Thrombolysis, the only Optimally Rapid Reperfusion Treatment
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Abstract
Thrombolysis with tissue plasminogen activator (tPA) has been plagued by inadequate efficacy and a high risk of intracranial hemorrhage (ICH), which led to its replacement by procedures like percutaneous coronary intervention (PCI) whenever possible. Since this requires hospitalization, it is time-consuming, and compromising salvage of brain tissue and myocardium. Thrombolysis is the only first-line treatment that can provide sufficiently timely treatment for optimal recovery of organ function. However, for this potential to be realized, its efficacy and safety must be significantly improved over the current method. By adopting the sequential, synergistic fibrinolytic paradigm of the endogenous system, already verified by a clinical trial, this becomes possible. The endogenous system’s function is evidenced by the fibrinolytic product D-dimer that is invariably present in blood, and which increases >20-fold in the presence of thromboembolism. This system uses tPA to initiate lysis, which is then completed by the other fibrin-specific activator prourokinase (proUK). Since tPA and proUK in combination are synergistic in fibrinolysis, it helps explain their efficacy at their low endogenous concentrations.
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GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lancet. 1990; 336: 65-71. Ref.: https://goo.gl/5BcND7
ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. Lancet 1992; 339: 753-770. Ref.: https://goo.gl/cNYjDk
GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Eng J Med 1993; 329: 673-682. Ref.: https://goo.gl/tDc4Tb
Brophy JM, Joseph L. Placing trials in context using Bayesian analysis. GUSTO revisited by Reverend Bayes. JAMA 1995; 273: 871-875. Ref.: https://goo.gl/j3PpnF
Voskuilen M, Vermond A, Veeneman GH, van Boom JH, Klasen EA. Fibrinogen lysine residue Aα157 plays a crucial role in the fibrin-induced acceleration of plasminogen activation, catalyzed by tissue-type plasminogen activator. J Biol Chem. 1987; 262; 5944-5946. Ref.: https://goo.gl/HNvZ3H
Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem. 1982; 257: 2912-2919. Ref.: https://goo.gl/jFRdfA
Liu JN, Gurewich V. A comparative study of the promotion of tissue plasminogen activator and pro-urokinase-induced plasminogen activation by fragments D and E-2 of fibrin. J Clin Invest. 1991; 88: 2012-2017. Ref.: https://goo.gl/NohYzy
Suenson E, Lützen O, Thorsen S. Initial plasmin-degradation of fibrin as the basis of a positive feed-back mechanism in fibrinolysis. Eur J Biochem. 1984; 140: 513-5229. Ref.: https://goo.gl/nucZSA
Marder VJ, Sherry S. Thrombolytic therapy: current status. N Engl J Med 1988; 318: 1512-1520. Ref.: https://goo.gl/pComu6
Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996; 348: 771-775. Ref.: https://goo.gl/LK4akV
Schofield PM. Acute myocardial infarction: the case for pre-hospital thrombolysis with or without percutaneous coronary intervention. Heart. 2005; 91: 7-11. Ref.: https://goo.gl/YTrUh8
Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost. 1999; 82: 259-270. Ref.: https://goo.gl/y7fZSc
Chandler WL, Jascur ML, Henderson PJ. Measurement of different forms of tissue plasminogen activator in plasma. Clin Chem. 2000; 46: 38-46. Ref.: https://goo.gl/J2j26v
Baglin TP, Landown R, Frasson R, Huntington JA. Discovery and characterization of an antibody directed against exosite 1 of thrombin. J Thromb Haemos. 2016; 4: 137-142. Ref.: https://goo.gl/EJJEmS
Pannell R, Black J, Gurewich V. The complementary modes of action of tissue plasminogen activator (t-PA) and pro-urokinase (pro-UK) by which their synergistic effect on clot lysis may be explained. J Clin Invest. 1988; 81: 853-859. Ref.: https://goo.gl/c3zdcV
Gurewich V, Pannell R. 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. 1987; 57: 372-378. Ref.: https://goo.gl/GgWwzV
Vaughan DE, Vautloutle E, Collen D. Urokinase binds to platelets through a specific saturable, low affinity mechanism. Fibrinolysis. 1990; 4: 141. Ref.: https://goo.gl/hbESgz
Gurewich V, Johnstone MT, Pannell R. The selective uptake of high molecular weight urokinase-type plasminogen activator by human platelets. Fibrinolysis. 1995; 9: 188-195. Ref.: https://goo.gl/KHGDQQ
Grau E, Moroz LA. Fibrinolytic activity of normal human blood monocytes. Thromb Res. 1989; 53: 145-162. Ref.: https://goo.gl/RqjzL9
Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemostas. 2015; 13: 98-105. Ref.: https://goo.gl/UckqPw
Singh I, Burnand KG, Collins M, Luttun A, Collen D, et al. Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation. 2003; 107: 869-875. Ref.: https://goo.gl/Wsb6M2
Rijken DC, Hoylaerts M, Collen D. Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator. J Biol Chem. 1982; 257: 2920-2925. Ref.: https://goo.gl/yhRLr3
Pannell R, Gurewich V. A comparison of the rates of clot lysis in a plasma milieu induced by tissue plasminogen activator (t-PA) and rec-prourokinase: evidence that t-PA has a more restricted mode of action. Fibrinolysis. 1992; 6: 1-5. Ref.: https://goo.gl/7WYcct
Harpel PC, Chang TS, Verderber E. Tissue plasminogen activator and urokinase mediate the binding of Glu-plasminogen to plasma fibrin I. Evidence for new binding sites in plasmin-degraded fibrin I. J Biol Chem. 1985; 260: 4432-4430. Ref.: https://goo.gl/cGwU86
Liu J, Gurewich V. Fragment E-2 from fibrin substantially enhances pro-urokinase-induced glu-plasminogen activation. A kinetic study using a plasmin-resistant mutant pro-urokinase Ala-158-rpro-UK. Biochemistry. 1992; 31: 6311-6317. Ref.: https://goo.gl/5cRPnh
Petersen LC. Kinetics of reciprocal pro-urokinase/plasminogen activation. Stimulation by a template formed by the urokinase receptor bound to poly (D-lysine). Eur J Biochem. 1997; 245: 316-323. Ref.: https://goo.gl/nkfoqD
Zarich SW, Kowalchuk GJ, Weaver WD, Loscalzo J, Sassower M, Manzo K, Byrnes C, Muller JE, Gurewich V for the PATENT Study Group. Sequential combination thrombolytic therapy for acute myocardial infarction: results of the pro-urokinase and t-PA enhancement of thrombolysis (PATENT) trial. J Am Coll Cardio. 1995; 26: 374-379. Ref.: https://goo.gl/qHExpB
The 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: 1615-1622. Ref.: https://goo.gl/NkBbWC