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Thromb Haemost 1991; 65(04): 389-393
DOI: 10.1055/s-0038-1648158
Original Article
Schattauer GmbH Stuttgart

Stimulation of Plasmin Activity by Aspirin

Ariel Milwidsky
1   The Department of Obstetrics and Gynecology, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel
,
Zvendana Finci-Yeheskel
2   The Department of Clinical Biochemistry, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel
,
Michael Mayer
2   The Department of Clinical Biochemistry, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel
› Author Affiliations
Further Information

Publication History

Received: 08 May 1990

Accepted after revision 16 November 1990

Publication Date:
02 July 2018 (online)

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Summary

This study demonstrates an enhancing effect of aspirin on the amidolytic activity of plasmin. The stimulation of plasmin by aspirin was concentration-dependent and was attained at aspirin concentrations above 2 × 10−4 M. Aspirin produced a small, reproducible and statistically significant stimulation of the chromogenic activity of plasmin upon H-D-Valyl-L-Leucyl-L-Lysine-p-nitroanilide (3-2251) or pyro-Glu-Gly-Arg-p-nitroanilide (S-2444). Kinetic analysis demonstrated a slight decrease in the affinity of plasmin for substrate 3-2251 in the presence of aspirin, reflected by a change of the Km from 3.2 × 10-4 M to 3.8 × 10-4 M, and an increase of the Vm. The reciprocal Lineweaver-Burk curve indicated an uncompetitive type of stimulation. The stimulatory effect of aspirin was abolished by the lysine analogue α-aminohexanoic acid (AHA) but not by the α-amino acid glutamic acid. The effect of AHA suggests a specific involvement of lysine binding sites (LBS) on plasmin in the interaction of the enzyme with aspirin. Tlansient acidification of plasmin abolished its response to aspirin, to AHA and to their combination. The addition of aspirin to diluted human control or pregnancy plasma in vitro stimulated the plasma-mediated cleavage of the chromogenic substrate3-2251. In contrast to its effect on plasmin, aspirin failed to change the activity of tissue-type or urokinasetype plasminogen activators. It is conceivable that in addition to the antithrombotic effect of aspirin ascribed to its interaction with the platelets, aspirin also directly stimulates plasmin activity.

 

