Download PDF
Thromb Haemost 2001; 86(03): 739-745
DOI: 10.1055/s-0037-1616127
In Focus
Schattauer GmbH

Plasmin Induces Local Thrombolysis without Causing Hemorrhage: A Comparison with Tissue Plasminogen Activator in the Rabbit

Victor J. Marder
1   Vascular Medicine Program, Los Angeles Orthopaedic Hospital/University of California, Los Angeles
,
Kyle Landskroner
2   Department of Pharmacology, Bayer Corporation, Berkeley, California
,
Valery Novokhatny
3   Department of Biochemistry, Bayer Corporation, Raleigh, North Carolina, USA
,
Thomas P. Zimmerman
3   Department of Biochemistry, Bayer Corporation, Raleigh, North Carolina, USA
,
Mansze Kong
1   Vascular Medicine Program, Los Angeles Orthopaedic Hospital/University of California, Los Angeles
,
Joel J. Kanouse
1   Vascular Medicine Program, Los Angeles Orthopaedic Hospital/University of California, Los Angeles
,
Gary Jesmok
2   Department of Pharmacology, Bayer Corporation, Berkeley, California
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

The direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites.

These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.

Keywords

Plasmin - TPA - thrombolysis - hemorrhage - rabbits
 

  • References

  • 1 Franzosi MG, Santoro E, De Vita C, Geraci E, Lotto A, Maggioni AP, Mauri F, Rovelli F, Santoro L, Tavazzi L, Tognoni G. Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 study. The GISSI Investigators. Circulation 1998; 98: 2659-65.
    CrossrefPubMedGoogle Scholar
  • 2 Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Anglo-Scandinavian Study of Early Thrombolysis. Lancet 1990; 335: 1175-8.
    PubMedGoogle Scholar
  • 3 Ouriel K, Shortell CK, DeWeese JA, Green RM, Francis CW, Azodo MVU, Gutierrez OS, Manzione JV, Cox C, Marder VJ. A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia. J Vasc Surg 1994; 19: 1021-30.
    CrossrefPubMedGoogle Scholar
  • 4 An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.. The GUSTO Investigators. N Engl J Med 1993; 329: 673-82.
    CrossrefPubMedGoogle Scholar
  • 5 Gore JM, Sloan M, Price TR, Randall AM, Bovill E, Collen D, Forman S, Knatterud GL, Sopko G, Terrin ML. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, Phase II pilot and clinical trial. Circulation 1991; 83: 448-59.
    CrossrefPubMedGoogle Scholar
  • 6 Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest 1997; 111: 1241-5.
    CrossrefPubMedGoogle Scholar
  • 7 Ouriel K, Gray B, Clair DG, Olin J. Complications associated with the use of urokinase and recombinant tissue plasminogen activator for catheter-directed peripheral arterial and venous thrombolysis. J Vasc Interv Radiol 2000; 11: 295-8.
    CrossrefPubMedGoogle Scholar
  • 8 Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. N Engl J Med 1998; 338: 1105-11.
    CrossrefPubMedGoogle Scholar
  • 9 Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial.. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Lancet 1999; 354: 716-22.
    CrossrefPubMedGoogle Scholar
  • 10 Marder VJ. The use of thrombolytic agents: Choice of patient, drug administration, laboratory monitoring. Ann Int Med 1979; 90: 802-8.
    CrossrefPubMedGoogle Scholar
  • 11 Ambrus JL, Ambrus CM, Back N, Sokal JE, Collins GL. Clinical and experimental studies on fibrinolytic enzymes. Ann New York Acad Sci 1957; 68: 97-102.
    CrossrefPubMedGoogle Scholar
  • 12 Alkjaersig N, Fletcher AP, Sherry S. The mechanism of clot dissolution by plasmin. J Clin Invest 1959; 38: 1086-95.
    CrossrefPubMedGoogle Scholar
  • 13 Sherry S, Fletcher AP, Alkjaersig N. Fibrinolysis and fibrinolytic activity in man. Physiol Rev 1959; 39: 343-82.
    CrossrefPubMedGoogle Scholar
  • 14 Verstraete M, Vermylen J, Amery A. Enzymatic clot dissolution in man: a new therapeutic approach. Acta Clinica Belgica 1964; 19: 271-90.
    CrossrefPubMedGoogle Scholar
  • 15 Douglas AS, McNicol GP. Thrombolytic therapy. Brit Med Bull 1964; 20: 228-32.
    CrossrefPubMedGoogle Scholar
  • 16 Collen D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb Haemost 1980; 43: 77-89.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Cohn EJ, Strong LE, Hughes Jr WL, Mulford DJ, Ashworth JN, Melin M, Taylor HL. J Amer Chem Soc 1946; 68: 459-75.
    CrossrefPubMed
