Download PDF
Thromb Haemost 1975; 33(03): 573-585
DOI: 10.1055/s-0038-1647851
Original Article
Schattauer GmbH

Plasminogen-Plasmin System IX. Specific Binding of Tranexamic Acid to Plasmin

Masahiro Iwamoto
1   Research Institute, Daiichi Seiyaku, Co., Ltd., Edogawa-ku, Tokyo 132, Japan
› Author Affiliations
Further Information

Publication History

Received 02 October 1975

Accepted 02 January 1975

Publication Date:
02 July 2018 (online)

    Permissions and Reprints

Summary

Interactions between tranexamic acid and protein were studied in respect of the antifibrinolytic actions of tranexamic acid. Tranexamic acid did neither show any interaction with fibrinogen or fibrin, nor was incorporated into cross-linked fibrin structure by the action of factor XIII. On the other hand, tranexamic acid bound to human plasmin with a dissociation constant of 3.5 × 10−5 M, which was very close to the inhibition constant (3.6 × 10−5 M) for this compound in inhibiting plasmin-induced fibrinolysis. The binding site of tranexamic acid on plasmin was not the catalytic site of plasmin, because TLCK-blocked plasmin also showed a similar affinity to tranexamic acid (the dissociation constant, 2.9–4.8 × 10−5 M).

In the binding studies with the highly purified plasminogen and TLCK-plasmin preparations which were obtained by affinity chromatography on lysine-substituted Sepharose, the molar binding ratio was shown to be 1.5–1.6 moles tranexamic acid per one mole protein.

On the basis of these and other findings, a model for the inhibitory mechanism of tranexamic acid is presented.

 

