Inhibition of fibrinolysis in blood: circadian fluctuation and possible relevance to coronary artery disease

  • F. Andreotti
  • G. J. Davies
  • A. Maseri
  • C. Kluft


The end-product of coagulation is a clot with a fibrin meshwork. Fibrin, however, is not a permanent structure, but stimulates a biochemical pathway that leads to its lysis pathway and fragmentation of the clot. Essential components of this, as a consequence, are the plasminogen activators (PAs). PAs convert the zymogen plasminogen to the ultimate fibrinolytic enzyme plasmin (Fig. 1). At least two types of PAs have been identified in plasma: one produced and secreted by endothelial cells (first isolated in urine), called tissue-type PA (t-PA), and another called urinary-type PA or urokinase (UK). UK was later also identified in plasma, mainly as a proenzyme known as pro-urokinase (pro-UK). t-PA and pro-UK both activate plasminogen, preferentially in the presence of fibrin, but by different mechanisms (for review, see [5]).


Plasminogen Activator Plasminogen Activator Inhibitor Fibrinolytic Activity Circadian Variation Fibrinolytic System 
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.
    Aillaud MF, Pignol F, Alessi MC, Harle JR, Escande M, Mongin M, Juhan-Vague I (1986) Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor, factor VIII: C and in erythrocyte sedimentation rate with age. Thromb Haemost 55: 330–332Google Scholar
  2. 2.
    Aimer L-O, Ohlin H (1987) Elevated levels of the rapid inhibitor of plasminogen-activator (tPAI) in acute myocardial infarction. Thromb Res 47: 335–339CrossRefGoogle Scholar
  3. 3.
    Andreotti F, Davies GJ, Hackett D, Khan MI, deBart A, Aber VR, Maseri A, Kluft C (1988) Major circadian fluctuations of fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol, in press.Google Scholar
  4. 4.
    Andreotti F, Davies GJ, Hackett D, Khan MI, deBart A, Dooijewaard G, Maseri A, Kluft C (1988) Circadian variation of fibrinolytic factors in normal human plasma. Fibrinolysis 2 (2): 90–92Google Scholar
  5. 5.
    Bachmann F (1987) Fibrinolysis. In: Verstraete M, Vermylen J, Leijnen L, Arnout J (eds) Thrombosis and Haemostasis. and Leuven University Press, Leuven, p 227–265Google Scholar
  6. 6.
    Binnema DJ, van Iersel JJL, Dooijewaard G (1986) Quantitation of urokinase antigen in plasma and culture media by use of an ELI SA. Thromb Res 43: 569–577PubMedCrossRefGoogle Scholar
  7. 7.
    Bosma PJ, van den Berg EA, Kooistra T, Siemieniak DR, Slightom JL (1988) Human plasminogen activator inhibitor-1 gene; promoter and structural gene nucleotide sequences. J Biol Chem in pressGoogle Scholar
  8. 8.
    Brommer EJP, Boks AL, Koopman J, Haverkate F (1985) Protraction of whole blood and plasma clot lysis in patients with high levels of an inhibitor of tissue-type plasminogen activator. Thromb Res 39: 271–280PubMedCrossRefGoogle Scholar
  9. 9.
    Chakrabarti R, Hocking ED, Fearnley GR, Mann RD, Attwell TN, Jackson D (1968) Fibrinolytic activity and coronary artery disease. Lancet 1: 987–990PubMedCrossRefGoogle Scholar
  10. 10.
    Cepelak VV, Barcal R, Lang N, Cepelakova H (1966) Zum Tag-and Nachtrhythmus der Fibrinolyse. Zschr Inn Med 21: 202–204Google Scholar
  11. 11.
    Cepelak VV, Barcal R, Cepelakova H, Mayer 0 (1978) Circadian Rhythm of Fibrinolysis In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC, eds. Progress in Chemical Fibrinolysis and Thrombolysis. Raven Press, New York, p 571–578Google Scholar
  12. 12.
    Davies MJ, Thomas A (1984) Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 310: 1137–1140PubMedCrossRefGoogle Scholar
  13. 13.
    DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang T (1980) Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303: 897–902PubMedCrossRefGoogle Scholar
  14. 14.
    Dooijewaard G, van Iersel JJL, Brommer EJP (1986) Quantitation of Pro-UK, UK and UK. Inhibitor levels in plasma of patients and healthy men. Fibrinolysis 1 (1): A142Google Scholar
  15. 15.
    Estelles A, Tormo G, Aznar J, Espana F, Tormo V (1985) Reduced fibrinolytic activity in coronary heart disease in basal conditions and after exercise. Thromb Res 40: 373–383PubMedCrossRefGoogle Scholar
  16. 16.
    Fearnley GR, Balmforth G, Fearnley E (1957) Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis. Clin Sci 16: 645–650PubMedGoogle Scholar
  17. 17.
    Franzen J, Nilsson B, Johansson BW, Nilsson IM (1983) Fibrinolytic activity in men with acute myocardial infarction before 60 years of age. Acta Med Scand 214: 339–344PubMedCrossRefGoogle Scholar
  18. 18.
    Gidron E, Margalit R, Oliven A, Shalitin Y (1977) Effect of myocardial infarction on components of fibrinolytic system. Br Heart J 39: 19–24PubMedCrossRefGoogle Scholar
  19. 19.
    Gram J, Jespersen J (1987) A selective depression of tissue plasminogen activator (t-PA) activity in euglobulins characterises a risk group among survivors of acute myocardial infarction. Thromb Haemost 57: 137–139PubMedGoogle Scholar
  20. 20.
    Grimaudo V, Hauert J, Bachmann F, Kruithof EKO (1988) Diurnal variation of the fibrinolytic system. Thromb Haemost 59: 495–499PubMedGoogle Scholar
  21. 21.
    Hamsten A, Wiman B, de Faire U, Blomback M (1985) Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 313: 1557–1563PubMedCrossRefGoogle Scholar
  22. 22.
    Hamsten A, Blomback M, Wiman B, Svensson J, Szamosi A, de Faire U, Mettinger L (1986) Haemostatic function in myocardial infarction. Br Heart J 55: 58–66PubMedCrossRefGoogle Scholar
  23. 23.
    Hamsten A, Walldius G, Szamosi A, Blomback M, de Faire U, Dahlen G, Landou C, Wiman B (1987) Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2: 3–9PubMedCrossRefGoogle Scholar
  24. 24.
    Hashimoto T, Kobayashi A, Yamaxaki N, Sugawara Y, Takada Y, Takada A (1987) Relationship between age and plasma t-PA, PA-inhibitor and PA activity. Thromb Res 46: 625Google Scholar
  25. 25.
    Huber K, Resch I, Rose D, Schuster E, Glogar D, Binder BR (1987) Circadian variation of plasminogen activator inhibitor (PAI) and the incidence of severe ischaemic attacks in patients with coronary artery disease. Thromb Haemost 58 (1): A224Google Scholar
  26. 26.
    Hume R (1958) Fibrinolysis in myocardial infarction. Br Heart J 20: 15–20PubMedCrossRefGoogle Scholar
  27. 27.
    Jespersen J, Kluft C (1986) Inhibition of tissue-type plasminogen activator in women using oral contraceptives and in normal women during a menstrual cycle. Thromb Haemost 55: 388–389PubMedGoogle Scholar
  28. 28.
    Kluft C (1978) Cl-inactivator-resistant fibrinolytic activity in plasma euglobulin fractions: Its relation to vascular activator in blood and its role in euglobulin fibrinolysis. Thromb Res 13: 135–151PubMedCrossRefGoogle Scholar
  29. 29.
    Kluft C, Verheijen JH, Jie AFH, Rijken DC, Preston FE, Sue-Ling HM, Jespersen J, Aasen AO (1985) The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 45: 605–610PubMedCrossRefGoogle Scholar
  30. 30.
    Kluft C, Verheijen JH, Rijken DC, Chang GTG, Jie AFH, Onkelinx C (1985) Diurnal fluctuations in the activity of the fast-acting t-PA inhibitor. In: Davidson JF, Donati MB, Coccheri S (eds) Progress in Fibrinolysis. Churchill-Livingstone, Edinburgh, vol 7, p 117–119Google Scholar
  31. 31.