  • References

  • 1 Collen D. Molecular mechanisms of fibrinolysis and their application to fibrin-specific thrombolytic therapy. J Cell Biochem 1987; 33: 77-86
    CrossrefPubMedSearch in Google Scholar
  • 2 Saksela O, Rifkin DB. Cell-associated plasminogen activation: Regulation and physiological functions. Annu Rev Cell Biol 1988; 4: 93-126
    CrossrefPubMedSearch in Google Scholar
  • 3 Dano K, tsehrendt N, Lund LR. et al Cell surface plasminogen activation. In: Cancer Metastasis: Molecular and Cellular Biology, Host Immune Responses and Perspectives for Tieatment Schirrmacher Y, Schwartz-Albiez R. eds Springer Verlag; Berlin: 1989: 98-107
  • 4 Mayer M. Biochemical and biological aspects of the plasminogen activation system. Clin Biochem 1990; 23: 197-211
    CrossrefPubMedSearch in Google Scholar
  • 5 Lijnen HR, Collen D. Molecular mechanisms of thrombolytic therapy. Haemostasis 1986; 16 (Suppl. 03) Suppl 3-15
    PubMedSearch in Google Scholar
  • 6 Markus G, De Pasquale JL, Wissler FC. euantitative determination of the binding of epsilon-aminocaproic acid to native plasminogen. J Biol Chem 1978; 253: 727-732
    PubMedSearch in Google Scholar
  • 7 Collen D. On the regulation and control of fibrinolysis. Thromb Haemostas 1980; 43: 77-89
    PubMedSearch in Google Scholar
  • 8 Rickli EE, Otavski WI. A new method of isolation and some properties of heavy chain of human plasmin. Eur J Biochem 1975; 59: 441-447
    CrossrefPubMedSearch in Google Scholar
  • 9 Wiman B, Collen D. On the kinetics of the reaction between human antiplasmin and plasmin. Eur J Bioch em 1978; 84: 573-578
    PubMedSearch in Google Scholar
  • 10 Higazi A, Mayer M. Inhibition of plasmin by fibrinogen. Biochem J 1990; 269: 299-302
    CrossrefPubMedSearch in Google Scholar
  • 11 Higazi A, Mayer M. Effects of penicillins and β-aminohexanoic acid on the kinetics of human plasmin. Biochem J 1989; 260: 609-612
    CrossrefPubMedSearch in Google Scholar
  • 12 Ranby M, Brandstrom A. Biological control of tissue plasminogen activator-mediated fibrinolysis. Enzyme 1988; 40: 130-143
    CrossrefPubMedSearch in Google Scholar
  • 13 Moroz LA. Increased blood fibrinolytic activity after aspirin ingestion. N Engl J Med 1977; 296: 525-529
    CrossrefPubMedSearch in Google Scholar
  • 14 Louie S, Gurewich V. The antithrombotic effect of aspirin and dipyridamole in relation to prostaglandin synthesis. Thromb Res 1983; 30: 323-345
    CrossrefPubMedSearch in Google Scholar
  • 15 Fuster V, Cohen M, Halperin J. Aspirin in the prevention of coronary disease. N Engl J Med 1989; 321: 183-185
    CrossrefPubMedSearch in Google Scholar
  • 16 Green D, Davies Ro, Holmes GI, Johnson C, Kohl H, Reynolds N, Tsio C-H. Fibrinolytic activity after administration of diflunisal and aspirin. Haemostasis 1983; 13: 394-398
    PubMedSearch in Google Scholar
  • 17 Cattaneo M, Chahil A, Somers D, Kinlough-Rathbone RL, packham MA, Mustard JE. Effect of aspirin and sodium salicylate on thrombosis, fibrinolysis, prothrombin time and platelet survival in rabbits with indwelling aortic catheters. Blood 1983; 6l: 353-361
    PubMedSearch in Google Scholar
  • 18 Levin RI, Harpel PC, weil D, Chamg T-S, Rifkin DB. Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity. J Clin Invest 1984 74. 571-580
    PubMedSearch in Google Scholar
  • 19 Boumnameaux H, Gresele P, Hanss M, De Cock E, vermylen J, Collen D. Aspirin, indomethacin and dazoxiben do not affect the fibrinolytic activation induced by venous occlusion. Thromb Res 1985; 40: 161-170
    CrossrefPubMedSearch in Google Scholar
  • 20 Hammouda MW, Moroz LA. Aspirin and venous occlusion: Effects on blood fibrinolytic activity and tissue:type plasminogen activator ievels. Thromb Res 1986; 42: 73-82
    CrossrefPubMedSearch in Google Scholar
  • 21 De Gaetano G, Carriero MR, Cerletti C, Moussoni L. Low-dose aspirin does not prevent fibrinolytic response to venous occlusion. Biochem Pharmacol 1986; 35: 3147-3150
    CrossrefPubMedSearch in Google Scholar
  • 22 Levin RI, Harpel PA, Harpel JG, Recht PA. Inhibition of tissue plasminogen activator activity by aspirin in vivo and its relationship to levels of tissue plasminogen activator antigen, plasminogen activator inhibitor, and their complexes. Blood 1989; 74: 1635-1643
    PubMedSearch in Google Scholar
