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©Ferrata Storti Foundation review Haematologica 1994; 79:475-482 CURRENT CONCEPTS IN CORONARY THROMBOLYSIS Guido Grignani, Marisa Zucchella, Alessandra Brocchieri, Anna Saporiti Dipartimento di Medicina Interna e Terapia Medica, Sezione di Terapia Medica, Università di Pavia, IRCCS Policlinico San Matteo, Pavia, Italy ABSTRACT Thrombolytic therapy has become standard care in treating acute myocardial infarction. Fibrinolytic drugs such as streptokinase, APSAC and urokinase are non fibrin specific, and induce systemic activation of the fibrinolytic process, while t-PA and prourokinase are fibrin specific since they are able to activate mainly fibrin bound plasminogen. Both groups of thrombolytics exert different and opposing effects on the hemostatic balance: indeed, they have antithrombotic as well as prothrombotic properties, and this may be important for explaining therapeutic fail- ures or reocclusions. New strategies have been considered or are under investigation for further improving the already excellent efficacy of thrombolytic treatment in myocardial infarction: com- bined administration of fibrinolytic agents, thrombus-targeted thrombolytic drugs, association with other drugs both effective and ineffective on the hemostatic process. At present, however, the first priority still seems to be a continuing effort to increase the percentage of patients treated with thrombolytics, since the benefits of this therapy have already been clearly demonstrated. Key words: thrombolysis, myocardial infarction, antithrombotic effects, prothrombotic effects, fibrin specificity n the past 10 years, thrombolytics have process. become standard therapy for acute myocar- The aim of this review is to describe the char- Idial infarction. Although the ability of strep- acteristics of the main thrombolytic agents, to tokinase to lyse clots was first recognized in the illustrate their different and opposing effects on 1930s, thrombolytic therapy was not used to the hemostatic system, and to discuss implica- treat acute myocardial infarction until the early tions for further research. 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully Main thrombolytic drugs recognized. Since then different studies have Table 1 outlines the major features of the investigated the complex problems related to fib- thrombolytic agents currently in use. rinolytic treatment in acute myocardial infarc- tion: choice of drug, dose, the results in terms of Non fibrin specific drugs reperfusion and survival, the incidence of reoc- clusion, association with other drugs and side Streptokinase effects. The great effort directed to this area has This thrombolytic agent is a single chain pro- stimulated the search for new drugs and, more tein containing 415 amino acids, and having a importantly, has dramatically increased our molecular weight of 47 kD; it is produced by ͱ- knowledge about old and new thrombolytics. hemolytic strains of Streptococcus.1 Furthermore, widespread use of these drugs Streptokinase is a non enzyme protein which has allowed clarification of their different effects indirectly activates the fibrinolytic system by on the hemostatic balance; some of them are forming a 1:1 stoichiometric complex with fibrin specific, that is they activate mainly fib- plasminogen. This streptokinase-plasminogen rin-bound plasminogen, while others are able to activator complex then converts non complexed induce systemic activation of the fibrinolytic plasminogen to plasmin. Streptokinase adminis- Correspondence: Prof. Guido Grignani, Dipartimento di Medicina Interna e Terapia Medica, Sezione di Terapia Medica, Università di Pavia, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy. Received December 13, 1993; accepted July 4, 1994. 476 G. Grignani et al. tration provokes a decrease in plasma levels of minogen to form an activator complex, and plasminogen, Ͱ2-antiplasmin, fibrinogen, factor therefore a direct plasminogen activator.1 The V and factor VIII, and an increase in plasma lev- anisoylation protects the molecule from plas- els of fibrin(ogen) degradation products (FDP); min inhibitors; once in circulation, the agent it is the typical example of systemic activation of becomes active following deacylation. The drug fibrinolysis. was shown to be able to bind to endothelial Almost everyone has some level of circulating cells in culture, to human fibrin and plasma antibodies to streptokinase as a consequence of clots,11,12 and this may explain its long half-life previous infections by ͱ-hemolytic strains of (Table 1), which allows it to be administered as Streptococcus. After streptokinase administra- a single bolus over 5 minutes. Although there is tion such antibodies dramatically increase their evidence of fibrin specificity in vitro, there is no levels in plasma, or