to GPIbalpha induces platelet aggregation and fibrin clot retraction supported by resting alphaIIbbeta3 interaction with polymerized fibrin. Thromb Haemost 89:853–865PubMedGoogle Scholar
  111. 111.
    Soslau G, Class R, Morgan DA, Foster C, Lord ST, Marchese P, Ruggeri ZM (2001) Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J Biol Chem 276:21173–21183PubMedCrossRefGoogle Scholar
  112. 112.
    Lova P, Canobbio I, Guidetti GF, Balduini C, Torti M (2010) Thrombin induces platelet activation in the absence of functional protease activated receptors 1 and 4 and glycoprotein Ib-IX-V. Cell Signal 22:1681–1687PubMedCrossRefGoogle Scholar
  113. 113.
    Ritchie RH, Rosenkranz AC, Kaye DM (2009) B-type natriuretic peptide: endogenous regulator of myocardial structure, biomarker and therapeutic target. Curr Mol Med 9:814–825PubMedCrossRefGoogle Scholar
  114. 114.
    Blomback B, Banerjee D, Carlsson K, Hamsten A, Hessel B, Procyk R, Silveira A, Zacharski L (1990) Native fibrin gel networks and factors influencing their formation in health and disease. Adv Exp Med Biol 281:1–23PubMedCrossRefGoogle Scholar
  115. 115.
    Brass LF, Zhu L, Stalker TJ (2005) Minding the gaps to promote thrombus growth and stability. J Clin Invest 115:3385–3392PubMedCrossRefGoogle Scholar
  116. 116.
    Munnix IC, Cosemans JM, Auger JM, Heemskerk JW (2009) Platelet response heterogeneity in thrombus formation. Thromb Haemost 102:1149–1156PubMedGoogle Scholar
  117. 117.
    De Meyer SF, Vandeputte N, Pareyn I, Petrus I, Lenting PJ, Chuah MK, VandenDriessche T, Deckmyn H, Vanhoorelbeke K (2008) Restoration of plasma von willebrand factor deficiency is sufficient to correct thrombus formation after gene therapy for severe von willebrand disease. Arterioscler Thromb Vasc Biol 28:1621–1626PubMedCrossRefGoogle Scholar
  118. 118.
    Massberg S, Enders G, Leiderer R, Eisenmenger S, Vestweber D, Krombach F, Messmer K (1998) Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood 92:507–515PubMedGoogle Scholar
  119. 119.
    Burger PC, Wagner DD (2003) Platelet P-selectin facilitates atherosclerotic lesion development. Blood 101:2661–2666PubMedCrossRefGoogle Scholar
  120. 120.
    Wang K, Zhou X, Zhou Z, Mal N, Fan L, Zhang M, Lincoff AM, Plow EF, Topol EJ, Penn MS (2005) Platelet, not endothelial, P-selectin is required for neointimal formation after vascular injury. Arterioscler Thromb Vasc Biol 25:1584–1589PubMedCrossRefGoogle Scholar
  121. 121.
    Braun OO, Slotta JE, Menger MD, Erlinge D, Thorlacius H (2008) Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1. Eur J Pharmacol 592:128–132PubMedCrossRefGoogle Scholar
  122. 122.
    Sachais BS, Turrentine T, Dawicki McKenna JM, Rux AH, Rader D, Kowalska MA (2007) Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE −/− mice. Thromb Haemost 98:1108–1113PubMedGoogle Scholar
  123. 123.
    Gleissner CA, von Hundelshausen P, Ley K (2008) Platelet chemokines in vascular disease. Arterioscler Thromb Vasc Biol 28:1920–1927PubMedCrossRefGoogle Scholar
  124. 124.
    Koenen RR, von Hundelshausen P, Nesmelova IV, Zernecke A, Liehn EA, Sarabi A, Kramp BK, Piccinini AM, Paludan SR, Kowalska MA, Kungl AJ, Hackeng TM, Mayo KH, Weber C (2009) Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 15:97–103PubMedCrossRefGoogle Scholar
  125. 125.
