Studies with plasminogen activators

McNicol, George P (1965) Studies with plasminogen activators. PhD thesis, University of Glasgow.

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In the past decade, stimulated by the availability of fibrinolytic agents suitable for use in man in the treatment of thrombo-embolic vascular occlusion, there has been a great increase in interest in the components and functions of the fibrinolytic enzyme or plasminogen-plasmin system. This thesis reports studies with plasminogen activators, that is substances which activate the plasminogen-plasmin system and so bring about fibrinolysis. The thesis begins with a brief historical review of the development of ideas in fibrinolysis, and an account of current concepts of the components and functions of the plasminogen-plasmin system. There follows an account of the laboratory methods used in the thesis, including the euglobulin lysis and fibrin plate tests for plasminogen activator, plasminogen and fibrinogen assays, and as an index of the fibrinolytic coagulation defect, the thrombin clotting time. A description is given of a simple original method of preparing fibrinogen tagged with radioactive iodine, and of the electrophoretic and chromatographic properties of this tagged fibrinogen. Its use in a modified plasminogen-enriched radioactive clot assay system for plasminogen activator is described. The thesis continues with an account of the biochemical effects of administration to man of a variety of plasminogen activators. Streptokinase, an activator of bacterial origin, was given to six subjects and intense plasminogen-plasmin system activity was induced, with a serious associated coagulation defect. The need for individualisation of initial dosage because of varying levels of antibody to streptokinase was confirmed. A commercial preparation of urokinase, a physiological plasminogen activator present in human urine, was studied. Serum was found to inhibit urokinase and the preparation studied had coagulative properties in vitro and in vivo, Actase, a commercial "plasmin" preparation found to consist largely of streptokinase, was given to two subjects and the fibrinolytic response investigated; little activity was produced by administration of the manufacturer's recommended dosage. Complamin, a nicotinic acid-theophylline ester, fibrinolytically inert in vitro, was found to be a potent stimulus to production of plasma fibrinolytic activity when injected intravenously. However, the fibrinolytic response was transient and resistance to Complamin developed rapidly. Experiments involving study of the fibrinolytic responses to Complamin and exercise are described, which suggest that resistance to Complamin was not due to exhaustion of the body's reserve of fibrinolytic activity. Most of the tissues of the body are rich in plasminogen activator, and tissue activator is an obvious possible source of plasminogen activator for therapeutic use. For this reason, plasminogen-plasmin system activity in surgical operations, in which tissue activator may be released into the circulation, was studied. A similar pattern of fibrinolytic activity to that produced by streptokinase was found, with liability to a serious coagulation defect. Tissue activator does not therefore appear on the basis of these observations to have unique merits as a potential therapeutic agent. The thesis concludes with an account of experiments with artificial thrombi prepared in vitro by a modification of the method of Chandler. Such thrombi were perfused with streptokinase in an artificial circulation and factors affecting their response were studied. Thrombi made from blood with normal or raised platelet counts were found to release platelet emboli into the circulation, whereas thrombi made from thrombocytopenic blood were almost completely digested. The findings suggest that in vivo thrombolytic agents might cause breakdown of thrombi into platelet emboli, which would represent an obvious hazard in the case of coronary and cerebral thrombosis. Thrombi made from hyperlipidaemic blood were markedly resistant to lysis, an observation supporting the view that hyperlipidaemia may predispose to thrombotic vascular occlusion. Despite intensive efforts in many laboratories, the goal of routine therapeutic use of plasminogen activators has not yet been achieved. Some of the biochemical considerations involved in their use are presented in this thesis. From attempts made to solve the many problems which still remain should emerge more understanding of the components and functions in health and disease of the fibrinolytic enzyme system.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: E M McGirr
Keywords: Pharmacology
Date of Award: 1965
Depositing User: Enlighten Team
Unique ID: glathesis:1965-72236
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 May 2019 15:12
Last Modified: 24 May 2019 15:12

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