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New Developments in Thrombolytic Therapy

  • D. Collen
  • H. K. Gold
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 281)

Summary

Thrombotic complications of cardiovascular disease are a main cause of death and disability and, consequently, thrombolysis could favorably influence the outcome of such life-threatening diseases as myocardial infarction, cerebrovascular thrombosis and venous thromboembolism.

Thrombolytic agents are plasminogen activators that convert plasminogen, the inactive proenzyme of the fibrinolytic system in blood, to the proteolytic enzyme plasmin. Plasmin dissolves the fibrin of a blood clot, but may also degrade normal components of the hemostatic system and predispose to bleeding. Currently, five thrombolytic agents are either approved for clinical use or under clinical investigation in patients with acute myocardial infarction. These include streptokinase, urokinase, recombinant tissue-type plasminogen activator (rt-PA), anisoylated plasminogen streptokinase activator complex (APSAC) and single chain urokinase-type plasminogen activator (scu-PA, prourokinase). The first generation thrombolytic agents, streptokinase (and probably also urokinase), are only moderately efficacious and their administration is associated with extensive systemic fibrinogen breakdown. In comparative studies performed in patients with acute myocardial infarction, recombinant tissue-type plasminogen activator (rt-PA) is a more effective and fibrin-specific thrombolytic agent than streptokinase. The acylated plasminogen streptokinase activator complex (APSAC) has a profile of thrombolytic efficacy and fibrin-specificity that is similar or somewhat better than that of streptokinase, but has the advantage that it can be administered by bolus injection. Single chain urokinase-type plasminogen activator is more fibrin-specific than urokinase. Comparative data on the efficacy and safety of this agent are limited as it is in the early stage of clinical investigation.

Reduction of infarct size, preservation of ventricular function and/or reduction in mortality has been observed with streptokinase, rt-PA and APSAC. Therefore, thrombolytic therapy will probably become routine therapy for early acute myocardial infarction.

In patients with acute myocardial infarction, intravenous streptokinase recanalizes 40–45 percent of occluded coronary arteries and reduces mortality by 25 percent; it costs approximately $200 for a therapeutic dose of 1,500,000 units. Recombinant tissue-type plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent (65–70 percent) reperfusion, but it costs over $1,000 for a therapeutic dose of 100 mg. Side effects (mainly bleeding) and the incidence of reocclusion associated with the use of streptokinase and rt-PA are not markedly different. Whether the higher efficacy of rt-PA will translate into a comparably larger reduction of mortality remains to be determined in large comparative clinical trials. Both agents are available for clinical use. The choice of agent for the treatment of acute myocardial infarction at present must be based on considerations of lower cost of streptokinase versus the higher efficacy for coronary recanalization of rt-PA.

Recent reviews of thrpmbolytic agents have reached apparently contradictory conclusions with respect to the comparative properties of thrombolytic agents (1–3). In particular, the data on the relative efficacy for coronary thrombolysis, the speed of reperfusion, the frequency of reocclusion, the occurrence of bleeding complications, and the impact on mortality have been presented and interpreted differently.

All available thrombolytic agents still suffer significant shortcomings, including the need for large doses to be therapeutically efficient, a limited fibrin-specificity and residual toxicity in terms of bleeding complications. New developments towards further improved efficacy and fibrin-specificity of thrombolytic therapy include the use of combinations of synergistic thrombolytic agents, mutants of t-PA and scu-PA, chimeric t-PA/scu-PA molecules, antibody-targeted thrombolytic agents, and/or combinations of fibrin-dissolving agents with anti-platelet strategies.

In this communication, we will briefly review the components of the fibrinolytic system, the mechanism of fibrin-specific thrombolysis, the present state of clinical trials with thrombolytic agents in acute myocardial infarction, and finally, new trends in thrombolytic therapy.

Keywords

Acute Myocardial Infarction Plasminogen Activator Thrombolytic Therapy Thrombolytic Agent Acylated Plasminogen Streptokinase Activator Complex 
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.