    Lijnen HR (2001) Elements of the fibrinolytic system. Ann NY Acad Sci 936:226–236PubMedCrossRefGoogle Scholar
  126. 126.
    Castellino FJ, Ploplis VA (2005) Structure and function of the plasminogen/plasmin system. Thromb Haemost 93:647–654PubMedGoogle Scholar
  127. 127.
    Zorio E, Gilabert-Estellés J, España F, Ramón LA, Cosín R, Estellés A (2008) Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem 15:923–929PubMedCrossRefGoogle Scholar
  128. 128.
    Krone KA, Allen KL, McCrae KR (2010) Impaired fibrinolysis in the antiphospholipid syndrome. Curr Rheumatol Rep 12:53–57PubMedCrossRefGoogle Scholar
  129. 129.
    Thors B, Halldorsson H, Thorgeirsson G (2004) Thrombin and histamine stimulate endothelial nitric-oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3 K-Akt. FEBS Letts 573:175–180CrossRefGoogle Scholar
  130. 130.
    Anderson CN, Ohta K, Quick MM, Fleming A, Keynes R, Tannahill D (2003) Molecular analysis of axon repulsion by the notochord. Development 130:1123–1133PubMedCrossRefGoogle Scholar
  131. 131.
    Wroblewski BM, Siney PD, Fleming PA (2003) Wear of enhanced ultra-high molecular-weight polyethylene (Hylamer) in combination with a 22.225 mm diameter zirconia femoral head. J Bone Joint Surg Br 85:376–379PubMedCrossRefGoogle Scholar
  132. 132.
    Ferrara N (2009) VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw 20:158–163PubMedGoogle Scholar
  133. 133.
    Nagy JA, Dvorak AM, Dvorak HF (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251–275PubMedCrossRefGoogle Scholar
  134. 134.
    Gaengel K, Genove G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638PubMedCrossRefGoogle Scholar
  135. 135.
    Murakami M, Nguyen LT, Zhuang ZW, Moodie KL, Carmeliet P, Stan RV, Simons M (2008) The FGF system has a key role in regulating vascular integrity. J Clin Invest 118:3355–3366PubMedCrossRefGoogle Scholar
  136. 136.
    Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20:556–567PubMedCrossRefGoogle Scholar
  137. 137.
    Stouffer GA, Schmedtje JF, Gulba D, Huber K, Bode C, Aaron J, Runge MS (1996) Restenosis following percutaneous revascularization–the potential role of thrombin and the thrombin receptor. Ann Hematol 73(Suppl 1):S39–S41PubMedGoogle Scholar
  138. 138.
    Ragosta M, Barry WL, Gimple LW, Gertz SD, McCoy KW, Stouffer GA, McNamara CA, Powers ER, Owens GK, Sarembock IJ (1996) Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits. Circulation 93:1194–1200PubMedGoogle Scholar
  139. 139.
    Molskness TA, Woodruff TK, Hess DL, Dahl KD, Stouffer RL (1996) Recombinant human inhibin-A administered early in the menstrual cycle alters concurrent pituitary and follicular, plus subsequent luteal, function in rhesus monkeys. J Clin Endocrinol Metab 81:4002–4006PubMedCrossRefGoogle Scholar
  140. 140.
    McNamara CA, Sarembock IJ, Bachhuber BG, Stouffer GA, Ragosta M, Barry W, Gimple LW, Powers ER, Owens GK (1996) Thrombin and vascular smooth muscle cell proliferation: implications for atherosclerosis and restenosis. Semin Thromb Hemost 22:139–144PubMedCrossRefGoogle Scholar
  141. 141.
    Wolf DP, Alexander M, Zelinski-Wooten M, Stouffer RL (1996) Maturity and fertility of rhesus monkey oocytes collected at different intervals after an ovulatory stimulus (human chorionic gonadotropin) in in vitro fertilization cycles. Mol Reprod Dev 43:76–81PubMedCrossRefGoogle Scholar
  142. 142.
