Download PDF
Thromb Haemost 2003; 89(05): 820-825
DOI: 10.1055/s-0037-1613467
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Suppression of argatroban-induced endogenous thrombolysis by PKSI-527, and antibodies to TPA and UPA, evaluated in a rat arterial thrombolysis model

Masaru Hashimoto
1   Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe
2   High Technology Research Centre, Kobe Gakuin University, Kobe
,
Kazuhiro Oiwa
3   Communications Research Laboratory, Kansai Advanced Research Centre, Kobe
,
Osamu Matsuo
4   Second Department of Physiology, Kinki University School of Medicine, Osaka
,
Shigeru Ueshima
4   Second Department of Physiology, Kinki University School of Medicine, Osaka
,
Kiyotaka Okada
4   Second Department of Physiology, Kinki University School of Medicine, Osaka
,
Yoshio Okada
2   High Technology Research Centre, Kobe Gakuin University, Kobe
6   Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
,
Shosuke Okamoto
5   Kobe Research Projects on Thrombosis and Haemostasis, Kobe,
,
John C. Giddings
7   Department of Haematology, University of Wales College of Medicine, Cardiff, UK
,
Junichiro Yamamoto
1   Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe
2   High Technology Research Centre, Kobe Gakuin University, Kobe
› Author Affiliations
Further Information

Publication History

Received 25 September 2002

Accepted after revision 15 February 2003

Publication Date:
09 December 2017 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

We have previously confirmed, using a rat mesenteric arteriole thrombolysis model, that thrombin inhibition induces endogenous thrombolysis in vivo. In addition, we have shown that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in the down regulation of endogenous thrombolysis. However, the mechanism of endogenous thrombolysis or spontaneous plasmin generation in vivo remains unclear.

It has been shown in an in vitro system that plasma kallikrein activates pro-urokinase (pro uPA) and/or plasminogen, resulting in plasmin generation. These findings suggest that spontaneous fibrinolysis might be mediated by tPA and plasma kallikrein-dependent uPA. The aim of the present study was to examine whether these mechanisms play a dominant role in endogenous thrombolysis in vivo, using our rat mesenteric arterial thrombolysis model.

Argatroban infusion enhanced endogenous thrombolysis. PKSI-527, anti uPA and anti tPA IgGs suppressed argatroban-induced thrombolysis. Also, the antibody IgG preparations suppressed endogenous thrombolysis in the absence of argatroban. In the presence of PKSI-527, anti tPA IgG was more effective than anti uPA IgG in suppressing argatroban-induced thrombolysis. The results suggested that both tPA and plasma kallikrein-mediated uPA activation and tPA release contribute to endogenous fibrinolytic or thrombolytic mechanisms.

Keywords

Endogenous thrombolysis - plasma kallikrein - plasminogen activator - TAFI - animal model
 