  • 18 Deutsch DG, Mertz ET. Plasminogen: purification from human plasma by affinity chromatography. Science 1970; 170: 1095-6.
    CrossrefPubMedGoogle Scholar
  • 19 Robbins KC, Summaria L. Plasminogen and plasmin. Meth Enzymology 1976; 45: 257-73.
    PubMedGoogle Scholar
  • 20 Marder VJ, Shortell CK, Fitzpatrick PG, Kim C, Oxley D. An animal model of fibrinolytic bleeding based on the rebleed phenomenon: Application to a study of vulnerability of hemostatic plugs of different age. Thromb Res 1992; 67: 31-40.
    CrossrefPubMedGoogle Scholar
  • 21 Montoney M, Gardell SJ, Marder VJ. Comparison of the bleeding potential of vampire bat salivary plasminogen activator (Bat-PA) versus tissue plasminogen activator (t-PA) in an experimental (rabbit) model. Circulation 1995; 91: 1540-4.
    CrossrefPubMedGoogle Scholar
  • 22 Shebuski RJ, Storer BL, Fujita T. Effect of thromboxane synthase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis. Thromb Res 1988; 52: 381-92.
    CrossrefPubMedGoogle Scholar
  • 23 Fujita T, Hasan S, Storer BL, Shebuski RJ. Effect of selectiveendoperoxide/thromboxane A2 receptor antagonism with sulotroban on tPA-induced thrombolysis in a rabbit model of femoral arterial thrombosis. Fundam Clin Pharmacol 1989; 3: 643-53.
    CrossrefPubMedGoogle Scholar
  • 24 Bero CJ, Cardella JF, Reddy K, Fox PS, Healy DA, Jaffe J, Nicholas GG. Recombinant tissue plasminogen activator for the treatment of lower extremity peripheral vascular occlusive disease. J Vasc Interv Radiol 1995; 6: 571-7.
    CrossrefPubMedGoogle Scholar
  • 25 Tissue plasminogen activator for acute ischemic stroke.. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581-7.
    CrossrefPubMedGoogle Scholar
  • 26 Onundarson PT, Francis CW, Marder VJ. Depletion of plasminogen in vitro or during thrombolytic therapy limits fibrinolytic potential. J Lab Clin Med 1992; 120: 120-8.
    PubMedGoogle Scholar
  • 27 Badylak SF, Voytik SL, Henkin J, Burke SE, Sasahara AA, Simmons A. Enhancement of the thrombolytic efficacy of prourokinase by lys-plasminogen in a dog model of arterial thrombosis. Thromb Res 1991; 62: 115-26.
    CrossrefPubMedGoogle Scholar
  • 28 Robbie LA, Bennett B, Croll AM, Brown PA, Booth NA. Proteins of the fibrinolytic system in human thrombi. Thromb Haemost 1996; 75: 127-33.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Dotter CT, Rosch J, Seaman AJ. Selective clot lysis with low-dose streptokinase. Radiology 1974; 111: 31-7.
    CrossrefPubMedGoogle Scholar
  • 30 Sicard GA, Schier JJ, Totty WG, Gilula LA, Walker WB, Etheredge EE, Anderson CB. Thrombolytic therapy for acute arterial occlusion. J Vasc Surg 1985; 2: 65-78.
    CrossrefPubMedGoogle Scholar
  • 31 Heymans S, Vanderschueren S, Verhaeghe R, Stockx L, Lacroix H, Nevel-steen A, Laroche Y, Collen D. Outcome and one year follow-up of intra-arterial staphylokinase in 191 patients with peripheral arterial occlusion. Thromb Haemost 2000; 83: 666-71.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Stump DC, Califf RM, Topol EJ, Sigmon K, Thornton D, Masek R, Anderson L, Collen D. Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. The TAMI Study Group. Circulation 1989; 80: 1222-30.
    CrossrefPubMedGoogle Scholar
  • 33 Carlson SE, Aldrich MS, Greenberg HS, Topol EJ. Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment. Arch Neurol 1988; 45: 1070-3.
    CrossrefPubMedGoogle Scholar
  • 34 Jang IK, Gold HK, Ziskind AA, Fallon JT, Holt RE, Leinbach RC, May JW, Collen D. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis. Circulation 1989; 79: 920-8.
    CrossrefPubMedGoogle Scholar
  • 35 Nachman RL, Harpel PC. Platelet alpha2-macroglobulin and alpha1-anti-trypsin. J Biol Chem 1976; 251: 4512-21.
    PubMedGoogle Scholar
  • 36 Francis CW, Marder VJ. Rapid formation of very large α-polymers in cross-linked fibrin induced by high factor XIII concentrations: Probable role of platelets as the physiologic source. J Clin Invest 1987; 80: 1459-65.
    CrossrefPubMedGoogle Scholar
  • 37 Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results for all randomised trials of more than 1000 patients.. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Lancet 1994; 343: 311-22.
    PubMedGoogle Scholar