Download PDF
Thromb Haemost 2005; 93(04): 627-630
DOI: 10.1160/TH04-11-0724
Theme Issue Article
Schattauer GmbH

Thrombolytic agents

Désiré Collen
1   Center for Molecular and Vascular Biology, KU Leuven, Belgium
,
Roger H. Lijnen
1   Center for Molecular and Vascular Biology, KU Leuven, Belgium
› Author Affiliations
Further Information

Publication History

Received 08 November 2004

Accepted 16 March 2004

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

Thrombolytic agents are plasminogen activators that convert the zymogen plasminogen to the active enzyme plasmin, which degrades fibrin. Elucidation of the molecular mechanism of physiological fibrinolysis opened up a new era of fibrin-specific thrombolysis. Fibrin-specific plasminogen activators, including tissue-type plasminogen activator (t-PA), single-chain urokinase-type plasminogen activator (scu-PA) and staphylokinase (Sak), preferentially activate fibrin-associated plasminogen. Generated plasmin remains associated with fibrin, where it is protected from rapid inhibition and can efficiently degrade fibrin, avoiding systemic activation of the fibrinolytic system. Following a decade of clinical investigation t-PA and variants thereof are routinely used for treatment of patients with thromboembolic disease.

Keywords

Thrombolysis - plasminogen activator - thromboembolic disease
 

  • References

  • 1 Tillett WS, Garner RL. Fibrinolytic activity of hemolytic streptococci. J Exper Med 1933; 58: 485-502.
    CrossrefPubMedGoogle Scholar
  • 2 Astrup T, Permin PM. Fibrinolysis in animal organism. Nature 1947; 159: 681-2.
    CrossrefPubMedGoogle Scholar
  • 3 Lack CH. Staphylokinase: an activator of plasma protease. Nature 1948; 161: 559-60.
    CrossrefPubMedGoogle Scholar
  • 4 Macfarlane RG, Pilling J. Fibrinolytic activity of normal urine. Nature 1947; 159: 779
    CrossrefPubMedGoogle Scholar
  • 5 Williams JRB. The fibrinolytic activity of urine. Br J Exper Pathol 1951; 32: 530-7.
    PubMedGoogle Scholar
  • 6 Bernik MB. Increased plasminogen activator (urokinase) in tissue culture after fibrin deposition. J Clin Invest 1973; 52: 823-34.
    CrossrefPubMedGoogle Scholar
  • 7 Nolan C, Hall L, Barlow G. et al. Plasminogen activator from human embryonic kidney cell cultures. Evidence for a proactivator. Biochim Biophys Acta 1977; 496: 384-400.
    CrossrefPubMedGoogle Scholar
  • 8 Collen D. On the regulation and control of fibrinolysis. Thromb Haemost 1980; 43: 77-89.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004; 2: 541-6.
    CrossrefPubMedGoogle Scholar
  • 10 Pennica D, Holmes WE, Kohr WJ. et al. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 1983; 301: 214-21.
    CrossrefPubMedGoogle Scholar
  • 11 Lijnen HR, Collen D. Tissue-type plasminogen activator. In: Handbook of proteolytic enzymes, Barrett AJ, Rawlings ND, Woessner JF, eds, Academic Press, 1998; 184-90.
    PubMedGoogle Scholar
  • 12 Hoylaerts M, Rijken DC, Lijnen HR. et al. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257: 2912-9.
    CrossrefPubMedGoogle Scholar
  • 13 Thorsen S. The mechanism of plasminogen activation and the variability of the fibrin effector during tissue-type plasminogen activator-mediated fibrinolysis. Ann NY Acad Sci 1992; 667: 52-63.
    CrossrefPubMedGoogle Scholar
  • 14 The GUSTO Investigators An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-82.
    CrossrefPubMedGoogle Scholar
  • 15 GUSTO Angiographic Investigators The effects of tissue plasminogen activator, streptokinase or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-22.
    CrossrefPubMedGoogle Scholar