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References

  1. 1.
    D. Collen, D. C. Stump, H. K. Gold, Thrombolytic therapy. Ann. Rev. Med., 39:405–423 (1988).PubMedCrossRefGoogle Scholar
  2. 2.
    V. J. Marder, S. Sherry, Thrombolytic therapy: current status (first of two parts). N. Engl. J. Med., 318:1512–1520 (1988).PubMedCrossRefGoogle Scholar
  3. 3.
    V. J. Marder, S. Sherry, Thrombolytic therapy: current status (second of two parts). N. J. Engl. Med., 318:1585–1595 (1988).CrossRefGoogle Scholar
  4. 4.
    D. Collen, On the regulation and control of fibrinolysis. Thromb. Haemost., 43:77–89 (1980).PubMedGoogle Scholar
  5. 5.
    D. Collen, Molecular mechanisms and clinical applications of thrombolysis. Les Cahiers de la Fondation Louis Jeantet de Médicine, 1:41–54 (1986).Google Scholar
  6. 6.
    F. Bachmann. Fibrinolysis, in: Thrombosis and Haemostasis. Eds: M Verstraete, J. Vermylen, R. Lijnen, J. Arnout, Leuven University Press, Leuven, Belgium, p. 227–265 (1987).Google Scholar
  7. 7.
    M. A. De Wood, J. Spores, R. Notske, et al., Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N. Engl. J. Med., 303:897–902 (1980).CrossRefGoogle Scholar
  8. 8.
    K. P. Rentrop, Thrombolytic therapy in patients with acute myocardial infarction. Circulation, 71:627–631 (1985).PubMedCrossRefGoogle Scholar
  9. 9.
    Gruppo Italiano per lo studio della streptochinasi nell’infarto, miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet, 1:397–402 (1986).Google Scholar
  10. 10.
    F. Rovelli, C. De Vita, G. A. Feruglio, et al., GISSI trial: early results and late follow up. J. Am. Coll. Cardiol., 10:33B–39B (1987).PubMedCrossRefGoogle Scholar
  11. 11.
    M. L. Simoons, M. van de Brand, C. de Zwaan, et al., Improved survival after early thrombolysis in acute myocardial infarction. Lancet, 2:578–581 (1985).PubMedCrossRefGoogle Scholar
  12. 12.
    The ISAM Study Group, A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). Mortality, morbidity, and infarct size at 21 days. N. Engl. J. Med.,314:1465–1471 (1986).CrossRefGoogle Scholar
  13. 13.
    ISIS-2 (Second International Study of Infarct Survival) Collaborative Group, Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2, Lancet, 2:349–360 (1988).Google Scholar
  14. 14.
    J. W. Kennedy, G. V. Martin, and K. B. Davis, et al., The Western Washington intravenous streptokinase in acute myocardial infarction randomized trial. Circulation,77:345–352 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    H. D. White, R. M. Norris, and M. A. Brown, et al., Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N. Engl. J. Med., 317:850–855 (1987).PubMedCrossRefGoogle Scholar
  16. 16.
    D. Collen, Human tissue-type plasminogen activator: from the laboratory to the bedside Circulation, 72:18–20 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    A. D. Guerci, G. Gerstenblith, and J. A. Brinker, et al., A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty. N. Engl. J. Med., 317:1613–1618 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    M. O’Rourke, D. Baron, and A. Keogh, et al., Limitation of myocardial infarction by early infusion of recombinant tissue-type plasminogen activator. Circulation, 77:1311–1315 (1988).PubMedCrossRefGoogle Scholar
  19. 19.
    F. van de Werf, A. E. R. Arnold, Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. Br. Med. J., 297:1374–1379 (1988).CrossRefGoogle Scholar
  20. 20.
    R. G. Wilcox, G. von der Lippe, C. G. Olsson, G. Jenssen, A. M. Skene, and J. R. Hampton, Trial of tissue plasminogen activator (rt-PA) for mortality reduction in acute myocardial infarction: The Anglo-Scandinavian study of early thrombolysis (ASSET). Lancet, 2:525–530 (1988).PubMedCrossRefGoogle Scholar
  21. 21.
