Angiogenesis pp 253-263 | Cite as

Thrombin-Mediated Events Implicated in Post-Thrombotic Recovery

  • John W. FentonII
  • Frederick A. Ofosu
Part of the NATO ASI Series book series (NSSA, volume 263)


Thrombin (EC is the activation product of prothrombin, where the a-thrombin form is the direct product of blood coagulation and, for the most part, possesses all activities ascribed to thrombin.1–8 Although its gene may be expressed in central nervous tissue,9 prothrombin is a hepatic synthesized glycoprotein, which, like coagulation factors VII, XI, and X, as well as proteins C and S, requires vitamin K-dependent ry-carboxylation of certain glutamic acids (e.g., 10 for prothrombin) for post-translational completion.10 This requirement is the target of vitamin K antagonists, such as coumarins used as rodenticides or “blood thinner” in human medicine.11,12


Thrombin Generation Thrombin Receptor Prothrombin Activation Thrombin Concentration Central Nervous Tissue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J.W. Fenton II, M.J. Fasco, A.B. Stackrow, D.L. Aronson, A.M. Young, and J.S. Finlayson, Human Thrombins. Production, evaluation, and properties of a-thrombin. J. Biol. Chem. 252: 3587 - 3598 (1977).PubMedGoogle Scholar
  2. 2.
    J.W. Fenton II, B.H. Landis, D.A. Walz, and J.S. Finlayson, Human Thrombins, in: “Chemistry and Biology of Thrombin,” R.L. Lundblad, J.W. Fenton II, and K.G. Mann, eds., pp. 43 - 70, Ann Arbor Science Publishers, Ann Arbor, MI (1977).Google Scholar
  3. 3.
    J.W. Fenton II, Thrombin specificity. Ann. NY Acad. Sci. 370: 468 - 495, (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    J.W. Fenton II, Thrombin. Ann. NY Acad. Sci. 485: 5 - 15, (1986).PubMedCrossRefGoogle Scholar
  5. 5.
    J.W. Fenton II, Thrombin bioregulatory functions. Adv. Clin. Ensymol. 6: 186 - 193, (1988).Google Scholar
  6. 6.
    J.W. Fenton II, Regulation of thrombin generation and functions. Semin. Thromb. Hemost. 14: 234 - 240, (1988).CrossRefGoogle Scholar
  7. 7.
    J.W. Fenton II, F.A. Ofosu, D.G. Moon, J.M. Maraganore, Thrombin structure and function: why thrombin is the primary target for antithrombotics. Blood Coagul. Fibrinolys 2: 69 - 75, (1991).CrossRefGoogle Scholar
  8. 8.
    J.W. Fenton II, F.A. Ofosu, D.V. Brezniak, and H.I. Hassouna, Understanding thrombin and hemostasis. Hematol./Oncol. Clin. N. Am., in press, (1993).Google Scholar
  9. 9.
    M. Dihanich, M. Kaser, E. Reinhard, D.D. Cunningham, and D. Monard, Prothrombin mRNA is expressed by cells in the nervous system. Neuron 6: 575 - 581, (1991).PubMedCrossRefGoogle Scholar
  10. 10.
    S. Magnuson, T.E. Petersen, L. Sottrup-Jensen, and H. Claeys, Complete primary structure of prothrombin: isolation, structure, and reactivity of ten carboxylated glutamic acid residues and regulation of prothrombin activation by thrombin. In: Proteases and Biological Control. E. Reich, D.B. Rifkin, and E. Shaw, eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 123 - 149 (1975).Google Scholar
  11. 11.
    R.A. O’Reily, P.M. Aggeler, Determinants of the response to oral anticoagulant drugs in man. Pharmacol. Rev. 22: 35 - 96, (1970).Google Scholar
  12. 12.
    M.M. Bern, Considerations for lower doses of warfarin. Hematol./Oncol. Clin. North Am. 6: 1105 - 1114, (1992).Google Scholar
  13. 13.
