Fibrinolytic enzyme urokinase

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

The role of the fibrinolytic system is to dissolve any clots that are formed within the intact vascular system and so restrict clot formation to the site of injury. The digestion of the fibrin and hence its lysis is catalysed by the proteolytic enzyme, plasmin, another serine proteinase. Plasmin is formed from the inactive precursor, plasminogen, by the activity of yet other proteolytic enzymes, urokinase, streptokinase and tissue plasminogen activator (tPA) which are also serine proteinases. These enzymes only hydrolyse plasminogen that is bound to the fibrin. Any plasmin that escapes into the general circulation is inactivated by binding to a serpin (Box 17.2). 

Fibrinolytics. Figure 3 Plasminogen activation (a) Kinetics of plasminogen activation by uPA (urokinase-type) and tPA (tissue-type) plasminogen activators. Effect of fibrin (b) Ternary complex formation between enzyme (tPA), substrate (Pg) and cofactor (F) Abbreviations plasmin (P), fibrin (F), plasminogen (Pg). Plasmin, formed in time, is expressed in arbitrary units. 

Such clots—also known as emboli—present a serious hazard by their potential for blocking circulation of blood to vital organs. The considerable research devoted to agents that will lyse the fibrin in clots has led to the development of the clinically useful agent, uj-okinase. This drug is a fibrinolytic proteinaceous enzyme isolated from human urine. The difficulty involved in isolation of significant amounts and the antigenicity of urokinase and a related... 

A study in coronary patients has shown that fibrinogen levels are Increased over normal controls ° and that fibrinolytic activity is also decreased in these patients.The rate of degradation of fibrinogen is inhibited in rats fed an atherogenic diet. It would seem reasonable then that some control over the clinical outcome of atherosclerosis could be had by the use of fibrinolytic agents. The enzymes streptokinase and urokinase continue to be evaluated with some benefits reported in the therapy of acute Thromboembolism.Phenformin is still the only drug of interest as a fibrinolytic agent other than the enzymes and CPIB mentioned earlier. 

Other high molecular weight fibrinolytic substances are certain dextran fractions brinase, an enzyme derived from Aspergillus oryzae, ateroid, a naturally occuring mucopolysaccharide conplez and erythrokinase (EK) a protein isolated from red blood cells that activates human and bovine plasminogen in a manner similar to urokinase but idiich hats different physical properties ... 

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