Fibrinolysis [antikvár]

INTRODUCTION The modern era of fibrinolysis began about 50 years ago with the discovery that the culture media of certain strains of streptococci contained a substance which produced the rapid dissolution of human blood clots. It was soon demonstrated that the bacterial protein, now called streptokinase, acts indirectly by converting plasminogen, a plasma protein, to the active fibrinolytic enzyme, plasmin. Plasminogen and endogenous plasminogen activators were shown to be present in a wide variety of tissues and body fluids. Of special interest was the discovery of a plasminogen activator in urine, urokinase. The development of a reliable procedure for the partial purification of plasminogen opened the way to biochemical studies of all aspects of the fibrinolytic system including inhibitors. Animal and clinical studies showed that plasmin is an ineffective thrombolytic agent and that activators offered the most promising therapeutic approach. Extensive clinical trials have been carried out with highly purified streptokinase and urokinase. Two mechanisms have been described which lead to the activation of plasminogen within the blood stream: (1) the release of plasminogen activator(s) from the walls of blood vessels under a wide variety of physiological and pharmacological stimuli and (2) the appearance of plasmin activity following the activation of Factor XII (Hageman Factor), the initial step in the so-called contact activation system. Current research involves the elucidation of the structures of plasminogen, plasmin and some of the activators, particularly streptokinase and urokinase. The mechanism of activation by various activators is also being studied at a molecular level. Of particular interest is the interaction of streptokinase with plasminogen which involves the formation of a complex and is of interest not only in fibrinolysis but as a tool to study the activation of proteolytic enzymes at a fundamental level. Rapid advances are being made in the understanding of the plasma inhibitors of both plasmin and plasminogen activators and the physiological role of the inhibitors. Small molecular weight substances which induce fibrinolytic activity in the blood are being studied for possible clinical use and the action of plasmin on its natural substrate, fibrin, is under intensive investigation. The aim of this book is to present the most important aspects of our current knowledge of fibrinolysis with sufficient background and clarity so that a reader can understand the developments in each area which led up to the present state of our knowledge. We hope the reader with either a basic or a clinical viewpoint will gain a dynamic picture of the developments in a field, become acquainted with the most recent advances and will be in a position to understand (and contribute to) further progress. Since plasminogen and plasminogen activators have been found in many tissues and fluids in the body and interrelationships have been found between the fibrinolytic system, blood coagulation, inflammatory reactions and the complement system, it is important to keep in mind that clot-dissolving may prove to be the most obvious but not the only function of the fibrinolytic system. Daniel L. Kline Cincinnati, Ohio July 1, 1979