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Thromb Haemost 1999; 81(04): 601-604
DOI: 10.1055/s-0037-1614532
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Schattauer GmbH

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

Hiroyuki Matsuno
1   From the Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
2   Department of Physiology, Kinki University School of Medicine, Osakasayama City, Japan
,
Osamu Kozawa
1   From the Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
,
Masayuki Niwa
1   From the Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
,
Shigeru Ueshima
2   Department of Physiology, Kinki University School of Medicine, Osakasayama City, Japan
,
Osamu Matsuo
2   Department of Physiology, Kinki University School of Medicine, Osakasayama City, Japan
,
Désiré Collen
3   Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
,
Toshihiko Uematsu
1   From the Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
› Author Affiliations
Further Information

Publication History

Received 14 August 1998

Accepted after resubmission 16 December 1998

Publication Date:
09 December 2017 (online)

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Summary

The role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

 

  • References

  • 1 Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90: 2126-46.
    CrossrefPubMedGoogle Scholar
  • 2 Matsuo O, Rijken DC, Collen D. Thrombolysis by human tissue plasminogen activator and urokinase in rabbits with experimental pulmonary embolus. Nature 1981; 291: 590-1.
    CrossrefPubMedGoogle Scholar
  • 3 Matsuo O, Banjo H, Okada K, Tanaka K, Sucked M, Ida Y, Armour H. Thrombolytic effect of single-chain pro-urokinase in a rabbit jugular vein thrombosis model. Thromb Res. 1986; 42: 187-94.
    PubMedGoogle Scholar
  • 4 Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78: 3114-24.
    PubMedGoogle Scholar
  • 5 Plow EF, Herren T, Redlitz A, Miles LA, Hoover-Plow JL. The cell biology of the plasminogen system. FASEB J 1995; 9: 939-45.
    CrossrefPubMedGoogle Scholar
  • 6 Okada K, Ueshima S, Takaishi T, Yuasa H, Fukao H, Matsuo O. Effect of fibrin and α2-antiplasmin on plasminogen activation by staphylokinase. Am J Hematol 1996; 53: 151-7.
    CrossrefPubMedGoogle Scholar
  • 7 Levi M, Biemond BJ, van Zonneveld AJ, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85: 305-12.
    CrossrefPubMedGoogle Scholar
  • 8 Braaten JV, Handt S, Jerome WG, Kirkpatrick J, Lewis JC, Hantgan RR. Regulation of fibrinolysis by platelet-released plasminogen activator inhibitor 1: light scattering and ultrastructural examination of lysis of a model platelet-fibrin thrombus. Blood 1993; 81: 1290-9.
    PubMedGoogle Scholar
  • 9 Stringer HA, van Swieten P, Heijnen HF, Sixma JJ, Pannekoek H. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Studies with thrombi generated in the Chandler loop. Arterioscler Thromb 1994; 14: 1452-8.
    CrossrefPubMedGoogle Scholar
  • 10 Kunitada S, FitzGerald GA. Fitzgerald DJ. Inhibition of clot lysis and decreased binding of tissue-type plasminogen activator as a consequence of clot retraction. Blood 1992; 79: 1420-7.
    PubMedGoogle Scholar
  • 11 Matsuno H, Uematsu T, Nagashima S, Nakashima M. Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model. J Pharmacol Meth 1991; 25: 303-17.
    CrossrefPubMedGoogle Scholar
  • 12 Matsuno H, Uematsu T, Umemura K, Takiguchi Y, Wada K, Nakashima M. Effects of vapiprost, a novel thromboxane receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tissue-type plasminogen activator. Br J Pharmacol 1992; 106: 533-8.