    Kluft C (1988) t-PA in fibrin dissolution and haemostasis. In: Kluft C (ed) Tissue-type plasminogen activator (t-PA): physiological and clinical aspects. CRC press, Boca Raton, vol 1, p 47–49Google Scholar
  32. 32.
    Kluft C, Jie AFH, Rijken DC, Verheijen JH (1988) Daytime fluctuations in blood of tissue-type plasminogen activator (t-PA) and its fast-acting inhibitor (PAI-1). Thromb Haemost 59: 329–332Google Scholar
  33. 33.
    Kluft C, Andreotti F (1988) Consequences of the circadian fluctuation in plasminogen activator inhibitor 1 (PAI-1) for studies on blood fibrinolysis. Fibrinolysis 2 (2): 93–95Google Scholar
  34. 34.
    Komamura K, Hirayama A, Yamamoto K, Nanto S, Mishima M, Kodoma K (1988) Transient increase in endogenous plasma tissue plasminogen activator in patients with acute myocardial infarction. JACC 11 (2): 53AGoogle Scholar
  35. 35.
    Kruithof EKO, Nicoloso G, Bachmann F (1987) Plasminogen activator inhibitor 1. Development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 70: 1645–1653Google Scholar
  36. 36.
    Kruithof EKO, Gudinchet A, Bachmann F (1988) PAI-1 and PAI-2 in various disease states. Thromb Haemost 59: 7–12PubMedGoogle Scholar
  37. 37.
    Kunitz SC, Gross CR, Heyman A, Kase CS, Mohr JP, Price TR, Wolf PA (1984) The pilot stroke data bank: definition, design and data. Stroke 15: 740–746PubMedCrossRefGoogle Scholar
  38. 38.
    Mann RD (1967) Effect of age, sex and diurnal variation on the human fibrinolytic system. J Clin Path 20: 223–226PubMedCrossRefGoogle Scholar
  39. 39.
    Marshall J (1977) Diurnal variation in occurrence of strokes. Stroke 88: 230–231CrossRefGoogle Scholar
  40. 40.
    Mehta J, Mehta P, Lawson D, Saldeen T (1987) Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. JACC 9: 263–268PubMedCrossRefGoogle Scholar
  41. 41.
    Menon IS, White RWB, Smith PA, Dewar HA (1967) Diurnal variations of fibrinolytic activity and plasma-1 1-hydroxycorticosteroid levels. Lancet 2: 531–533PubMedCrossRefGoogle Scholar
  42. 42.
    Merskey C, Gordon H, Lackner H (1960) Blood coagulation and fibrinolysis in relation to coronary heart disease. Br Med J: 219–226Google Scholar
  43. 43.
    Muller JE, Stone PH, Turl ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK et al. (1985) Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 313: 1315–1322PubMedCrossRefGoogle Scholar
  44. 44.
    Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangos I, Stone PH (1987) Circadian variation in the frequency of sudden cardiac death. Circulation 75: 131–138PubMedCrossRefGoogle Scholar
  45. 45.
    Neerstrand H, Ostergaard P, Bergqvist D, Matzsch T, Hedner MU (1987) tPA inhibitor, tPA:Ag, Plasminogen, and a2-antiplasmin after low molecular weight heparin or standard heparin. Fibrinolysis 1: 39–43Google Scholar
  46. 46.
    Nilsson TK, Johnson 0 (1987) The exztrinsic fibrinolytic system in survivors of myocardial infarction. Thromb Res 48: 621–630CrossRefGoogle Scholar
  47. 47.
    Ogston D, Fullerton HW (1965) Plasma fibrinolytic activity following recent myocardial and cerebral infarction. Lancet 2: 99–101CrossRefGoogle Scholar
  48. 48.
    Paramo JA, Colucci M, Cohen D (1985) Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 291: 573–574CrossRefGoogle Scholar
  49. 49.