    S. Iwanaga, T. Miyata, F. Tokunaga, and T. Muta, Molecular mechanism of hemolymph clotting system in limulus. Thromb. Res. 68: 1 - 32 (1992).PubMedCrossRefGoogle Scholar
  14. 14.
    D.M. Irwin, K.A. Robertson, T.A. MacGillivray, Structure and evolution of the bovine prothrombin gene. J. Mol. Biol. 200: 31 - 45 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    M.T. Stubbs and W. Bode, A player of many parts: the spotlight falls on thrombin’s structure, Thromb. Res. 69: 1 - 58 (1993).PubMedCrossRefGoogle Scholar
  16. 16.
    F.A. Ofosu, P. Sie, G.J. Modi, F. Fernandez, M.R. Buchanan, M.A. Blajchman, B. Boneu, and J. Hirsh, The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of anticoagulant effects of heparin. Biochem. J. 243: 579 - 588 (1987).PubMedGoogle Scholar
  17. 17.
    S. Begiun, T. Lindhout, H.C. Hemker, The mode of action of heparin in plasma. Thromb. Haemost. 60: 457 - 462 (1988).Google Scholar
  18. 18.
    F.A. Ofosu, J. Hirsh, C.T. Esmon, G.J. Modi, L.M. Smith, N. Anvari, M.R. Buchanan, J.W. Fenton II, and M.A. Blajchman, Unfractionated heparin inhibits thrombin-catalyzed amplification reactions of coagulation more efficiently than those catalyzed by factor Xa. Biochem. J. 257: 143 - 150 (1989).PubMedGoogle Scholar
  19. 19.
    X.J. Yang, M.A. Blajchman, S. Graven, L.M. Smith, N. Anvari, F.A. Ofosu, Activation of factor V during intrinsic and extrinsic coagulation. Inhibition by heparin, hirudin and D-Phe-Pro-Arg-CH2C1. Biochem. J. 272: 399 - 406 (1990).PubMedGoogle Scholar
  20. 20.
    F.A. Ofosu, J.W. Fenton II, J. Maraganore, M.A. Blajchman, X. Yang, L. Smith, N. Anvari, M.R. Buchanan, J. Hirsh, Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of a-thrombin. Biochem. J. 283: 893 - 897 (1992).PubMedGoogle Scholar
  21. 21.
    A.B. Malik, J.W. Fenton II, Thrombin-mediated increase in vascular endothelial permeability. Semin, Thromb. Hemost. 18: 193 - 199 (1992).CrossRefGoogle Scholar
  22. 22.
    S.M. Prescott, A.R. Seegert, G.A. Zimmerman, T.M. McIntyre, J.M. Maraganore, Hirudín-based peptides block the inflammatory effects of thrombin on endothelial cells. J. Biol. Chem. 265: 9614 - 9616 (1990).PubMedGoogle Scholar
  23. 23.
    A. Tordi, J.W. Fenton II, T.T. Andersen, E.W. Gelfand, Functional thrombin receptors on human T-lymphoblastoid cells. J. Immunol., in press, 1993.Google Scholar
  24. 24.
    R. Bar Shavit, A. Kahn, G.D. Wilner, J.W. Fenton II, Unique exosite region in thrombin stimulates monocyte chemotaxis. Science 220: 728 - 731 (1983).CrossRefGoogle Scholar
  25. 25.
    R. Bizios, L. Lai, J.W. Fenton II, A.B. Malik, Thrombin-induced chemotaxis and aggregation of neutrophils. J. Cell. Physiol. 128: 485 - 490 (1987).CrossRefGoogle Scholar
  26. 26.
    G.T. Gustafson, V. Lerner, Thrombin, a stimulator of bone resorption. Biosci. Rep. 3: 255 - 261 (1983).PubMedCrossRefGoogle Scholar
  27. 27.
