Title
Mechanisms of plasminogen activation; minisymposium: The role of the fibrinolytic system in the pathophysiology and treatment of thrombosis
Author
Lijnen, H.R.
Bachmann, F.
Collen, D.
Ellis, V.
Pannekoek, H.
Rijken, D.C.
Thorsen, S.
TNO Preventie en Gezondheid
Publication year
1994
Abstract
The fibrinolytic system consists of an inactive proenzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in-vivo impact of fibrinolytic components on thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen activator genes in mice impairs thrombolysis in a significant manner, whereas inactivation of the plasminogen activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use, all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin-selectivity continues. Several lines of research towards improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, or plasminogen activators from animal or bacterial origin. A reduction in short- and long-term mortality has been obtained in patients with myocardial infarction treated with all thrombolytic drugs currently licensed for therapeutic use. The hypothesis that more rapid reperfusion of flow through the infarct-related artery after initiation of thrombolytic therapy may better preserve left ventricular function and improve survival was convincingly demonstrated in the GUSTO-1 trial. Myocardial infarction will continue to be the largest field for thrombolytic therapy, at least until its efficacy is demonstrated in ischaemic stroke. Thrombolytic treatment is indicated in major pulmonary embolism in haemodynamically compromised patients, but its therapeutic advantage is much less well defined in smaller pulmonary emboli and deep venous thrombosis. Catheter-directed local thrombolysis can be considered in some patients with peripheral arterial occlusions. Thrombolytic agents constitute a powerful therapeutic advance. As for any class of effective drugs, newcomers will substitute for older compounds, whilst clinicians will refine their therapeutic expertise.
Subject
Biology
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TNO identifier
288156
Source
Journal of internal medicine, 236, 415-424
Document type
article