COMPARATIVE STUDIES OF SOME ANTIFIBRINOLYTIC AGENTS AND PROTEINASE INHIBITORS *

In order to evaluate the physiological significance of fibrinolytic agents in blood or tissues, it is necessary to know whether the assayed activity is a true measure of the fibrinolytic activity or it is influenced by inhibitory agents. It is well known that it is difficult to obtain an accurate measurement of the fibrinolytic activity of blood because of the excessive amount of inhibitory agents present. HOW the assayed activity should be evaluated in terms of its significance in the organism where it is present together with inhibitors is still an unsolved problem. In order to provide a set of useful data, accurate methods for the separate determination of fibrinolytically active agents and of inhibitors must be provided. Using such assays, the concentration of active agents and inhibitors should be followed under various physiological conditions and in various animal species. The active agents and their inhibitors should be prepared in purified form, their chemical properties determined, and their interactions studied. Recent years have seen substantial progress in these directions and a pattern is beginning to emerge of the interactions taking place in the living organism, which certainly will develop further during coming years and will eventually provide us with the information needed to evaluate the physiological significance of fibrinolysis in health and disease. Since the research group of the present author over many years has been engaged in certain aspects of this work, it is the intention to present here a description of our approaches and their results as based on the combined efforts by several associates. The approaches have been along the following lines: ( 1 ) An effort to devise specific plasma assay methods better than the simple isoelectric precipitation procedure. (2) A systematic and comparative study of known, naturally occurring protease inhibitors and of synthetic compounds. (3) The isolation and purification of inhibitors occurring in the organism. (4) A comparative study of the chemical properties of naturally occurring inhibitors. ( 5 ) A study of the physiology of naturally occurring inhibitors.