  • 16 Kohnert U, Rudolph R, Verheijen JH. et al. Biochemical properties of the kringle 2 and protease domains are maintained in the refolded t-PA deletion variant BM 06.022. Prot Engineer 1992; 5: 93-100.
    CrossrefPubMedGoogle Scholar
  • 17 The GUSTO-III investigators A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118-23.
    CrossrefPubMedGoogle Scholar
  • 18 Paoni NF, Keyt BA, Refino CJ. et al. A slow clearing, fibrin-specific, PAI-1 resistant variant of t-PA (T103N, KHRR296–299AAAA). Thromb Haemost 1993; 70: 307-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Guerra DR, Karha J, Gibson CM. Safety and efficacy of tenecteplase in acute myocardial infarction. Expert Opin Pharmacother 2003; 4: 791-8.
    CrossrefPubMedGoogle Scholar
  • 20 Den Heijer P, Vermeer F, Ambrosioni E. et al. Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase. Circulation 1998; 98: 2117-25.
    CrossrefPubMedGoogle Scholar
  • 21 Suzuki S, Saito M, Suzuki N. et al. Thrombolytic properties of a novel modified human tissue-type plasminogen activator (E6010): a bolus injection of E6010 has equivalent potency of lysing young and aged canine coronary thrombi. J Cardiovasc Pharmacol 1991; 17: 738-46.
    CrossrefPubMedGoogle Scholar
  • 22 Katoh M, Suzuki Y, Miyamoto T. Biochemical and pharmacokinetic properties ofYM866, a novel fibrinolytic agent. Thromb Haemost 1991; 65: 1193 (Abstract 1794).
    PubMedGoogle Scholar
  • 23 Krätzschmar J, Haendler B, Langer G. The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: cloning and expression. Gene 1991; 105: 229-37.
    CrossrefPubMedGoogle Scholar
  • 24 Lijnen HR, Collen D. Strategies for the improvement of Thrombolytic agents. Thromb Haemost 1991; 66: 88-110.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Lijnen HR, Collen D. New thrombolytic strategies and agents. Hematologica 2000; 85 (Suppl. 02) 106-9.
    PubMedGoogle Scholar
  • 26 Baker Jr WF. Thrombolytic therapy. Clin Appl Thromb Hemost 2002; 8: 291-314.
    CrossrefPubMedGoogle Scholar
  • 27 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13-20.
    CrossrefPubMedGoogle Scholar
  • 28 de Lemos JA, Gibson CM, Antman EM. et al. Abciximab and early adjunctive percutaneous coronary intervention are associated with improved ST-segment resolution after thrombolysis. Observations from the TIMI 14 trial. Am Heart J 2001; 141: 592-8.
    CrossrefPubMedGoogle Scholar
  • 29 Holmes WE, Pennica D, Blaber M. et al. Cloning and expression of the gene for pro-urokinase in Escherichia coli. Biotechnology 1985; 3: 923-9.
    CrossrefPubMedGoogle Scholar
  • 30 Gurewich V, Pannell R, Louie S. et al. Effective and fibrin-specific clot lysis by a zymogen precursor form of urokinase (pro-urokinase). A study in vitro and in two animal species. J Clin Invest 1984; 73: 1731-9.
    CrossrefPubMedGoogle Scholar
  • 31 Lijnen HR, Van Hoef B, Nelles L. et al. Plasminogen activation with single-chain urokinase-type plasminogen activator (scu-PA). Studies with active site mutagenized plasminogen (Ser740---->Ala) and plasmin-resistant scu-PA (Lys158---->Glu). J Biol Chem 1990; 265: 5232-6.
    CrossrefPubMedGoogle Scholar
  • 32 Liu JN, Gurewich V. Fragment E-2 from fibrin substantially enhances pro-urokinase-induced Glu-plasminogen activation. A kinetic study using the plasminresistant mutant pro-urokinase Ala-158-rpro-UK. Biochemistry 1992; 31: 6311-7.
    CrossrefPubMedGoogle Scholar
  • 33 Fleury V, Lijnen HR, Anglès-Cano E. Mechanism of the enhanced intrinsic activity of single-chain urokinase- type plasminogen activator during ongoing fibrinolysis. J Biol Chem 1993; 268: 18554-9.
    CrossrefPubMedGoogle Scholar
  • 34 Van de Werf F, Vanhaecke J, De Geest H. et al. Coronary thrombolysis with recombinant single-chain urokinase-type plasminogen activator (rscu-PA) in patients with acute myocardial infarction. Circulation 1986; 74: 1066-70.