    Christenson LK, Stouffer RL (1996) Proliferation of microvascular endothelial cells in the primate corpus luteum during the menstrual cycle and simulated early pregnancy. Endocrinology 137:367–374PubMedCrossRefGoogle Scholar
  143. 143.
    Chung SW, Park JW, Lee SA, Eo SK, Kim K (2010) Thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell. Biochem Biophys Res Commun 396:748–754PubMedCrossRefGoogle Scholar
  144. 144.
    Vendrov AE, Madamanchi NR, Niu XL, Molnar KC, Runge M, Szyndralewiez C, Page P, Runge MS (2010) NADPH oxidases regulate CD44 and hyaluronic acid expression in thrombin-treated vascular smooth muscle cells and in atherosclerosis. J Biol Chem 285:26545–26557PubMedCrossRefGoogle Scholar
  145. 145.
    Vidwan P, Lee S, Rossi JS, Stouffer GA (2010) Relation of platelet count to bleeding and vascular complications in patients undergoing coronary angiography. Am J Cardiol 105:1219–1222PubMedCrossRefGoogle Scholar
  146. 146.
    Hsieh HL, Tung WH, Wu CY, Wang HH, Lin CC, Wang TS, Yang CM (2009) Thrombin induces EGF receptor expression and cell proliferation via a PKC(delta)/c-Src-dependent pathway in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 29:1594–1601PubMedCrossRefGoogle Scholar
  147. 147.
    Martin K, Weiss S, Metharom P, Schmeckpeper J, Hynes B, O’Sullivan J, Caplice N (2009) Thrombin stimulates smooth muscle cell differentiation from peripheral blood mononuclear cells via protease-activated receptor-1, RhoA, and myocardin. Circ Res 105:214–218PubMedCrossRefGoogle Scholar
  148. 148.
    Gad M, Claesson MH, Pedersen AE (2003) Dendritic cells in peripheral tolerance and immunity. APMIS 111:766–775PubMedCrossRefGoogle Scholar
  149. 149.
    Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58PubMedCrossRefGoogle Scholar
  150. 150.
    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811PubMedCrossRefGoogle Scholar
  151. 151.
    Yanagita M, Kobayashi R, Kashiwagi Y, Shimabukuro Y, Murakami S (2007) Thrombin regulates the function of human blood dendritic cells. Biochem Biophys Res Commun 364:318–324PubMedCrossRefGoogle Scholar
  152. 152.
    Kissel K, Berber S, Nockher A, Santoso S, Bein G, Hackstein H (2006) Human platelets target dendritic cell differentiation and production of proinflammatory cytokines. Transfusion 46:818–827PubMedCrossRefGoogle Scholar
  153. 153.
    Osugi Y, Vuckovic S, Hart DN (2002) Myeloid blood CD11c(+) dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes. Blood 100:2858–2866PubMedCrossRefGoogle Scholar
  154. 154.
    Liu Y, Shaw SK, Ma S, Yang L, Luscinskas FW, Parkos CA (2004) Regulation of leukocyte transmigration: cell surface interactions and signaling events. J Immunol 172:7–13PubMedGoogle Scholar
  155. 155.
    Mine S, Fujisaki T, Suematsu M, Tanaka Y (2001) Activated platelets and endothelial cell interaction with neutrophils under flow conditions. Intern Med 40:1085–1092PubMedCrossRefGoogle Scholar
  156. 156.
    Cadroy Y, Dupouy D, Boneu B, Plaisancie H (2000) Polymorphonuclear leukocytes modulate tissue factor production by mononuclear cells: role of reactive oxygen species. J Immunol 164:3822–3828PubMedGoogle Scholar
  157. 157.