    E. Braunwald, G. L. Knatterud, E. Passamani, T. L. Robertson, and R. Solomon, Update from the thrombolysis in myocardial infarction trial. J. Am. Coll. Cardiol., 10:970 (1987).PubMedCrossRefGoogle Scholar
  22. 22.
    M. L. Brochier, L. Quillet, and H. Kulbertus, et al., Intravenous anisoylated plasminogen streptokinase activator complex versus intravenous streptokinase in evolving myocardial infarction. Drugs 3, (Suppl 3):140–145 (1987).CrossRefGoogle Scholar
  23. 23.
    J. L. Anderson, R. L. Rothbard, and R. A. Hackworthy, et al., Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: Controlled comparison with intracoronary streptokinase. J. Am. Coll. Cardiol., 11:1153–1163 (1988).PubMedCrossRefGoogle Scholar
  24. 24.
    AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet, 1:545–549 (1988).Google Scholar
  25. 25.
    S. Sherry, Appraisal of various thrombolytic agents in the treatment of acute myocardial infarction. Am. J. Med. 83 Suppl. 2A:31–46 (1987).PubMedCrossRefGoogle Scholar
  26. 26.
    K. P. Rentrop, F. Feit, and H. Blanke, et al., Effects of intracoronary streptokinase and intracoronary nitroglycerin infusion on coronary angiographic patterns and mortality in patients with acute myocardial infarction. N. Engl. J. Med., 311:1457–1463 (1984).PubMedCrossRefGoogle Scholar
  27. 27.
    K. L. Neuhaus, U. Tebbe, G. Sauer, G. Rahlf, H. Kreuzer, and H. Kostering. Hochdosierte intravenose Kurzinfusion von Streptokinase beim acuten Myocardinfarkt, in: G. Trübestein, F. Etzel, eds. Fibrinolytische Therapie. FK Schattauer Verlag Stuttgart/New York, 475–480 (1983).Google Scholar
  28. 28.
    R. Schröder, G. Biamino, and E. R. Leitner, et al., Intravenous short-term infusion of streptokinase in acute myocardial infarction. Circulation, 67:536–548 (1983).PubMedCrossRefGoogle Scholar
  29. 29.
    W. J. Rogers, J. A. Mantle, and W. P. Hood, et al., Prospective randomized trial of intravenous and intracoronary streptokinase in acute myocardial infarction. Circulation, 68:1051–1061 (1983).PubMedCrossRefGoogle Scholar
  30. 30.
    E. L. Alderman K. R. Jutzy, and L. E. Berte, et al., Randomized comparison of intravenous versus intracoronary streptokinase for myocardial infarction. Am. J. Cardiol., 54:14–19 (1984).PubMedCrossRefGoogle Scholar
  31. 31.
    J. R. Spann, S. Sherry, and B. A. Carabello, et al., Coronary thrombolysis by intravenous streptokinase in acute myocardial infarction: acute and follow-up studies. Am. J. Cardiol., 53:655–661 (1984).PubMedCrossRefGoogle Scholar
  32. 32.
    L. D. Hillis, J. Borer, and E. Braunwald, et al., High dose intravenous streptokinase for acute myocardial infarction: preliminary results of a multicenter trial. J. Am. Coll. Cardiol., 6:957–962 (1985).PubMedCrossRefGoogle Scholar
  33. 33.
    The TIMI Study Group, Special Report. The thrombolysis in myocardial infarction (TIMI) trial. N. Engl. J. Med., 312:932–936 (1985).Google Scholar
  34. 34.
    M. de Marneffe, E. Van Thiel, and M. Ewalenko, et al., High-dose intravenous thrombolytic therapy in acute myocardial infarction: efficiency, tolerance, complications and influence on left ventricular performance. Acta. Cardiol., 40:183–198 (1985).PubMedGoogle Scholar
  35. 35.