    Petralito A, Mangiafico RA, Gibiino S, Cuffari MA, Mlano MF, Fiore CE (1982) Daily modifications of plasma fibrinogen, platelets aggregation, Howell’s time, PTT, TT, and antithrombin III in normal subjects and in patients with vascular disease. Chronobiologia 9: 195–201Google Scholar
  50. 50.
    Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Bucht G (1986) Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme-linked immunosorbent assay. Clin Chem 32: 2160–2165PubMedGoogle Scholar
  51. 51.
    Rosing DR, Brakman P, Redwood DR, Goldstein RE, Beiser GD, Astrup T, Epstein SE (1970) Blood fibrinolytic activity in man: Diurnal variation and the response to varying intensities of exercise. Circ Res 27: 171–184Google Scholar
  52. 52.
    Rosing DR, Redwood DR, Brakman P, Astrup T, Epstein SE (1973) Impairment of the diurnal fibrinolytic response in man: effects of aging, type IV hyperlipoproteinemia and coronary artery disease. Circ Res 32: 752–758PubMedCrossRefGoogle Scholar
  53. 53.
    Simpson HCR, Meade TW, Stirling Y, Mann JI, Chakrabarti R, Woolf L (1983) Hypertriglyceridemia and hypercoagulability. Lancet 1: 786–790PubMedCrossRefGoogle Scholar
  54. 54.
    Six A, Liem MK, Haas FJLM, van Hemel NM, Dooijewaard G, Kluft C (1988) The state of the fibrinolytic system during the early phase of myocardial infarction and unstable angina. Fibrinolysis 2(1): Al5Google Scholar
  55. 55.
    Sprengers ED, Kluft C (1987) Plasminogen activator inhibitors. Blood 69: 381–387.PubMedGoogle Scholar
  56. 56.
    Stibbe J, Kluft C, Brommer EP, Gomes M, de Jong DS, Nauta J (1984) Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 14: 375–382PubMedCrossRefGoogle Scholar
  57. 57.
    Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Ruthenford JD, Willich SN, Gleason RE, Williams GH, Muller JE (1987) Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 316: 1514–1518PubMedCrossRefGoogle Scholar
  58. 58.
    Verheijen JH, Chang GTG, Kluft C (1984) Evidence for the occurrence of a fast acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemost 51: 392–395PubMedGoogle Scholar
  59. 59.
    Verheijen JH, Rijken DC, Chang GTG, Preston FE, Kluft C (1984) Modulation of rapid plasminogen activator inhibitor in plasma by stanozolol. Thromb Haemost 51: 396–397PubMedGoogle Scholar
  60. 60.
    Verheugt FWA, ten Cate JW, Sturk A, Imandt L, Verhorst PMJ, van Eenige MJ, Verwey W, Roos JP (1987) Tissue plasminogen activator activity and inhibition in acute myocardial infarction and angiographically normal coronary arteries. Am J Cardiol 59: 1075–1079PubMedCrossRefGoogle Scholar
  61. 61.
    Walker ID, Davidson JF, Hutton I, Lawrie TDV (1977) Disordered “fibrinolytic potential” in coronary heart disease. Thromb Res 10: 509–520PubMedCrossRefGoogle Scholar
  62. 62.
    Willich SN, Levy D, Rocco MB. Tofler GH, Stone PH, Muller JE (1987) Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study Population. Am J Cardiol 60: 801–806PubMedCrossRefGoogle Scholar
  63. 63.
    Willich SN, Sintonen SP, Bhatia SS, Tofler GH, Shook TL, Muller JE, Williams GH, Stone PH (1988) Morning increase of platelet aggregability in patients with coronary artery disease. JACC 11: 204AGoogle Scholar
  64. 64.
    World Health Organization Myocardial Infarction Community Registers (1979) In: Public Health in Europe. Regional Office for Europe (WHO), Copenhagen, Vol 5, p 1–232.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • F. Andreotti
    • 1
  • G. J. Davies
    • 1
  • A. Maseri
    • 1
  • C. Kluft
    • 2
  1. 1.Cardiovascular Research Unit RPMSHammersmith HospitalLondonUK
  2. 2.TNO Gaubius InstituteLeidenThe Netherlands

Personalised recommendations