    Todoroki H, Higure A, Okamoto K, Okazaki K, Nagafuchi Y, Takeda S, Katoh H, Itoh H, Ohsato K, Nakamura S (1998) Possible role of platelet-activating factor in the in vivo expression of tissue factor in neutrophils. J Surg Res 80:149–155PubMedCrossRefGoogle Scholar
  158. 158.
    Higure A, Okamoto K, Hirata K, Todoroki H, Nagafuchi Y, Takeda S, Katoh H, Itoh H, Ohsato K, Nakamura S (1996) Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis. Thromb Haemost 75:791–795PubMedGoogle Scholar
  159. 159.
    McGee MP, Li LC (1991) Functional difference between intrinsic and extrinsic coagulation pathways. Kinetics of factor X activation on human monocytes and alveolar macrophages. J Biol Chem 266:8079–8085PubMedGoogle Scholar
  160. 160.
    Tracy PB, Eide LL, Mann KG (1985) Human prothrombinase complex assembly and function on isolated peripheral blood cell populations. J Biol Chem 260:2119–2124PubMedGoogle Scholar
  161. 161.
    Tracy PB, Rohrbach MS, Mann KG (1983) Functional prothrombinase complex assembly on isolated monocytes and lymphocytes. J Biol Chem 258:7264–7267PubMedGoogle Scholar
  162. 162.
    Morrissey JH (2001) Tissue factor: an enzyme cofactor and a true receptor. Thromb Haemost 86:66–74PubMedGoogle Scholar
  163. 163.
    Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B (1994) P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 91:8767–8771PubMedCrossRefGoogle Scholar
  164. 164.
    McGee MP, Foster S, Wang X (1994) Simultaneous expression of tissue factor and tissue factor pathway inhibitor by human monocytes. A potential mechanism for localized control of blood coagulation. J Exp Med 179:1847–1854PubMedCrossRefGoogle Scholar
  165. 165.
    Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109:2698–2704PubMedCrossRefGoogle Scholar
  166. 166.
    Bar-Shavit R, Kahn A, Wilner GD, Fenton JW 2nd (1983) Monocyte chemotaxis: stimulation by specific exosite region in thrombin. Science 220:728–731PubMedCrossRefGoogle Scholar
  167. 167.
    Colognato R, Slupsky JR, Jendrach M, Burysek L, Syrovets T, Simmet T (2003) Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood 102:2645–2652PubMedCrossRefGoogle Scholar
  168. 168.
    Chang CJ, Hsu LA, Ko YH, Chen PL, Chuang YT, Lin CY, Liao CH, Pang JH (2009) Thrombin regulates matrix metalloproteinase-9 expression in human monocytes. Biochem Biophys Res Commun 385:241–246PubMedCrossRefGoogle Scholar
  169. 169.
    Kalmes A, Vesti BR, Daum G, Abraham JA, Clowes AW (2000) Heparin blockade of thrombin-induced smooth muscle cell migration involves inhibition of epidermal growth factor (EGF) receptor transactivation by heparin-binding EGF-like growth factor. Circ Res 87:92–98PubMedGoogle Scholar
  170. 170.
    Madamanchi NR, Li S, Patterson C, Runge MS (2001) Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK-STAT pathway. J Biol Chem 276:18915–18924PubMedCrossRefGoogle Scholar
  171. 171.
    Rauch BH, Rosenkranz AC, Ermler S, Bohm A, Driessen J, Fischer JW, Sugidachi A, Jakubowski JA, Schror K (2010) Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol 30:2434–2442PubMedCrossRefGoogle Scholar
  172. 172.
    Ellis CA, Tiruppathi C, Sandoval R, Niles WD, Malik AB (1999) Time course of recovery of endothelial cell surface thrombin receptor (PAR-1) expression. Am J Physiol Cell Physiol 276:C38–C45Google Scholar
  173. 173.
    Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ (1989) Stimulated secretion of endothelial vWF is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140. J Biol Chem 264:7768–7771PubMedGoogle Scholar
  174. 174.