    D. Collen E. J. Topol, and A. J. Tiefenbrunn, et al., Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation, 70:1012–1017 (1984).PubMedCrossRefGoogle Scholar
  36. 36.
    D. O. Williams, J. Borer, and E. Braunwald, et al., Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial. Circulation, 73:338–346 (1986).PubMedCrossRefGoogle Scholar
  37. 37.
    H. K. Gold, R. C. Leinbach, and H. D. Garabedian, et al., Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation, 73:347–352 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    H. S. Mueller, A. K. Rao, and S. A. Forman., Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J. Am. Coll. Cardiol., 10:479–490 (1987).PubMedCrossRefGoogle Scholar
  39. 39.
    H. J. R. M. Bonnier, R. F. Visser, H. C. Klomps, and H. J. M. L. Hoffmann, Comparison of intravenous anisoylated plasminogen streptokinase activator complex and intracoronary streptokinase in acute myocardial infarction. Am. J. Cardiol., 62:2530 (1988).CrossRefGoogle Scholar
  40. 40.
    P. Dewilde, Y. Taeymans, D. Demoor, L. Huygehens, and P. Block, Intravenous thrombolysis with BRL 26921 in acute myocardial infarction. Presented at the International Symposium on Cardiovascular Pharmacotherapy, Geneva, (1985) Abstract 96.Google Scholar
  41. 41.
    V. J. Marder, R. L. Rothbard, P. G. Fitzpatrick, and C. W. Francis, Rapid lysis of coronary artery thrombi with anisoylated plasminogen: streptokinase activator complex. Treatment by bolus intravenous injection. Ann. Intern. Med., 104:304–310 (1986).PubMedGoogle Scholar
  42. 42.
    A. D. Timmis, B. Griffin, J. C. P. Crick, J. S. Flax, and E. Sowton, An interim report of a double-blind placebo controlled recanalisation study of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Drugs, 33 (Suppl 3):14650 (1987).CrossRefGoogle Scholar
  43. 43.
    G. J. Taylor, F. L. Mike11, and H. W. Moses, et al., Intravenous versus intracoronary streptokinase therapy for acute myocardial infarction in community hospitals. Am. J. Cardiol., 54:256–260 (1984).PubMedCrossRefGoogle Scholar
  44. 44.
    F. Schwartz, M. Hofmann, G. Schuler, K. von Olshausen, R. Zimmermann, and W. Kübler, Thrombolysis in acute myocardial infarction: effect of intravenous followed by intracoronary streptokinase application on estimates of infarct size. Am. J. Cardiol., 53:1505–1510 (1984).CrossRefGoogle Scholar
  45. 45.
    M. Verstraete, R. Bernard, and M. Bory, et al., Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet, 1:842–847 (1985).PubMedCrossRefGoogle Scholar
  46. 46.
    A. Cribier, J. Berland, N. Saoudi, M. Redonnet, N. Moore, and B. Letac, Intracoronary streptokinase, OK!…, Intravenous streptokinase, first? Heparin or intravenous streptokinase in acute infarction: preliminary results of a prospective randomized trial with angiographic evaluation in 44 patients. Haemostasis, 16 (Suppl 3):122–129 (1986).PubMedGoogle Scholar
  47. 47.
    P. Monnier, U. Sigwart, and A. Vincent, et al., Anisoylated plasminogen streptokinase activator complex versus streptokinase in acute myocardial infarction. Preliminary results of a randomised study. Drugs, 33 (Suppl 3):175–178 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    J. Chesebro, G. Knatterud, and E. Braunwald, Correspondence section. N. Engl. J. Med., 319:1544 (1988).Google Scholar
  49. 49.
    R. S. Stack, C. M. O’Connor, and D. B. Mark, et al., Coronary perfusion during acute myocardial infarction with a combined therapy of coronary angioplasty and high-dose intravenous streptokinase. Circulation, 77:151–161 (1988).PubMedCrossRefGoogle Scholar
  50. 50.