    D.N. Tatakis, C. Dolce, R. Dziak, J.W. Fenton II, Thrombin effects on osteoblastic cells. II. structure-function relationships. Biochem. Biophys. Res. Commun. 174: 181 - 188 (1991).PubMedCrossRefGoogle Scholar
  28. 28.
    D.H. Carney, G.S. Herbosa, J. Stiernberg, J.S. Bergmann, E.A. Gordon, D. Scott, J.W. Fenton II, Semin. Thromb. Hemost. 12: 231 - 240 (1986).CrossRefGoogle Scholar
  29. 29.
    D.A. Walz, J.W. Fenton II, and P.H. Johnson, Human thrombin induces angiogenesis. Thromb. Haemost. 65: 1252 (1991).Google Scholar
  30. 30.
    N.E. Tsopanoglou, E. Pipíli-Synetos, and M.E. Maragoudakis, Thrombin promotes angiogenesis by a mechanism independent of fibrin formation. Am. J. Physiol., in press, 1993.Google Scholar
  31. 31.
    N.A. Nelken, S.J. Sorfer, J. O’Keefe, T-KH, Vu, I.F. Charo, and S.R. Coughlin, Thrombin receptor expression in normal and atherosclerotic human arteries. J. Clin. Invest. 90: 1614 - 1621 (1992).PubMedCrossRefGoogle Scholar
  32. 32.
    C.A. McNamara, I.J. Sarembock, L.W. Gimple, J.W. Fenton II, S.R. Coughlin, G.K. Owens, Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytícally activated receptor. J. Clin. Invest. 91: 94 - 98 (1993).PubMedCrossRefGoogle Scholar
  33. 33.
    E.J. Duboví, J.D. Geratz, and R.R. Tidwell, Enhancement of respirator syncytial virus-induced cytopathology by trypsin, thrombin, and plasmin. Infect. Immunol. 40: 351 - 358 (1983).Google Scholar
  34. 34.
    M.Z. Wojtukiewicz, D.G. Tang, K.K. Nelson, D.A. Walz, C.A. Diglio, and K.V. Honn, Thrombin enhances tumor cell adhesive and metastatic properties via increased aIIbß3 expression on the cell surface. Thromb. Res. 68: 233 - 245 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    D.L. Morris, J.B. Ward Jr., P. Nechay, E.B. Whorton Jr., J.W. Fenton II, and D.H. Carney, Highly purified human a-thrombin promotes morphological transformation of BALB/c 3T3 cells. Carcinogenesis 13: 67 - 73 (1992).CrossRefGoogle Scholar
  36. 36.
    L.R. Zacharski, M.Z. Wojtukiewicz, V. Costantini, D.L. Ornstein, V.A. Memoli, Pathways of coagulation/fibrinolysis activation in malignancy. Semin. Thromb. Hemost. 18: 104 - 116 (1992).PubMedCrossRefGoogle Scholar
  37. 37.
    R.M. Snider, M. McKinney, C. Forray, E. Richelson, Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase. Proc. Natl. Acad. Sci. USA 81: 3905 - 3909 (1984).PubMedCrossRefGoogle Scholar
  38. 38.
    G. Rovelli, S.R. Stone, K.T. Preisaner, D. Monard, Specific interaction of vitronectin with the cell-secreted protease inhibitor glia-derived nexin and its thrombin complex. Eur. J. Biochem. 192: 797–803 (1990).PubMedCrossRefGoogle Scholar
  39. 39.
    H.S. Suidan, S.R. Stone, B.A. Hemmings, D. Monard, Thrombin causes neurite retraction in neuronal cells through activation of cell surface receptors. Neuron 8: 363 - 375 (1992).PubMedCrossRefGoogle Scholar
  40. 40.
    J. Marx, A new link in the brain’s defenses. Science 256: 1278 - 1280 (1992).PubMedCrossRefGoogle Scholar
  41. 41.
    D. Monard, Thrombin and its inhibitors. Science 257: 145 - 146 (1992)PubMedGoogle Scholar
  42. 42.