    Moy AB, Engelenhoven JV, Bodmer J, Kamath J, Keese C, Giaever I, Shasby S, Shasby DM (1996) Histamine and thrombin modulate endothelial focal adhesion through centripetal and centrifugal forces. J Clin Invest 97:1020–1027PubMedCrossRefGoogle Scholar
  175. 175.
    Popovic M, Laumonnier Y, Burysek L, Syrovets T, Simmet T (2008) Thrombin-induced expression of endothelial CX3CL1 potentiates monocyte CCL2 production and transendothelial migration. J Leukoc Biol 84:215–223PubMedCrossRefGoogle Scholar
  176. 176.
    DiMuzio PJ, Pratt KJ, Park PK, Carabasi RA (1994) Role of thrombin in endothelial cell monolayer repair in vitro. J Vasc Surg 20:621–628PubMedCrossRefGoogle Scholar
  177. 177.
    Houliston RA, Keogh RJ, Sugden D, Dudhia J, Carter TD, Wheeler-Jones CP (2002) Protease-activated receptors upregulate cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 88:321–328PubMedGoogle Scholar
  178. 178.
    Shinohara T, Suzuki K, Takada K, Okada M, Ohsuzu F (2002) Regulation of proteinase-activated receptor 1 by inflammatory mediators in human vascular endothelial cells. Cytokine 19:66–75PubMedCrossRefGoogle Scholar
  179. 179.
    Suidan HS, Bouvier J, Schaerer E, Stone SR, Monard D, Tschopp J (1994) Granzyme a released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc Natl Acad Sci 91:8112–8116PubMedCrossRefGoogle Scholar
  180. 180.
    Kaur J, Woodman RC, Ostrovsky L, Kubes P (2001) Selective recruitment of neutrophils and lymphocytes by thrombin: a role for NF-kappaB. Am J Physiol: Heart and Circ Physiol 281:H784–H795Google Scholar
  181. 181.
    Bizios R, Lai L, Fenton JW 2nd, Malik AB (1986) Thrombin-induced chemotaxis and aggregation of neutrophils. J Cell Physiol 128:485–490PubMedCrossRefGoogle Scholar
  182. 182.
    Cao H, Dronadula N, Rao GN (2006) Thrombin induces expression of FGF-2 via activation of PI3 K-Akt-Fra-1 signaling axis leading to DNA synthesis and motility in vascular smooth muscle cells. Am J Physiol Cell Physiol 290:C172–C182PubMedCrossRefGoogle Scholar
  183. 183.
    Furuhashi I, Abe K, Sato T, Inoue H (2008) Thrombin-stimulated proliferation of cultured human synovial fibroblasts through proteolytic activation of proteinase-activated receptor-1. J Pharmacol Sci 108:104–111PubMedCrossRefGoogle Scholar
  184. 184.
    Gruber R, Jindra C, Kandler B, Watzak G, Fischer MB, Watzek G (2004) Proliferation of dental pulp fibroblasts in response to thrombin involves mitogen-activated protein kinase signalling. Int Endod J 37:145–150PubMedCrossRefGoogle Scholar
  185. 185.
    Marin V, Farnarier C, Gres S, Kaplanski S, Su MS, Dinarello CA, Kaplanski G (2001) The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment. Blood 98:667–673PubMedCrossRefGoogle Scholar
  186. 186.
    Hallam TJ, Pearson JD, Needham LA (1988) Thrombin-stimulated elevation of human endothelial-cell cytoplasmic free calcium concentration causes prostacyclin production. Biochem J 251:243–249PubMedGoogle Scholar
  187. 187.
    Prescott SM, Zimmerman GA, McIntyre TM (1984) Human endothelial cells in culture produce platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when stimulated with thrombin. Proc Natl Acad Sci USA 81:3534–3538PubMedCrossRefGoogle Scholar
  188. 188.