    CrossrefPubMedGoogle Scholar
  • 35 PRIMI Trial Study Group Randomised doubleblind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancet 1989; 1: 863-8.
    PubMedGoogle Scholar
  • 36 Spiecker M, Windeler J, Vermeer F. et al. Thrombolysis with saruplase versus streptokinase in acute myocardial infarction: five-years results of the PRIMI trial. Am Heart J 1999; 138: 518-24.
    CrossrefPubMedGoogle Scholar
  • 37 Bar FW, Meyer J, Vermeer F. et al. Comparison of saruplase and alteplase in acute myocardial infarction. SESAM Study Group. The Study in Europe with Saruplase and Alteplase in Myocardial Infarction. Am J Cardiol 1997; 79: 727-32.
    CrossrefPubMedGoogle Scholar
  • 38 Tebbe U, Windeler J, Boesl I. et al. On behalf of the LIMITS Study Group. Thrombolysis with recombinant unglycosylated single-chain urokinase-type plasminogen activator (Saruplase) in acute myocardial infarction: influence on early patency rate (LIMITS Study). J Am Coll Cardiol 1995; 26: 365-73.
    CrossrefPubMedGoogle Scholar
  • 39 Zarich SW, Kowalchuk GJ, Weaver WD. et al. Sequential combination thrombolytic therapy for acute myocardial infarction: results of the Pro-Urokinase and t-PA Enhancement of Thrombolysis (PATENT) trial. J Am Coll Cardiol 1995; 26: 374-9.
    CrossrefPubMedGoogle Scholar
  • 40 del Zoppo GJ, Higashida RT, Furlan AJ. et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998; 29: 4-11.
    CrossrefPubMedGoogle Scholar
  • 41 Furlan AJ, Abou-Chebi A. The role of recombinant pro-urokinase (r-pro-UK) and inra-arterial thrombolysis in acute ischaemic stroke: the PROACT trials. Prolyse in Acute Cerebral Thromboembolism. Curr Med Res Opin 2002; 18 (Suppl. 02) s44-7.
    CrossrefPubMedGoogle Scholar
  • 42 Rabijns A, De Bondt HL, De Ranter C. Three-dimensional structure of staphylokinase, a plasminogen activator with therapeutic potential. Nat Struct Biol 1997; 4: 357-60.
    CrossrefPubMedGoogle Scholar
  • 43 Behnke D, Gerlach D. Cloning and expression in Escherichia coli, Bacillus subtilis and Streptococcus sanguis of a gene for staphylokinase: a bacterial plasminogen activator. Mol Gen Genet 1987; 210: 52834
    CrossrefPubMedGoogle Scholar
  • 44 Collen D, Zhao ZA, Holvoet P. et al. Primary structure and gene structure of staphylokinase. Fibrinolysis 1992; 6: 22631
    CrossrefPubMedGoogle Scholar
  • 45 Lijnen HR, Collen D. Staphylokinase, a fibrin-specific bacterial plasminogen activator. Fibrinolysis 1996; 10: 119-26.
    CrossrefPubMedGoogle Scholar
  • 46 Collen D. Staphylokinase: a potent, uniquely fibrin- selective thrombolytic agent. Nat Med 1998; 4: 279-84.
    CrossrefPubMedGoogle Scholar
  • 47 Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999; 82: 259-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Laroche Y, Heymans S, Capaert S. et al. Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes. Blood 2000; 96: 1425-32.
    CrossrefPubMedGoogle Scholar
  • 49 Collen D, Sinnaeve P, Demarsin E. et al. Polyethylene glycol-derivatized cysteine-substitution variants of recombinant staphylokinase for single-bolus treatment of acute myocardial infarction. Circulation 2000; 102: 1766-72.
    CrossrefPubMedGoogle Scholar
  • 50 Armstrong P, Burton J, Palisaitis D. et al. Collaborative angiographic patency trial of recombinant staphylokinase (CAPTORS). Am Heart J 2000; 139: 820-3.
    CrossrefPubMedGoogle Scholar
  • 51 Armstrong PW, Burton J, Pakola S. et al CAPTORS II Investigators. Collaborative Angiographic Patency Trial of Recombinant Staphylokinase (CAPTORS II). Am Heart J 2003; 146: 484-8.
    CrossrefPubMedGoogle Scholar