  • 23 Beaufils M, Donsimoni R, llzam S, Colan JC. prevention of preeclampsia by early antiplatelet therapy. Lancet 1985; i: 840-842
    PubMedSearch in Google Scholar
  • 24 Wallenburg HCS, Makovitz JW, Dekker GA, Rotmans O. Low-dose aspirin prevents pregnancy-induced hypertension and preeclampsia in angiotensin sensitive primigravidae. Lancet 1986; i: 1-3
    PubMedSearch in Google Scholar
  • 25 Wallenberg HCS, Rotmans N. Prevention of recurrent idiopathic fetal growth retardation by low-dose aspirin and dipyridamole. Am J Obstet Gynecol 1987; 157: 1230-5
    CrossrefPubMedSearch in Google Scholar
  • 26 Trudinger BJ, Cook CM, Thompson RS. et al Low-dose aspirin therapy improves fetal weight in umbilical placental insufficiency. Am J Obstet Gynecol 1988; 159: 681-685
    CrossrefPubMedSearch in Google Scholar
  • 27 Schiff E, Peleg E, Goldenberg M, Rosenthal I, Ruppin E, Thmarkin M, Barkai G, Ben-Baruch G, Yahal I, Blankstein J, Goldmatr B, Mashiach S. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high-risk pregnancies. N Engl J Med 1989; 321: 351-356
    CrossrefPubMedSearch in Google Scholar
  • 28 Sibai BH, Mirro R, Chesney CM, Leffler C. Low-dose aspirin in pregnancy. Obstet Gynecol 1989; 74: 551-557
    PubMedSearch in Google Scholar
  • 29 Ylikorkala O, Pekonen E, Viinikka L. Renal prostacyclin and thromboxane in normotensive and preeclamptic pregnant women and their infants. J Clin Endoc Met 1986; 63: 1307-1312
    PubMedSearch in Google Scholar
  • 30 Fitzgerald DJ, Rocki W, Murray R, Mayo G, Fitzgerald GA. Thromboxane A2 synthesis in pregnancy-induced hypertension. Lancet 1990; 335: 751-754
    CrossrefPubMedSearch in Google Scholar
  • 31 Deutsch DG, Mertz ET. Plasminogen: Purification from human plasma by affinity chromatography. Science 1970; 170: 1095-1096
    CrossrefPubMedSearch in Google Scholar
  • 32 Yioland BN, Byrne R, Castellino EI. The effect of alpha-, omegaamino acids on human plasminogen structure and activation. J Biol Chem 1978; 253: 5395-5401
    PubMedSearch in Google Scholar
  • 33 Wiman B, Collen D. Molecular mechanism of physiological fibrinolysis. Nature 1978; 272: 549-550
    CrossrefPubMedSearch in Google Scholar
  • 34 Thorsen S. Differences in the binding to fibrin of native plasminogen and plasminogen modified by proteolytic degradation. Influence of omega-aminocarboxylic acid. Biochim Biophys Acta 1975 393. 55-65
    PubMedSearch in Google Scholar
  • 35 Wiman B, Wallen P. The specific interaction between plasminogen and fibrin. A physiological role of the lysine binding site in plasminogen. Thromb Res 1977; 11: 213-222
    PubMedSearch in Google Scholar
  • 36 Saksela O. Plasminogen activation and regulation of pericellular proteolysis. Biochim Biophys Acta 1985; 823: 35-65
    PubMedSearch in Google Scholar
  • 37 Rijken DC, Groeneveld E. Isolation and functional characterization of the heavy and light chains of human tissue-type plasminogen activator. J Biol Chem 1986; 261: 3098-5102
    PubMedSearch in Google Scholar
  • 38 Vaugham De, Declerck PJ, DE Mol M, Collen D. Recombinant plasminogen activator inhibitor-l reverses the bleeding tendency associated with the combined administration of tissue-type plasminogen activator and aspirin in rabbits. J Clin Invest 1989; 84: 586-591
    CrossrefPubMedSearch in Google Scholar
  • 39 Loscalzo J, Vaugham DE. Tissue plasminogen activator promotes platelet disaggregration in plasma. J Clin Invest 1987; 79: 1749-1755
    CrossrefPubMedSearch in Google Scholar
  • 40 De Gaetano G, Cerletti C, Dejana E, Latini R. Pharmacology of platelet inhibition in humans: Implications of the salicylate-aspirin interaction. Circulation 1985; 72: 1185-1593
    CrossrefPubMedSearch in Google Scholar
  • 41 Astedt B, Isacsoil S, Nilsson IM. Fibrinolytic activity of veins during pregnancy. Acta Obstet Gynecol Scand 1970; 49: 171-173
    CrossrefPubMedSearch in Google Scholar
  • 42 Wiman B, Csemiczky G, Marsk L, Robbe H. The level of fast inhibitor of tissue plasminogen activator in plasma during pregnancy. Thromb Haemostas 1984; 52: 124-126
    PubMedSearch in Google Scholar
  • 43 Chmielewska J, Ranby M, Wiman B. Evidence for a rapid inhibitor to tissue-type plasminogen activator in plasma. Thromb Res 1983; 31: 427-437
    CrossrefPubMedSearch in Google Scholar