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Tissue-Type Plasminogen Activator

A Review of its Pharmacology and Therapeutic Use as a Thrombolytic Agent

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Summary

Synopsis

Coronary arterial thrombolysis is becoming an established treatment of acute myocardial infarction. If given early enough, it recanalises occluded coronary arteries, salvages myocardial function and reduces mortality. A reduction of mortality in patients with acute myocardial infarction has now been demonstrated for streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC; anistreplase) and recombinant tissue-type plasminogen activator (rt-PA)

From the biochemical point of view, rt-PA has several attractive properties. It is similar to or identical with the physiological plasminogen activator in blood, it does not induce an antibody response, and it is more fibrin-specific than most or all other currently known thrombolytic agents. The rate of recanalisation of occluded coronary arteries with rt-PA is about 60 to 80% in non-comparative and placebo-controlled trials. rt-PA was similar in efficacy to urokinase in the only trial to compare the 2 agents. In 2 comparative trials evaluated by meta-analysis, rt-PA appeared more effective than streptokinase for the early recanalisation of occluded arteries. Both agents were comparable in their effects on left ventricular function in 2 comparative trials, but further study is needed to conclusively evaluate this parameter. Moreover, both agents reduce inhospital mortality, but much larger direct comparative trials are required before scientifically valid statements can be made on the relative clinical efficacy of available thrombolytic agents in terms of their effects on both morbidity and mortality.

Thus, rt-PA constitutes a notable contribution of recombinant DNA technology to the treatment of thromboembolic disease, the main cause of death and disability in Western societies.

Pharmacodynamic Properties

Recombinant tissue-type plasminogen activator (rt-PA) for clinical use is produced by bulk fermentation of a Chinese hamster ovary cell line transfected with the cDNA for the naturally occurring human product. The subsequently purified proteinase is a single polypeptide chain of 527 amino acids which is fully glycosylated and identical to the naturally occurring human protein.

The mechanism of action of rt-PA is similar to that of naturally occurring t-PA. t-PA has a high affinity to fibrin in a thrombus. In turn, t-PA has a high affinity and specificity towards fibrin-bound plasminogen, where it causes enzymatic degradation of the latter into plasmin and consequently thrombolysis. t-PA has only low affinity for plasminogen in the absence of fibrin. Thus, the fibrinolytic process induced by t-PA is fibrin-specific and causes only limited systemic plasminogen activation and fibrinogenolysis.

Various in vitro studies have demonstrated the fibrinolytic activity of t-PA against clots, while causing only minor systemic activation of the fibrinolytic system. The in vivo thrombolytic properties of t-PA have been confirmed in numerous and varied animal models of thrombolysis, including pulmonary emboli, thrombosis of jugular and femoral veins and coronary and femoral arteries. t-PA was more potent than u-PA (urokinase-type plasminogen activator), and it produced more rapid and more effective lysis. It was also more rapid and more effective than streptokinase. In addition, t-PA caused less extensive systemic breakdown of fibrinogen than u-PA and streptokinase. Preliminary animal studies suggest a use for t-PA in stroke and some ophthalmological conditions.

Pharmacokinetic Properties

The disposition of t-PA in plasma can be represented by a 2-compartment model composed of 1 central (plasma) compartment and 1 peripheral compartment. t-PA is rapidly cleared from circulation by the liver, with an initial half-life of only a few minutes in animals. However, fibrin-bound t-PA remains pharmacologically active at the clot site for several hours after withdrawal of the systemic infusion of rt-PA and its clearance from circulation. In healthy subjects intravenous infusion of commercially available rt-PA (8.3 μg/kg/min) yields a mean steady-state plasma concentration of about 1 to 1,5 mg/L. Other mean pharmacokinetic parameters in subjects were: initial half-life 3 to 4 minutes; terminal half-life about 30 minutes; plasma clearance about 40 L/h; and volumes of distribution of the central compartment and at steady-state of 3.9 and 7.2L, respectively. Estimation of t-PA may vary significantly depending on the assay system used and on the method of blood collection and storage.

Therapeutic Studies

Using coronary artery reperfusion or patency as end-points, intravenous infusion of rt-PA is superior to placebo in the treatment of acute myocardial infarction. At total doses of 40 to 100mg administered over 1 to 3 hours, rt-PA produces reperfusion in about 60 to 80% of infarct-related arteries, as demonstrated in non-comparative trials. Compared with placebo, rt-PA improves regional wall motion of the infarcted zone and enhances left ventricular function. The earlier rt-PA is administered after the onset of symptoms the better the chance of reperfusion and salvage of left ventricular function. Overall inhospital mortality after rt-PA therapy was low (4 to 7%), but there were no control groups in most studies. However, 2 recent placebo-controlled studies have shown that mortality is significantly reduced, especially if rt-PA is administered within 3 hours of the onset of symptoms. Reocclusion of the coronary arteries can occur in about 7 to 15% of patients after rt-PA therapy.