    J. Lopez-Sendón, R. SeabraiGomes, and F. Martin Santos, et al., Intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus intravenous streptokinase (SK) in myocardial infarction (AMI). A randomized multicenter trial. Eur. Heart J., 9 (Suppl A):10 (1988).Google Scholar
  51. 51.
    H. I. Miller, A. Roth, A. Parades, B. Shagarodsky, G. Barabash, and S. Laniado, A comparison of early thrombolytic therapy with streptokinase and tissue plasminogen activator in acute myocardial infarction. Eur. Heart J., 9 (Suppl A):215 (1988).Google Scholar
  52. 52.
    M. Verstraete, W. Bleifeld, and R. W. Brower, et al., Double-blind randomised trial of intravenous tissue-type plasminogen activator versus placebo in acute myocardial infarction. Lancet, 2:965–969 (1985).PubMedCrossRefGoogle Scholar
  53. 53.
    M. Verstraete, A. E. R. Arnold, and R. W. Brower, et al., Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: initial patency and influence of maintained infusion on reocclusion rate. Am. J. Cardiol., 60:231–237 (1987).PubMedCrossRefGoogle Scholar
  54. 54.
    E. J. Topol, D. C. Morris, and R. W. Smalling, et al., A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (Activase) in acute myocardial infarction. J. Am. Coll. Cardiol., 9:1205–1213 (1987).PubMedCrossRefGoogle Scholar
  55. 55.
    E. J. Topol, R. M. Califf, and B. S. George, et al., A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N. Engl. J. Med., 317:581–588 (1987).PubMedCrossRefGoogle Scholar
  56. 56.
    E. J. Topol, E. R. Bates, and J. A. Jr. Walton, et al., Community hospital administration of intravenous tissue plasminogen activator in acute myocardial infarction: improved timing. Thrombolytic efficacy and ventricular function. J. Am. Coll. Cardiol., 10:1173–1177 (1987).PubMedCrossRefGoogle Scholar
  57. 57.
    E. J. Topol, B. S. George, and D. J. Kereiakes, et al., A multicenter, randomized, controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction. J. Am. Coll. Cardiol., 11:232A (1988).CrossRefGoogle Scholar
  58. 58.
    M. L. Simoons, A. E. R. Arnold, and A. Betriu, et al., Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet, 1: 197–203 (1988).PubMedCrossRefGoogle Scholar
  59. 59.
    J. A. Johns, H. K. Gold, and R. C. Leinbach, et al., Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. A randomized study of maintenance infusion of recombinant human tissuetype plasminogen activator. Circulation, 78:546–556 (1988).PubMedCrossRefGoogle Scholar
  60. 60.
    The TIMI Research Group, Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI IIA results. J. Am. Med. Assoc., 260:2849–2858 (1988).CrossRefGoogle Scholar
  61. 61.
    A. J. McNeill, J. S. Shannon, and S. R. Cunningham, et al., A randomised dose ranging study of recombinant tissue plasminogen activator in acute myocardial infarction. Br. Med. J., 296:1768–1771 (1988).CrossRefGoogle Scholar
  62. 62.
    K. L. Neuhaus, U. Tebbe, and M. Gottwik, et al., Intravenöse Infusion von recombinant tissue plasminogen activator (rt-PA) and Urokinase beim akuten Myokardinfarkt: Zwischenergebnisse der G.A.U.S.-Studie (German Activator Urokinase Study). Klin. Wschr., 66:102–108 (1988).PubMedGoogle Scholar
  63. 63.
    K. L. Neuhaus, W. Fuerer, U. Tebbe, S. Jeep-Tebbe, and A. Vogt, Efficacy of a 90-minute infusion of 100 mg tissue plasminogen activator (rt-PA) in acute myocardial infarction. Eur. Heart J., 9 (Suppl A):9 (1988).Google Scholar
  64. 64.
    W. Kasper, T. Meinertz, and H. Wollschläger, et al., Coronary thrombolysis during acute myocardial infarction by intravenous BRL 26921, a new anisoylated plasminogen-streptokinase activator complex. Am. J. Cardiol., 58:418–421 (1986).PubMedCrossRefGoogle Scholar
  65. 65.