    CrossrefPubMedGoogle Scholar
  • 13 Hirata Y, Takiguchi Y, Wada K, Matsuno H, Umemura K, Uematsu T, Nakashima M. Roles of platelet-activating factor, thromboxane A2, ADP and thrombin in thrombogenesis in the guinea pig. Eur J Pharmacol 1993; 231: 421-5.
    CrossrefPubMedGoogle Scholar
  • 14 Takiguchi Y, Shimazawa M, Nakashim M. A comparative study of the anti-thrombotic effect of aurintricarboxylic acid on arterial thrombosis in rats and guinea pigs. Br J Pharmacol 1996; 118: 1633-8.
    CrossrefPubMedGoogle Scholar
  • 15 Carmeliet P, Kieckens L, Schoonjans L, Ream B, Van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 1993; 92: 2746-55.
    CrossrefPubMedGoogle Scholar
  • 16 Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC. Physiological consequence of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-24.
    CrossrefPubMedGoogle Scholar
  • 17 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92: 2756-60.
    CrossrefPubMedGoogle Scholar
  • 18 Carmeliet P, Stassen JM, Van Vlaenderen I, Meidell RS, Collen D, Gerard RD. Adenovirus-mediated transfer of tissue-type plasminogen activator augments thrombolysis in tissue-type plasminogen activator-deficient and plasminogen activator inhibitor-1-overexpressing mice. Blood 1997; 90: 1527-34.
    PubMedGoogle Scholar
  • 19 Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995; 92: 2585-93.
    CrossrefPubMedGoogle Scholar
  • 20 Matsuno H, Kozawa O, Niwa M, Kaida T, Hayashi H, Uematsu T. GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster. Br J Pharmacol 1997; 122: 1099-104.
    CrossrefPubMedGoogle Scholar
  • 21 DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897-902.
    CrossrefPubMedGoogle Scholar
  • 22 Boehrer JD, Glamann DB, Lange RA, Willard JE, Brogan WC, Eichhorn EJ, 3rd Grayburn PA, Anwar A, Hillis LD. Effect of coronary angioplasty on late potentials one to two weeks after acute myocardial infarction. Am J Cardiol 1992; 70: 1515-9.
    CrossrefPubMedGoogle Scholar
  • 23 Simes RJ, Topol EJ, Holmes DR, White Jr HD, Rutsch WR, Vahanian A, Simoons ML, Morris D, Betriu A, Califf RM. et al Link between the angio-graphic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995; 91: 1923-8.
    CrossrefPubMedGoogle Scholar
  • 24 Strickland S, Reich E, Sherman I M. Plasminogen activator in early embryo-genesis: enzyme production by trophoblast and parietal endoderm. Cell 1976; 9: 231-40.
    CrossrefPubMedGoogle Scholar
  • 25 Rifkin DB, Moscatelli D, Bizik J, Quarto N, Blei F, Dennis P, Flaumenhaft R, Mignatti P. Growth factor control of extracellular proteolysis. Cell Diff Devel 1990; 32: 313-8.
    PubMedGoogle Scholar
  • 26 Fujii S, Sobel BE. Induction of plasminogen activator inhibitor by products released from platelets. Circulation 1990; 82: 1485-93.
    CrossrefPubMedGoogle Scholar
  • 27 Reilly CF, Fujita T, Mayer EJ, Siegfried ME. Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. Arterioscl Thromb 1991; 11: 1276-86.
    CrossrefPubMedGoogle Scholar
  • 28 Marsh JJ, Konopka RG, Lang IM, Wang HY, Pedersen C, Chiles P, Reilly CF, Moser KM. Suppression of thrombolysis in a canine model of pulmonary embolism. Circulation 1994; 90: 3091-7.
    CrossrefPubMedGoogle Scholar
  • 29 Dieval J, Nguyen G, Gross S, Delobel J, Kruithof EK. A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1. Blood 1991; 77: 528-32.
    PubMedGoogle Scholar
  • 30 Lee MH, Vosburgh E, Anderson K, McDonagh J. Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. Blood 1993; 81: 2357-62.
    PubMedGoogle Scholar