    D.A. Walz, G.F. Anderson, R.E. Ciaglowski, M. Aiken, J.W. Fenton II, Thrombin-elicited contractile responses of aortic smooth muscle. Proc. Soc. Expl. Biol. Med. 180: 518 - 526 (1985).Google Scholar
  43. 43.
    D.L. Aronson, L. Stevan, A.P. Ball, B.R. Franza Jr., and J.S. Finlayson, Generation of the combined prothrombin activation peptide (F1.2) during the clotting of blood and plasma. J. Clin. Invest. 60: 1410–1418 (1977).PubMedCrossRefGoogle Scholar
  44. 44.
    C.Y. Liu, H.L. Nossel, K.L. Kaplan, The binding of thrombin by fibrin. J. Biol. Chem. 254: 10421 - 10425 (1979).PubMedGoogle Scholar
  45. 45.
    G.D. Wilner, M.P. Danitz, S.M. Mudd, K.H. Hsieh, and J.W. Fenton II, Selective immobilization of a-thrombin by surface-bound fibrin. J. Lab. Clin. Med. 97: 403 - 411 (1981).PubMedGoogle Scholar
  46. 46.
    A.M. Lincoff, J.J. Popma, S.G. Ellis, T.A. Hacker, and E.J. Topol, Abrupt vessel closure complicating coronary angioplasty, clinical angiographic therapeutic. J. Am. Coll. Cardol. 19: 926 - 933 (1992).CrossRefGoogle Scholar
  47. 47.
    J.J. Weitz, M. Hudoba, D. Massel, J. Maraganore, and J. Hirsch, Clot-bound thrombin is protected from inactivation by heparinantithrombin III but us susceptible to inactivation by antithrombin III-independent inhibitors. J. Clin. Invest. 86: 385391 (1990).Google Scholar
  48. 48.
    R. Bar-Shavit, A. Edlor, and I. Vlodaysky, Binding of thrombin to subendothelial extracellular matrix. J. Clin. Invest. 84: 1096–1104.Google Scholar
  49. 49.
    P. Zoldhelyi, J.H. Chesebro, and W.G. Owen, Hírudin as a molecular probe for thrombin in vitro and during systemic coagulation in the pig. Proc. Natl. Acad. Sci. USA 90: 1819 - 1823 (1993).PubMedCrossRefGoogle Scholar
  50. 50.
    C.W. Francis, and V.J. Marder, Degradation of cross-linked fibrin by human leukocyte proteases. J. Lab. Clin. Med. 107: 342 - 352 (1986).PubMedGoogle Scholar
  51. 51.
    D.V. Brezniak, M.S. Brower, J.I. Witting, D.A. Walz, and J.W. Fenton II, Human a-to ‘..thrombin cleavage occurs with neutrophil cathepsin G or chymotrypsin while fibrinogen clotting activity is retained. Biochemistry 29: 3536 - 3542 (1990).PubMedCrossRefGoogle Scholar
  52. 52.
    R. Bar-Shavit, V. Sabbah, M.G. Lampugnani, P.C. Marchisio, J.W. Fenton II, I. Vlodaysky, and E. Dejane, An Arg-Gly-Asp sequence within thrombin promotes endothelial cell adhesion. J. Cell. Biol. 112: 335 - 344 (1991).PubMedCrossRefGoogle Scholar
  53. 53.
    D.H. Carney, R. Mann, W.R. Redin, S.D. Pernia, D. Berry, J.P. Heggers, P.G. Hayward, M.C. Robson, J. Christie, C. Annabli, J.W. Fenton II, and K.C. Glenn, Enhancement of incisional wound healing and neovascularization in normal rats by thrombin and synthetic thrombin receptor-activating peptides. J. Clin. Invest. 89: 1469–1477 (1992).PubMedCrossRefGoogle Scholar
  54. 54.