    J. P. Monassier, M. Brochier, and B. Charbonnier, et al., EMINASE versus streptokinase à la phase aiguë de l’infarctus du myocarde: étude randomisée (étude I.R.S. II). 14e Congrès de Cardiologie de langue française; 25–30 (1987).Google Scholar
  66. 66.
    L. Relik-Van Wely, J. M. J. van der Pol, and R. F. Visser, et al., A preliminary report, on the angiographic assessed patency and reocclusion in patients treated with APSAC for acute myocardial infarction (AMI). A Dutch Multicentre Study. Eur. Heart J., 9 (Suppl A):8 (1988).Google Scholar
  67. 67.
    P. Vogt, M. D. Schaller, P. Monnier, and U. Kaufamann, et al., Systemic thrombolysis in acute myocardial infarction: Bolus injection of APSAC versus infusion of streptokinase. Eur. Heart J., 9 (Supppl A):213 (1988).CrossRefGoogle Scholar
  68. 68.
    D. G. Mathey, J. Schofer, F. H. Sheehan, H. Becher, V. Tilsner, and H. T. Dodge, Intravenous urokinase in acute myocardial infarction. Am. J. Cardiol., 55:878–882 (1985).PubMedCrossRefGoogle Scholar
  69. 69.
    K. L. Neuhaus, U. Tebbe, and M. Gottwik, et al., Intravenöse Infusion von recombinant tissue plasminogen activator (rt-PA) and Urokinase beim akuten Myokardinfarkt: Zwischenergebnisse der G.A.U.S.-Studie (German Activator Urokinase Study). Klin. Wschr., 66:102–108 (1988).PubMedGoogle Scholar
  70. 70.
    E. J. Topol, R. M. Califf, and B. S. George, et al., Coronary arterial thrombolysis with combined infusion of recombinant tissue-type plasminogen activation and urokinase in acute myocardial infarction. Circulation, 77:1100–1107 (1988).PubMedCrossRefGoogle Scholar
  71. 71.
    J. H. Chesebro, G. Knatterud, and R. Robert, et al., Thrombolysis in myocardial infarction (TIMI) trial. Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation, 76:142–154 (1987).PubMedCrossRefGoogle Scholar
  72. 72.
    Primi trial study group, Randomised double-blind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancent, 1:863–867 (1989).Google Scholar
  73. 73.
    P. L. Raynaud, and B. Desveaux, Réocclusion après traitement par l’Actilyse. Arch. Mal. Coeur., 81 (Suppl 1):25–32 (1988).PubMedGoogle Scholar
  74. 74.
    R. S. Kent, A. G. Batson, and J. K. LittleJohn, Thrombolytic effect of tissue-type plasminogen activator, in: Controversies in Thrombolysis. Eds: R. Schroder, S. Sherry, K. L. Mettinger. Current Medical Literature Ltd, London (in press).Google Scholar
  75. 75.
    H. D. White, J. T. Rivers, and A. H. Maslowski, et al., Effect of intravenous streptokinase as compared with that of tissue plasminogen activator on left ventricular function after first myocardial infarction. N. Engl. J. Med., 320:817–821 (1989).PubMedCrossRefGoogle Scholar
  76. 76.
    B. Magnani, for the PAIMS Investigators, Plasminogen activator Italian multicenter study (PAIMS). Comparison of intravenous recombinant single-chain human tissue-type plasminogen activator (rt-PA) with intravenous streptokinase in acute myocardial infarction. J. Am. Coll. Cardiol., 13:19–26 (1989).CrossRefGoogle Scholar
  77. 77.
    S. Schulman, D. Lockner, S. Granqvist, G. Bratt, C. Paul, and D. Nyman, A comparative randomized trial of low dose versus high dose streptokinase in deep vein thrombosis of the thigh. Thromb. Haemost., 51:261–265 (1984).PubMedGoogle Scholar
  78. 78.