  • References

  • 1 Antman EM.. for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994; 90: 1624-30.
    CrossrefPubMedGoogle Scholar
  • 2 GUSTO IIb investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Eng J Med 1996; 335: 775-82.
    CrossrefPubMedGoogle Scholar
  • 3 Jang IK, Gold HK, Ziskind AA, Leinbach RC, Fallon JT, Collen D.. Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition. Circulation 1990; 81: 219-25.
    CrossrefPubMedGoogle Scholar
  • 4 Badimon L, Badimon JJ, Lassila R, Lassila R, Heras M, Chesebro JH, Fuster V.. Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial flow condition in porcine model: effects of hirudins, heparin, and calcium chelation. Blood 1991; 78: 423-34.
    PubMedGoogle Scholar
  • 5 Yamashita T, Yamamoto J, Sasaki Y, Matsuoka A.. The antithrombotic effect of low molecular weight synthetic thrombin inhibitors, argatroban and PPACK, on He-Ne laser-induced thrombosis in rat mesenteric microvessels. Thromb Res 1993; 69: 93-100.
    CrossrefPubMedGoogle Scholar
  • 6 Sasaki Y, Morii S, Yamashita T, Yamamoto J.. Antithrombotic effect of argatroban on the pial vessels of the rat: a study with He-Ne laser-induced thrombus formation. Haemostasis 1993; 23: 104-11.
    PubMedGoogle Scholar
  • 7 Hashimoto M, Watanabe S, Oiwa K.. et al. Enhanced thrombolysis induced by argatroban or activated protein C in the presence or absence of staphylokinase, measured in an in vivo animal model using mesenteric arterioles. Haemostasis 2001; 31: 80-9.
    PubMedGoogle Scholar
  • 8 Schneider J.. Heparin and the thrombin inhibitor argatroban enhance fibrinolysis by infused or bolus-injected saruplase (r-scu-PA) in rabbit femoral artery thrombosis. Thromb Res 1991; 64: 677-89.
    CrossrefPubMedGoogle Scholar
  • 9 Gold HK, Yasuda T, Jang I.. et al. Animal models for arterial thrombolysis and prevention of reocclusion. Circulation 1991; 83 [suppl IV] IV-26-IV-40.
    CrossrefPubMedGoogle Scholar
  • 10 Bajzar L, Nesheim M.. The effect of activated protein C on fibrinolysis in cell-free plasma can be attributed specifically to attenuation of prothrombin activation. J Biol Chem 1993; 268: 8608-16.
    PubMedGoogle Scholar
  • 11 von dem Borne PA, Bajzar L, Meijers JCM.. et al. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99: 2323-7.
    CrossrefPubMedGoogle Scholar
  • 12 Bajzar L, Nesheim ME, Tracy PB.. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 1996; 88: 2093-100.
    PubMedGoogle Scholar
  • 13 Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME.. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-81.
    CrossrefPubMedGoogle Scholar
  • 14 Krement P, Liao P, Bajzar L.. A novel approach to arterial thrombolysis. Blood 1999; 94: 2735-43.
    PubMedGoogle Scholar
  • 15 Redlitz A, Nicolini FA, Malycky JL, Topol EJ, Plow EF.. Inducible carboxypeptidase activity. Circulation 1996; 93: 1328-30.
    CrossrefPubMedGoogle Scholar
  • 16 Nagashima M, Werner M, Wang M.. et al. An inhibitor of activated thrombin-activatable fibrinolysis inhibitor potentiates tissue-type plasminogen activator-induced thrombolysis in a rabbit jugular vein thrombolysis model. Thromb Res 2000; 98: 333-42.
    CrossrefPubMedGoogle Scholar
  • 17 Hashimoto M, Oiwa K, Watanabe S.. et al. Enhancement of endogenous plasminogen activator-induced thrombolysis by argatroban and activated protein C and its control by thrombin-activatable fibrinolysis inhibitor, measured in an arterial thrombolysis model in vivo using rat mesenteric arterioles. Thromb Haemost 2002; 87: 110-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Ichinose A, Fujikawa K, Suyama T.. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986; 261: 3486-9.
    PubMedGoogle Scholar
  • 19 Hauert J, Nicoloso G, Schleuning WD.. et al. Plasminogen activators in dextran sulphate-activated euglobulin fractions: a molecular analysis of factor XII- and prekallikreinde-pendent fibrinolysis. Blood 1989; 73: 994-9.
    PubMedGoogle Scholar
  • 20 Motta G, Rojkjaer R, Hasan AAK.. et al. High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: A novel mechanism for contact activation. Blood 1998; 91: 516-28.
    PubMedGoogle Scholar
  • 21 Motta G, Shariat-madar Z, Mahdi F, Sampaio CAM, Schmaier AH.. Assembly of high molecular weight kininogen and activation of prekallikrein on cell matrix. Thromb Haemost 2001; 86: 840-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Wanaka K, Okamoto S, Bohgaki M.. et al. Effect of a highly selective plasma-kallikrein synthetic inhibitor on contact activation relating to kinin generation, coagulation and fibrinolysis. Thromb Res 1990; 57: 889-95.