    Kell PJ, Creer MH, Crown KN, Wirsig K, McHowat J (2003) Inhibition of platelet-activating factor (PAF) acetylhydrolase by methyl arachidonyl fluorophosphonate potentiates PAF synthesis in thrombin-stimulated human coronary artery endothelial cells. J Pharmacol Exp Ther 307:1163–1170PubMedCrossRefGoogle Scholar
  189. 189.
    Schini VB, Hendrickson H, Heublein DM, Burnett JC Jr, Vanhoutte PM (1989) Thrombin enhances the release of endothelin from cultured porcine aortic endothelial cells. Eur J Pharmacol 165:333–334PubMedCrossRefGoogle Scholar
  190. 190.
    Morimoto S, Takahashi T, Shimizu K, Kanda T, Okaishi K, Okuro M, Murai H, Nishimura Y, Nomura K, Tsuchiya H, Ohashi I, Matsumoto M (2005) Electromagnetic fields inhibit endothelin-1 production stimulated by thrombin in endothelial cells. J Int Med Res 33:545–554PubMedGoogle Scholar
  191. 191.
    Sporn LA, Marder VJ, Wagner DD (1986) Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 84:185–190CrossRefGoogle Scholar
  192. 192.
    Sporn LA, Marder VJ, Wagner DD (1989) Differing polarity of the constitutive and regulated secretory pathways for von Willebrand factor in endothelial cells. J Cell Biol 108:1283–1289PubMedCrossRefGoogle Scholar
  193. 193.
    Kerk N, Strozyk EA, Poppelmann B, Schneider SW (2010) The mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cells. J Invest Dermatol 130:2259–2268PubMedCrossRefGoogle Scholar
  194. 194.
    Fukushima M, Nakashima Y, Sueishi K (1989) Thrombin enhances release of tissue plasminogen activator from bovine corneal endothelial cells. Invest Ophthalmol Vis Sci 30:1576–1583PubMedGoogle Scholar
  195. 195.
    Gudmundsdottir IJ, Megson IL, Kell JS, Ludlam CA, Fox KA, Webb DJ, Newby DE (2006) Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans. Circulation 114:1625–1632PubMedCrossRefGoogle Scholar
  196. 196.
    Gelehrter TD, Sznycer-Laszuk R (1986) Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J Clin Invest 77:165–169PubMedCrossRefGoogle Scholar
  197. 197.
    Harlan JM, Thompson PJ, Ross RR, Bowen-Pope DF (1986) Alpha-thrombin induces release of platelet-derived growth factor-like molecule(s) by cultured human endothelial cells. J Cell Biol 103:1129–1133PubMedCrossRefGoogle Scholar
  198. 198.
    Kavanaugh WM, Harsh GR IV, Starksen NF, Rocco CM, Williams LT (1988) Transcriptional regulation of the A and B chain genes of platelet-derived growth factor in microvascular endothelial cells. J Biol Chem 263:8470–8472PubMedGoogle Scholar
  199. 199.
    Isenovic ER, Kedees MH, Haidara MA, Trpkovic A, Mikhailidis DP, Marche P (2010) Involvement of ERK1/2 kinase in insulin-and thrombin-stimulated vascular smooth muscle cell proliferation. Angiology 61:357–364PubMedCrossRefGoogle Scholar
  200. 200.
    Bogatcheva NV, Garcia JG, Verin AD (2002) Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry 67:75–84PubMedCrossRefGoogle Scholar
  201. 201.
    Cernuda-Morollon E, Ridley AJ (2006) Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res 98:757–767PubMedCrossRefGoogle Scholar
  202. 202.
    Rahman A, Anwar KN, True AL, Malik AB (1999) Thrombin-induced p65 homodimer binding to downstream NF-kappa B site of the promoter mediates endothelial ICAM-1 expression and neutrophil adhesion. J Immunol 162:5466–5476PubMedGoogle Scholar
  203. 203.
    Yong K, Khwaja A (1990) Leukocyte cellular adhesion molecules. Blood Rev 4:211–225PubMedCrossRefGoogle Scholar
  204. 204.
    Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:61–68PubMedGoogle Scholar
  205. 205.