become detectable if previ- evidence of this in vivo because administration ously absent. Antibody titer progressively of APSAC induces systemic activation of fibri- increases for several weeks and then slowly nolysis (decrease in plasma levels of fibrinogen decreases, but it may persist for years at levels and other coagulation factors, increase in plas- higher than the basal value.2-4 Therefore in the ma levels of FDP). Furthermore, the drug pos- case of reocclusion a second dose of streptoki- sesses the same antigenicity characteristics and nase is likely to be effective only when adminis- produces the same effects on blood pressure as tered within 48 hours of the first one; after that streptokinase. time other thrombolytics have to be used.5-8 In spite of the large incidence of such antibodies, Urokinase allergic reactions associated with streptokinase Urokinase is a 2-chain serine protease which administration are very rare. activates plasminogen directly without forming Hypotension as a result of thrombolytic thera- an activator complex and, like streptokinase, is py is best described for streptokinase. This effect not specific for fibrin-bound clot.1 is probably the result of plasmin induced First isolated from human urine, urokinase kallikrein activation and release of bradykinin,9 has generally been synthesized from human or it could be due to more complex mechanisms fetal kidney tissue culture; therefore it is non involving platelet activating factor.10 In any case, antigenic and lacks the problems of neutraliza- although patients with low systolic blood pres- tion by antibodies. Hypotension is not routine- sure during streptokinase infusion have a high ly encountered. mortality, the level of systolic blood pressure This drug has been administered recently in before infusion is more closely associated with association with t-PA, in the hope of taking outcome.9 advantage of the systemic effects of the former and the rapid thrombolytic activity of the Anisoylated plasminogen streptokinase activator latter.13,14 The results indicate the important role complex (APSAC) of fibrinogen and FDP levels in the occurrence This second generation thrombolytic agent of reocclusion. This further stresses the impor- consists of streptokinase bound to lys-plas- tance of considering all the various effects of Table 1. Characteristics of the main thrombolytic agents. SK APSAC UK t-PA pro-UK Molecular weight (kD) 47 131 35-55 63-70 47 Fibrin specificity No No No Yes Yes Metabolism Hepatic Hepatic Hepatic Hepatic Half-life (min) 18-23 70-120 14-20 3-4 6-8 Antigenicity Yes Yes No No No SK: streptokinase; APSAC: anisoylated plasminogen streptokinase activator complex; UK: urokinase; t-PA: tissue plasminogen activator; pro-UK: prourokinase Current concepts in coronary thrombolysis 477 thrombolytics on the hemostatic system and is demonstrated by two large controlled clinical not only their ability to lyse the clot. trials: the GISSI-2 and the ISIS-3.20 Fibrin-specific drugs Prourokinase Prourokinase is a short-lived, single-chain Tissue plasminogen activator precursor of urokinase that exhibits relative fib- Native tissue plasminogen activator (t-PA) is a rin specificity, perhaps because a component in serine protease consisting of a single-chain gly- plasma competes with plasminogen for binding coprotein with a molecular weight of 70 kD;1 of this factor, a process which is inhibited by amino acids account for 84% of the molecule, fibrin.1 and carbohydrates for the remaining 16%. For The thrombolytic activity of prourokinase is thrombolytic therapy recombinant t-PA is similar to that of t-PA. In a recent study pro- employed. The main characteristic of this drug urokinase was shown to require heparin for is its fibrin specificity, since the presence of fib- optimal clot lysis in a canine femoral artery rin greatly increases its ability to convert plas- thrombosis model.21 In another study, in man, minogen into plasmin. In vivo administration of the effects of prourokinase were compared with t-PA is, however, associated with a slight those of streptokinase in acute myocardial decrease in fibrinogen levels,15,16 but systemic infarction: the reperfusion rate was higher with activation of fibrinolysis is much lower than that prourokinase after 60 minutes and similar with observed after streptokinase administration. It both agents after 90 minutes.22 In this last study has been suggested that weight-adjusted dosing prourokinase was shown to induce lower sys- is essential to providing an optimal risk-benefit temic activation of fibrinolysis than that ratio for the use of t-PA during myocardial observed with streptokinase. infarction;17,18 thus, most studies support weight- adjusted, rapid (90 minutes) infusion.1 Another important factor influencing
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