    L. W. Gimple, H. K. Gold, and R. C. Leinbach, et al., Bleeding time measurement predicts spontaneous bleeding during thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). J. Am. Coll. Cardiol., 11:231A (1988).Google Scholar
  79. 79.
    F. D. A. Summary Basis for Approval of Alteplase (86–0236). (1987) p. 15.Google Scholar
  80. 80.
    M. Friedman, The coronary thrombus: its origin and fate. Human Pathol., 2:81–128 (1971).CrossRefGoogle Scholar
  81. 81.
    M. J. Davies, and A. C. Thomas, Plaque fissuring - the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br. Heart J., 53:363–373 (1985).PubMedCrossRefGoogle Scholar
  82. 82.
    H. R. Lijnen, C. Zamarron, M. Blaber, M. E. Winkler, and D. Collen, Activation of plasminogen by pro-urokinase. I. Mechanism. J. Biol. Chem., 261:1253–1258 (1986).PubMedGoogle Scholar
  83. 83.
    D. Collen, F. De Cock, E. Demarsin, H. R. Lijnen, and D. C. Stump, Absence of synergism between tissue-type plasminogen activator (t-PA), single chain urokinase-type plasminogen activator (scu-PA) and urokinase on clot lysis in a plasma milieu in vitro. Thromb. Haemost., 56:35–39 (1986).PubMedGoogle Scholar
  84. 84.
    V. Gurewich, and R. Pannell, Synergism of tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA) on clot lysis in vitro and a mechanism for this effect. Thromb. Haemost., 57:372 (1987).PubMedGoogle Scholar
  85. 85.
    D. Collen, J. M. Stassen, D. C. Stump, M. Verstraete, Synergism of thrombolytic agents in vivo. Circulation, 74:838–842 (1986).PubMedCrossRefGoogle Scholar
  86. 86.
    A. A. Ziskind, H. K. Gold, T. Yasuda, M. Kanke, and J. L. Guererro, et al., Coronary thrombolysis in dogs with synergistic combinations of human tissue-type plasminogen activator (r-PA) and single chain urokinase-type plasminogen activator (scu-PA). Clin. Res., 35:337A (1987).Google Scholar
  87. 87.
    D. Collen, D. C. Stump, and F. Van de Werf, Coronary thrombolysis in patients with acute myocardial infarction by intravenous infusion of synergic thrombolytic agents. Am. Heart J., 112:1083–1084 (1986).PubMedCrossRefGoogle Scholar
  88. 88.
    D. Collen, and F. van de Werf, Coronary arterial thrombolysis with low-dose synergistic combinations of recombinant tissue-type plasminogen activator (rt-PA) and recombinant single-chain urokinase-type plasminogen activator (rscu-PA) for acute myocardial infarction. Am. J. Cardiol., 60:431–444 (1987).PubMedCrossRefGoogle Scholar
  89. 89.
    P. Cambier, F. Van de Werf, G. R. Larsen, and D. Collen, Pharmacokinetics and thrombolytic properties of a nonglycosylated mutant of human tissuetype plasminogen activator, lacking the finger and growth domains, in dogs with copper coil-induced coronary artery thrombosis. J. Cardiovasc. Pharmacol., 11:468–472 (1988).PubMedCrossRefGoogle Scholar
  90. 90.
    L. Nelles, H. R. Lijnen, D. Collen, and W. E. Homes, Characterization of recombinant human single chain urokinase-type plasminogen activator mutants produced by site-specific mutagenesis of lysine 158. J. Biol. Chem., 262:5682–5689 (1987).PubMedGoogle Scholar
  91. 91.
    D. Collen, J. Mao, and J. M. Stassen, et al., Thrombolytic properties of Lys-158 mutants of recombinant single chain urokinase-type plasminogen activator in rabbits with jugular vein thrombosis. J. Vasc. Med. Biol., 1:46–49 (1989).Google Scholar
  92. 92.