    U.B. Rasmussen, V. Vouret-Craviari, S. Jallot, Y. Schlesinger, G. Pages, A. Parirani, J.-P Lecocq, J. Pouyssegur, and E. Van ObberghenSchilling, DNA cloning and expression of a hamster a-thrombin receptor coupled to Cat+ mobilization. FEBS Lett. 288: 123 - 128 (1991)PubMedCrossRefGoogle Scholar
  55. 55.
    T.-K.H. Vu, D.T. Hung, V.I. Wheaton, and S.R. Coughlin, Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057 - 1068 (1991).PubMedCrossRefGoogle Scholar
  56. 56.
    E.G. Levin, D.M. Stern, P.P. Nawroth, R.A. Marlar, D.S. Fair, J.W. Fenton II, and L.A. Harker, Specificity of the thrombin-induced release of tissue plasminogen activator from cultured human endothelial cells. Thromb. Haemost. 56: 115 - 119 (1986).PubMedGoogle Scholar
  57. 57.
    K.T. Preissner, and D. Jenne, Structure of vitronectin and its biological role in haemostasis. Thromb. Haemost. 66: 123 - 132 (1991).PubMedGoogle Scholar
  58. 58.
    H. Lum, A.B. Malik, and J.W. Fenton II, unpublished data (1992).Google Scholar
  59. 59.
    L. Liu, M.A. Blajchman, L. Dewar, J.W. Fenton II, M. Andrew, M. Delorme, J. Ginsberg, and F.A. Ofosu, unpublished data (1993).Google Scholar
  60. 60.
    M.J. Berridge, Inositol trisphosphate and calcium signalling. Nature 361: 315 - 325 (1993).PubMedCrossRefGoogle Scholar
  61. 61.
    V. Vouret-Craviari, E. Van Obberghen-Schilling, E. Van Obberghen, and J. Pouyssegur, Differential activation of p44mapk (ERK1) by a-thrombin and thrombin-receptor peptide. Biochem. J. 289: 209 - 214 (1993).PubMedGoogle Scholar
  62. 62.
    C. Kanthou, G. Parry, E. Wijelath, V.V. Kakkar, and C. Demoliou-Mason, Thrombin-induced proliferation and expression of growth factor-A chain gene in human vascular smooth muscle cells. FEBS Lett. 314: 143 - 148 (1992).PubMedCrossRefGoogle Scholar
  63. 63.
    Y. Sugama, C. Tiruppathi, K. Janakidevi, T.T. Andersen, J.W. Fenton II, and A.B. Malik, Thrombin-induced expression of endothelial Pselectin and ICAM-1: a mechanism for stabilizing neutrophil adhesion. J. Cell. Biol. 119: 935 - 944 (1992).PubMedCrossRefGoogle Scholar
  64. 64.
    H. Lum, T.T. Andersen, A. Siflinger-Birnboim, C. Tiruppathi, M.S. Goligorsky, J.W. Fenton II, and A.B. Malik, Thrombin receptor peptide inhibits thrombin-induced increase in endothelial permeability by receptor desensitization. J. Cell. Biol. 120: 1491–1499 (1993).PubMedCrossRefGoogle Scholar
  65. 65.
    J.L. Catalfamo, T.T. Andersen, and J.W. Fenton II, unpublished data (1992).Google Scholar
  66. 66.
    C.A. McNamara, I.J. Sarembock, L.W. Gimple, J.W. Fenton II, S.R. Coughlin, and G.K. Owens, unpublished data (1993).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • John W. FentonII
    • 1
    • 2
  • Frederick A. Ofosu
    • 3
  1. 1.Wadsworth Center for Laboratories and ResearchNew York State Department of HealthAlbanyUSA
  2. 2.Department of Physiology and Cell Biology and Department of Biochemistry and Molecular BiologyAlbany Medical College of Union UniversityNew YorkUSA
  3. 3.Canadian Red Cross Society Blood Services Department of PathologyMcMaster UniversityHamiltonCanada

Personalised recommendations