    CrossrefPubMedGoogle Scholar
  • 23 Okada K, Yuasa H, Hagiya Y.. et al. Fibrinolytic activity in liver tissues of stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1995; (Suppl. 01) Suppl. S275-S6.
    PubMedGoogle Scholar
  • 24 Holmgren J, Svennerholm AM, Ouchterlony O.. Quantitation of vibriocidal antibodies using agar plague techniques. Acta Pathol Microbiol Scand [B] Microbiol Immunol 1971; 79: 708-14.
    PubMedGoogle Scholar
  • 25 Hashimoto M, Yamamoto J, Oiwa K.. et al. Suppression of endogenous thrombolysis by a synthetic plasma kallikrein inhibitor, PKSI-527, and antibodies to tPA and uPA, evaluated in a rat arterial thrombolysis model. Supplement to the journal Thrombosis and Haemostasis, July [Suppl] 2001 abstract P440.
    PubMedGoogle Scholar
  • 26 Iwamoto M.. Plasminogen-plasmin system IX. Specific binding of tranexamic acid to plasmin. Thrombus Diathes Haemorrh 1975; 33: 573-85.
    PubMedGoogle Scholar
  • 27 Jang IK, Brown DFM, Giugliano RP.. et al. A multicenter randomised study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol 1999; 33: 1879-85.
    CrossrefPubMedGoogle Scholar
  • 28 Yamamoto J, Ishii I, Sasaki Y, Nagamatsu Y, Matsuda E, Ando E.. Antithrombotic effect of ticlopidine on He-Ne laser-induced thrombus formation in rat mesenteric microvessels. Haemostasis 1992; 22: 147-52.
    PubMedGoogle Scholar
  • 29 Smith D, Gilbert M, Owen WG.. Tissue plasminogen activator release in vivo in response to vasoactive agents. Blood 1985; 66: 835-9.
    PubMedGoogle Scholar
  • 30 Brown NJ, Nadeau JH, Vaughan DE.. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997; 77: 522-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Matsuo O, Rijken DC, Collen D.. Comparison of the relative fibrinogenolytic, Fibrinolytic and thrombolytic properties of tissue plasminogen activator and urokinase in vitro. Thromb Haemost 1981; 45: 225-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Park S, Harker LA, Marzec UM, Levin EG.. Demonstration of single chain urokinase-type plasminogen activator on human platelet membrane. Blood 1989; 73: 1421-5.
    PubMedGoogle Scholar
  • 33 Carroll RC, Radcliffe RD, Taylor FB, Gerrard JM.. Plasminogen, plasminogen activator, and platelets in the regulation of clot lysis. J Lab Clin Med 1982; 100: 986-96.
    PubMedGoogle Scholar
  • 34 Gurewich V, Pannell R.. A comparative study of the efficacy and specificity of tissue plasminogen activator and pro-urokinase: demonstration of synergism and of different thresholds of non-selectivity. Thromb Res 1986; 44: 217-28.
    CrossrefPubMedGoogle Scholar
  • 35 Gurewich V, Emmons F, Pannell R.. Spontaneous clot lysis in whole human plasma by endogenous tissue type and urokinase type plasminogen activators: demonstration of a promoting effect by t-PA and by platelets on urokinase. Fibrinolysis 1988; 2: 143-9.
    PubMedGoogle Scholar
  • 36 Loza JP, Gurewich V, Johnstone M, Pannell R.. Platelet-bound prekallikrein promotes prourokinase-induced clot lysis: a mechanism for targeting the factor XII dependent intrinsic pathway of fibrinolysis. Thromb Haemost 1994; 71: 347-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Povlishoch JT, Rosenblum WI.. Injury of brain microvessels with a herium-neon laser and Evans blue can elicit local platelet aggregation without endothelial denudation. Arch Pathol Lab Med 1987; 111: 415-21.
    PubMedGoogle Scholar
  • 38 Yamamoto J, Oyama T, Ishii I.. et al. The differential involvement of von Willebrand factor, fibrinogen and fibronectin in acute experimental thrombosis in rat cerebral and mesenteric microvessels. Jpn J Physiol 1997; 47: 431-41.
    CrossrefPubMedGoogle Scholar
  • 39 Hashimoto M, Onobayashi Y, Oiwa K.. et al. Enhanced endogenous thrombolysis induced by a specific factor Xa inhibitor, DX-9065a, evaluated in a rat arterial thrombolysis model in vivo. Thromb Res 2002; 106: 165-8.
    CrossrefPubMedGoogle Scholar
  • 40 Hamsten A, Wiman B, De Faire U, Blomback M.. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
    CrossrefPubMedGoogle Scholar
  • 41 Fransis RB, Kawanishi D, Baruch T.. et al. Impaired fibrinolysis in coronary artery disease. Am Heart J 1988; 115: 776-80.
    CrossrefPubMedGoogle Scholar