  • References

  • 1 Abiko Y, Iwamoto M, Shimizu M. Plasminogen-Plasmin system. I. Purification and properties of human plasminogen. Journal of Biochemistry 1968; 64: 743
    PubMedGoogle Scholar
  • 2 Abiko Y, Iwamoto M, Shimizu M. Plasminogen-Plasmin system. II. Purification and properties of human plasmin. Journal of Biochemistry 1968; 64: 751
    PubMedGoogle Scholar
  • 3 Abiko Y, Iwamoto M, Tomikawa M. Plasminogen-Plasmin system. V. A stoichiometric equilibrium complex of plasminogen and a synthetic inhibitor. Biochimica et Biophysica Acta 1969; 185: 424
    CrossrefPubMedGoogle Scholar
  • 4 Abiko Y, Iwamoto M. Plasminogen-Plasmin system. VII. Potentiation of antifibrinolytic action of a synthetic inhibitor tranexamic acid, by α2-macroglobulin antiplasmin. Biochimica et Biophysica Acta 1970; 214: 411
    CrossrefPubMedGoogle Scholar
  • 5 Ambrus C. M, Ambrus J. L, Lassman H. B, Mink I. B. Mechanism of action of inhibitors of the fibrinolysin system. Annals New York Academy of Science 1968; 146: 430
    CrossrefPubMedGoogle Scholar
  • 6 Ambrus C. M, Ambrus J. M, Lassman H. B, Mink I. B. Heterogeneity of activity of various types of plasmins and the spectra of inhibition of some plasmin inhibitors. Research Communications in Chemical Pathology and Pharmacology 1970; 1: 67
    PubMedGoogle Scholar
  • 7 Brockway W. J, Castellino F. J. The mechanism of the inhibition of plasmin activity by ε-aminocaproic acid. The Journal of Biological Chemistry 1971; 246: 4641
    PubMedGoogle Scholar
  • 8 Brockway W. J, Castellino F. J. Measurement of the binding of antifibrinolytic amino acids to various plasminogens. Archives of Biochemistry and Biophysics 1972; 151: 194
    CrossrefPubMedGoogle Scholar
  • 9 Castellino F. J, Brockway W. J, Kerry Thomas J, Hui-Tseh Liao Rawitch A. B. Rotational diffusion analysis of the conformational alterations produced in plasminogen by certain antifibrinolytic amino acids. Biochemistry 1973; 12: 2787
    CrossrefPubMedGoogle Scholar
  • 10 Hayashi K, Ohba Y. SDS-Polyacrylamide gel electrophoresis (in Japanese). Protein Nucleic Acid and Enzyme 1972; 17: 304
    PubMedGoogle Scholar
  • 11 Hirose M, Kano Y. Binding of ligands by proteins: A simple method with Sephadex gel. Biochimica et Biophysica Acta 1971; 251: 376
    CrossrefPubMedGoogle Scholar
  • 12 Hummel J. P, Dreyer W. J. Measurement of protein-binding phenomena by gel filtration. Biochimica et Biophysica Acta 1962; 63: 530
    CrossrefPubMedGoogle Scholar
  • 13 Iwamoto M, Abiko Y, Shimizu M. Plasminogen-Plasmin system. III. Kinetics of plasminogen activation and inhibition of plasminogen-plasmin system by some synthetic inhibitors. Journal of Biochemistry 1968; 64: 759
    PubMedGoogle Scholar
  • 14 Iwamoto M, Abiko Y. Further kinetic studies on the inhibition of fibrinolysis by synthetic inhibitors. Journal of Biochemistry 1969; 65: 821
    PubMedGoogle Scholar
  • 15 Iwamoto M, Abiko Y. Plasminogen-Plasmin system. VI. Preparation of α2-maeroglobulin antiplasmin from human plasma. Biochimica et Biophysica Acta 1970; 214: 402
    CrossrefPubMedGoogle Scholar
  • 16 Landmann H. Studies on the mechanism of action of synthetic antifibrinolytics. A comparison with the action of derivatives of benzamidine on the fibrinolytic process. Thrombosis et Diathesis Haemorrhagica 1973; 29: 253
    PubMedGoogle Scholar
  • 17 Lowry O. H, Rosebrough N. J, Farr A. L, Randall R. J. Protein measurement with the folin phenol reagent. Journal of Biological Chemistry 1951; 193: 265
    PubMedGoogle Scholar
  • 18 Lukasiewicz H, Niewiarowski S, Worowski K, Lipiøski B. The plasmin inhibition by synthetic antifibrinolytic agents in relation to the type of substrate. Biochimica et Biophysica Acta 1968; 159: 503
    CrossrefPubMedGoogle Scholar
  • 19 Maxwell R. E, Lewandowski V, Nickel V. S. Effects of some amino acids on the inhibition of plasmin by antiplasmin. Biochimica et Biophysica Acta 1965; 99: 342
    CrossrefPubMedGoogle Scholar
  • 20 Maxwell R. E, Allen D. Interactions of E-aminocaproic acid with the thrombin clotting and fibrinolytic systems. Nature 1966; 209: 211
    CrossrefPubMedGoogle Scholar
  • 21 Maxwell R. E, Nawrocki J. W, Nickel V. S. Some complexities of multiple inhibitor interactions in fibrinolytic systems. Thrombosis et Diathesis Haemorrhagica 1968; 19: 117
    PubMedGoogle Scholar
  • 22 Mosesson M. W. The preparation of human fibrinogen free of plasminogen. Biochimica et Biophysica Acta 1962; 57: 204
    CrossrefPubMedGoogle Scholar
  • 23 Okamoto S, Takada Y, Okamoto U. An active stereo-isomer (transform) of AMCHA and its antifibrinolytic (antiplasminic) action in vitro and in vivo. Keio Journal of Medicine 1964; 13: 177
    CrossrefPubMedGoogle Scholar
  • 24 Okamoto S, Oshiba S, Mihara H, Okamoto U. Synthetic inhibitors of fibrinolysis : in vitro and in vivo mode of action. Annual New York Academy of Science 1968; 146: 414
    CrossrefPubMedGoogle Scholar
  • 25 Shaw E, Mares-Gttia M, Cohen W. Evidence for an active-center histidine in trypsin through the use of a specific reagent, 1-chloro-3-tosylamido-7-amino-2-heptanone, the chloromethyl ketone derived from Nα-tosyl-L-lysine. Biochemistry 1965; 4: 2219
    CrossrefPubMedGoogle Scholar
  • 26 Shimizu M, Naito T, Okano A, Aoyagi T. Trans-4-Aminomethyl-cyclohexanecarboxylic acid as a potent antiplasmin agent. Chemical and Pharmaceutical Bulletin 1965; 13: 1012
    PubMedGoogle Scholar
  • 27 Sjöholm I, Wiman B, Wallén P. Studies on the conformational changes of plasminogen induced during activation to plasmin and by 6-aminohexanoic acid. European Journal of Biochemistry 1973; 39: 471
    CrossrefPubMedGoogle Scholar
  • 28 Sodetz J. M, Brockway W. J, Castellino F. J. Multiplicity of rabbit plasminogen. Physical characterization. Biochemistry 1972; 11: 4451
    PubMedGoogle Scholar
  • 29 Wiman B, Wallén P. Activation of human plasminogen by an insoluble derivative of urokinase. Structural changes of plasminogen in the course of activation to plasmin and demonstration of a possible intermediate compound. European Journal of Biochemistry 1973; 36: 25
    CrossrefPubMedGoogle Scholar