    L. Nelles, H. R. Lijnen, D. Collen, and W. E. Holmes, Characterization of a fusion protein consisting of amino acids 1 to 263 of tissue-type plasminogen activator and amino acids 144 to 411 of urokinase-type plasminogen activator. J. Biol. Chem., 262:10855–10862 (1987).PubMedGoogle Scholar
  93. 93.
    D. Collen, J. M. Stassen, E. Demarsin, L. Kieckens, H. R. Lijnen, and L. Nelles, Pharmacokinetics and thrombolytic properties of chimaeric plasminogen activators consisting of the NH2-terminal region of human tissue-type plasminogen activator and the COOH-terminal region of human single chain urokinase-type plasminogen activator. J. Vasc. Med. Biol., 1:234–240 (1989).Google Scholar
  94. 94.
    E. Haber, and M. Runge, et al., Antibody targeted fibrinolysis. Thromb. Haemost. 57:253 (1987).Google Scholar
  95. 95.
    E. Haber, T. Quertermous, G. R. Matsueda, and M. S. Runge, Innovative approaches to plasminogen activator therapy. Science, 243:51–56 (1989).PubMedCrossRefGoogle Scholar
  96. 96.
    M. Dewerchin, H. R. Lijnen, B. Van Hoef, F. De Cock, and D. Collen, Biochemical properties of conjugates of urokinase-type plasminogen activator with a monoclonal antibody specific for crosslinked fibrin. Eur. J. Biochem., 185:141–149 (1989).PubMedCrossRefGoogle Scholar
  97. 97.
    D. Collen, M. Dewerchin, J. M. Stassen, L. Kieckens, and H. R. Lijnen, Thrombolytic and pharmacokinetic properties of conjugates of urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin. Fibrinolysis, 3:197–202 (1989).CrossRefGoogle Scholar
  98. 98.
    L. A. Harker, Clinical trials evaluating platelet-modifying drugs in patients with atherosclerotic cardiovascular disease and thrombosis. Circulation, 73:206–223 (1986).PubMedCrossRefGoogle Scholar
  99. 99.
    V. Fuster, L. Badimon, J. Badimon, P. C. Adams, V. Turitto, and J. H. Chesebro, Drugs interfering with platelet functions: mechanisms and clinical relevance, in: Thrombosis and Haemostasis. Eds: M. Verstraete, J. Vermylen, R. Lijnen, J. Arnout, Leuven University Press, p.349–418 (1987).Google Scholar
  100. 100.
    J. Loscalzo, and D. E. Vaughan, Tissue plasminogen activator promotes platelet disaggregation in plasma. J. Clin. Invest., 79:1749–1755 (1987).PubMedCrossRefGoogle Scholar
  101. 101.
    T. Yasuda, H. K. Gold, and R. C. Leinbach, et al., Tissue plasminogen activator (t-PA) resistant platelet rich white thrombus (WT) and combination treatment of t-PA and antiplatelet antibody to GPIIb/IIIa receptor (7E3). Circulation, 78:II-15 (1988).Google Scholar
  102. 102.
    H. K. Gold, B. S. Coller, and T. Yasuda, et al., Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation, 77:670–677 (1988).PubMedCrossRefGoogle Scholar
  103. 103.
    I. K. Jang, A. A. Ziskind, H. K. Gold, R. C. Leinbach, J. T. Fallon, and D. Cohen, Prevention of arterial platelet occlusion by selective thrombin inhibition. Circulation, 78:11–311 (1988).Google Scholar
  104. 104.
    S. R. Hanson, and L. A. Harker, Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc. Natl. Acad. Sci. USA, 85:3184–3188 (1988).PubMedCrossRefGoogle Scholar
  105. 105.
    K. A. Hajjar, N. M. Hamel, P. C. Harpel, and R. L. Nachman, Binding of tissue plasminogen activator to cultured human endothelial cells. J. Clin. Invest., 80:1712–1719 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • D. Collen
    • 1
  • H. K. Gold
    • 1
  1. 1.Center for Thrombosis and Vascular ResearchUniversity of Leuven, Belgium and Massachusetts General Hospital Harvard Medical SchoolBostonUSA

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