Cumulated results of non-comparative patency or reperfusion trials using comparable end-points demonstrate rt-PA to reperfuse coronary arteries more efficiently than streptokinase. Meta-analysis of patency data from 2 trials directly comparing the efficacies of rt-PA and streptokinase indicates a significantly higher frequency of patent arteries with rt-PA at 90 minutes after starting treatment. Reocclusion rates have not been evaluated in directly comparable trials, but appear to be similar. Bleeding complications in comparative trials appear somewhat, but not dramatically, lower with rt-PA than with streptokinase. The relative impact of streptokinase and rt-PA on preservation of left ventricular function has been evaluated in 2 comparative trials, which showed comparable effects for the 2 agents. However, further studies are needed to arrive at conclusive results. In small comparative trials not designed with mortality as end-points, the combined inhospital mortality was 5.4% for rt-PA and 7.7% for streptokinase. Large directly comparative trials designed to specifically address mortality are required to establish the relative impact of each drug on mortality. rt-PA and urokinase were of similar efficacy in the only trial to compare these 2 agents.

Several small studies and case reports have indicated that rt-PA may be useful in the treatment of a variety of other indications including pulmonary embolism, unstable angina pectoris, deep vein thrombosis, peripheral arterial occlusion, stroke and some ophthalmological conditions. However, controlled studies in larger numbers of patients will be required before any definite conclusions can be drawn concerning its efficacy in these indications.

Adverse Effects

Minor adverse effects such as nausea, vomiting, hypotension and fever have been reported with rt-PA, but these effects may not be attributable to the drug as they are frequent sequelae of myocardial infarction. No serious immunogenic reactions have been noted with rt-PA, unlike some other thrombolytic treatments, although mild hypersensitivity reactions such as urticaria have occasionally been observed.

Most interest concerning the tolerability of thrombolytic therapy has centred on the relative risk of systemic fibrinolytic activation and consequent bleeding complications. At usual therapeutic doses rt-PA induces little systemic fibrinolytic activation, in particular compared with streptokinase. However, in clinical practice rt-PA therapy remains associated with a residuai bleeding tendency. The type of bleeding associated with thrombolytic therapy may be divided into 2 kinds: superficial and internal. Superficial bleeding (e.g. venous cutdowns, arterial punctures, sites of recent surgical intervention) are relatively more frequent but not critical compared with the rare, more serious cases of internal bleeding involving the gastrointestinal tract, genitourinary tract, retroperitoneal and intracranial sites. Life-threatening intracranial bleeding occurred in some clinical studies of rt-PA when total doses up to 150mg were used, but there appears to be no increased risk of fatality from this complication since a total dose restriction to a maximum of 100mg has been instituted. In a controlled clinical trial in over 5000 patients who did not receive concomitant aspirin the stroke rates in rt-PA and control groups were similar.

Dosage and Administration

rt-PA is indicated for use in adults with acute myocardial infarction. Treatment should be initiated as soon as possible after the onset of symptoms (at the latest 6 hours after the onset of pain). In the US the recommended total dose is 100mg administered by intravenous infusion as 60mg in the first hour (of which 6 to 10mg is administered as a bolus over the first 1 to 2 minutes) followed by 20mg in each of the subsequent 2 hours. For patients weighing less than 65kg, a total dose of 1.25 mg/kg administered over 3 hours, as described above, may be used. In European countries the recommended total dose is 70 to 100mg in 90 minutes with a 10mg bolus, to a total dosage of 1 mg/kg. Dose regimens adjusted for bodyweight appear to result in an improvement in coronary patency, with a lower rate of haemorrhagic complications. A higher total dose of rt-PA must not be used as 150mg has been associated with an increased risk of intracranial bleeding. In most patients treated to date, heparin has been administered concomitantly for 48 hours or more. Aspirin and/or dipyridamole have been given during and/or following heparin treatment. rt-PA is contraindicated in the following situations: active internal bleeding; history of cerebrovascular accident; intracranial or intraspinal surgery or trauma within 2 months; intracranial neoplasm, arteriovenous aneurysm or malformation; known bleeding diathesis; and severe uncontrolled hypertension. There are several other conditions where the risk of rt-PA therapy may be increased and should be weighed against the anticipated benefits.

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  1. Centre for Thrombosis and Vascular Research, Campus Gasthuisberg, Leuven, Belgium

    Désiré Collen, Henri R. Lijnen, Peter A. Todd & Karen L. Goa

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  1. Désiré Collen
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Various sections of the manuscript reviewed by: P. Desnoyers, Laboratoire Central d’Hématologie, Hôtel-Dieu, Paris, France; DJ. Kereiakes, Cincinnati, Ohio, USA; V.J. Marder, University of Rochester Medical Center, Rochester, New York, USA; M. Nidorf, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; D.C. Rijken,Gaubius Institute, Leiden, The Netherlands; E. Seifried, Medizinische Universitätsklinik und Poliklinik, Universität Ulm, Ulm, West Germany; B.E. Sobel, Department of Internal Medicine, Cardiovascular Division, Washington School of Medicine, St Louis, Missouri, USA; A. Takada, Department of Physiology, School of Medicine, Hamamatsu University, Hamamatsu, Japan; P. Thompson, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; E.J. Topol, Division of Cardiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; S. Verheught, Department of Cardiology, Free University Hospital, Amsterdam, The Netherlands; M. Verstraete, Centre for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium; Harvey D. White, Cardiology Department, Greenlane Hospital, Auckland, New Zealand.

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Collen, D., Lijnen, H.R., Todd, P.A. et al. Tissue-Type Plasminogen Activator. Drugs 38, 346–388 (1989). https://doi.org/10.2165/00003495-198938030-00003

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