    Szaba FM, Smiley ST (2002) Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 99:1053–1059PubMedCrossRefGoogle Scholar
  206. 206.
    Chen D, Carpenter A, Abrahams J, Chambers RC, Lechler RI, McVey JH, Dorling A (2008) Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo. J Exp Med 205:1739–1746PubMedCrossRefGoogle Scholar
  207. 207.
    Marin V, Montero-Julian FA, Gres S, Boulay V, Bongrand P, Farnarier C, Kaplanski G (2001) The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J Immunol 167:3435–3442PubMedGoogle Scholar
  208. 208.
    Tokunou T, Ichiki T, Takeda K, Funakoshi Y, Iino N, Shimokawa H, Egashira K, Takeshita A (2001) Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21:1759–1763PubMedCrossRefGoogle Scholar
  209. 209.
    Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R (1999) Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 19:2364–2367PubMedCrossRefGoogle Scholar
  210. 210.
    Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A (1999) MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398:718–723PubMedCrossRefGoogle Scholar
  211. 211.
    Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596PubMedCrossRefGoogle Scholar
  212. 212.
    Maragoudakis ME, Kraniti N, Giannopoulou E, Alexopoulos K, Matsoukas J (2001) Modulation of angiogenesis and progelatinase a by thrombin receptor mimetics and antagonists. Endothelium 8:195–205PubMedCrossRefGoogle Scholar
  213. 213.
    Lesnik P, Haskell CA, Charo IF (2003) Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest 111:333–340PubMedGoogle Scholar
  214. 214.
    Saederup N, Chan L, Lira SA, Charo IF (2008) Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2−/− mice: evidence for independent chemokine functions in atherogenesis. Circulation 117:1642–1648PubMedCrossRefGoogle Scholar
  215. 215.
    Vicente CP, He L, Tollefsen DM (2007) Accelerated atherogenesis and neointima formation in heparin cofactor II deficient mice. Blood 110:4261–4267PubMedCrossRefGoogle Scholar
  216. 216.
    O’Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ, Woulfe DS, Brass LF (2000) Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 275:13502–13509PubMedCrossRefGoogle Scholar
  217. 217.
    Massberg S, Vogt F, Dickfeld T, Brand K, Page S, Gawaz M (2003) Activated platelets trigger an inflammatory response and enhance migration of aortic smooth muscle cells. Thromb Res 110:187–194PubMedCrossRefGoogle Scholar
  218. 218.
    Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, French PA, Dauerman HL, Becker RC (2009) Platelet functions beyond hemostasis. J Thromb Haemost 7:1759–1766PubMedCrossRefGoogle Scholar
  219. 219.
    Chintala M, Shimizu K, Ogawa M, Yamaguchi H, Doi M, Jensen P (2008) Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease. J Pharmacol Sci 108:433–438PubMedCrossRefGoogle Scholar
  220. 220.
    Hamilton JR (2009) Protease-activated receptors as targets for antiplatelet therapy. Blood Rev 23:61–65PubMedCrossRefGoogle Scholar
  221. 221.
    Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, Boykow G, Hsieh Y, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M (2008) Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 51:3061–3064PubMedCrossRefGoogle Scholar
  222. 222.
    Chackalamannil S (2003) G-protein coupled receptor antagonists-1: protease activated receptor-1 (PAR-1) antagonists as novel cardiovascular therapeutic agents. Curr Topics Med Chem 3:1115–1123CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Milan Popović
    • 1
    Email author
  • Katarina Smiljanić
    • 1
  • Branislava Dobutović
    • 1
  • Tatiana Syrovets
    • 2
  • Thomas Simmet
    • 2
  • Esma R. Isenović
    • 1
  1. 1.Department for Radiobiology and Molecular Genetics, Vinča InstituteUniversity of BelgradeBelgradeSerbia
  2. 2.Institute of Pharmacology of Natural Products & Clinical PharmacologyUlm UniversityUlmGermany

Personalised recommendations