Fibrinolytic enzyme plasminogen activator

Figure 34—3. Diagram of the fibrinolytic system. The useful thrombolytic drugs are shown on the left in bold type. These drugs increase the formation of plasmin, the major fibrinolytic enzyme. The activator shown in the shaded box is a complex of streptokinase and plasminogen. Aminocaproic acid, a useful inhibitor of fibrinolysis, is shown on the right. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill. 2001.)...

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. 

Summarizing the fibrinolytic therapy, it should be emphasized that efficient treatment needs urgent application of plasminogen activator (within a few hours) to prevent the formation of crosslinks in the fibrin structure (Fig. 2) and to find the localization of thrombus to emerge plasmin on the surface of fibrin to prevent rapid inactivation of the enzyme by the inhibitor system of fibrinolysis (Fig. 3). 

Liheratore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL. Vampire bat salivary plasminogen activator (desmoteplase) A unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003 34 537-543. 

The measurement of plasminogen activator inhibitor-1 (PAI-1), which complexes with tissue plasminogen activator (t-PA) and thus affects the ability of the latter to activate fibrinolysis, is useful in the assessment of fibrinolytic disorders (93). The complex formed by the fibrinolytic enzyme plasmin with its inhibitor... 

The answer is b. (Hardman, p 1352.) Streptokinase forms a stable complex with plasminogen. The resulting conformational change allows for formation of free plasmin, the active fibrinolytic enzyme. 

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). 

Although most of the enzyme-based drugs are inhibitors of enzymes, a number of enzyme preparations have also been developed as drugs for the treatment of a number of diseases. The development of enzymes as therapeutics has been made easier due to the advances in biotechnology. Most successful example of enzyme therapy includes various preparations of plasminogen activators (thrombolytic or fibrinolytic agents) such as a bacterial protein streptokinase and two plasminogen activators... 

Mechanism of Action A tissue plasminogen activator that activates the fibrinolytic system by directly cleaving plasminogen to generate plasmin, an enzyme that degrades the fibrin ot the thrombus. Therapeutic Effect Exerts CV-thrombolytic action. Pharmacokinetics Rapidlycleared from plasma. Eliminated primarilyby the liverand kidney. Haif-Hfe 13-16 min. 

Mechanism of Action An enzyme that activates the fibrinolytic system by converting plasminogen to plasmin, an enzyme that degrades fibrin clots. Acts indirectlybyform ing a complex with plasminogen, which converts plasminogen to plasmin. Action oc-curs within the thrombus, on its surface, and in circulating blood. Therapeutic Effect Destroys thrombi. 

Schematic representation of the fibrinolytic system. Plasmin is the active fibrinolytic enzyme. Several clinically useful activators are shown on the left in bold. Anistreplase is a combination of streptokinase and the proactivator plasminogen. Aminocaproic acid (right) inhibits the activation of plasminogen to plasmin and is useful in some bleeding disorders. t-PA, tissue plasminogen activator.

Acyl derivatives of fibrinolytic enzymes, both of plasminogen activators (tPA, uPA) and plasmin, were studied in detail,... 

Streptokinase and plasminogen form a complex having the characteristics of a plasminogen activator and activating plasminogen molecules not yet combined with streptokinase to plasmin. The concept of acylation of fibrinolytic enzymes... 

During platelet plug formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed to plasmin (fibri-nolysin) by plasminogen activators present in the tissue. Plasmin interferes in clot propagation and dissolves the fibrin network as wounds heal. At present, a number of fibrinolytic enzymes are available for treatment of myocardial infarctions or pulmonary emboli (see p. 201). 

An important application of fibrinolytic drugs has been to dissolve thrombi in acutely occluded coronary arteries, thereby to restore blood supply to ischaemic myocardium, to limit necrosis and to improve prognosis. The approach is to give a plasminogen activator intravenously by infusion or by bolus injection in order to increase the formation of the fibrinolytic enzyme plasmin. Those currently available include ... 

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