Fibrinolytic enzyme

Fibrinolytic enzymes (proteases) are used to dissolve thrombus, the insoluble aggregate of fibrin and platelet including several additional cellular and molecular components of the blood. 

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. 

Enzymology of proteases in a water-phase is well known, but its alteration in a compartment is poorly understood. There are dramatical changes in reaction rates, in enzyme contractions and in enzyme sensitivity to inhibitors, which are not exactly described. In addition, besides fibrin and platelets there are several cellular and molecular components present in a thrombus compartment, where their influence on the basic fibrinolytic reactions is not known. To study this aspect of fibrinolysis is a task of the near future [4]. 

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). 

Fibrinolytic effecting protease enzyme with glycoprotein structure relative mol mass ca. 30000. Isolation from the poison secretion (venom) of Agkistrodon rhodostoma (malayan pit viper) with chromatographic purification. 

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. 

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. 

Formulate a monitoring plan for a patient with ST-segment elevation acute coronary syndrome receiving fibrinolytics, aspirin, unfractionated heparin, intravenous nitroglycerin, intravenous (3-blockers followed by oral P-blockers, an angiotensin-converting enzyme inhibitor, and a statin. 

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... 

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... 

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. 

Peng, Y., Yang, X., and Zhang, Y. 2005. Microbial fibrinolytic enzymes an overview of source, production, properties and thrombolytic activity in vivo. Applied Microbiology and Biotechnology 69(2), 126-132. 

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). 

A large group of proteinases contain serine in their active center. The serine proteases include, for example, the digestive enzymes trypsin, chymotrypsin, and elastase (see pp. 94 and 268), many coagulation factors (see p. 290), and the fibrinolytic enzyme plos-min and its activators (see p. 292). 

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. 

A fibrinolytic system reverses thrombosis and thereby maintains hemostasis. Fibrinolytic enzymes and other factors work in concert to dissolve the clot using a series of rather nonspecific proteases that act locally by digesting the fibrin deposited at the site... 

TABLE 9.3. Enzymes that catalyze fibrinolytic activity leading to thrombolysis... 

Anistreplase (streptokinase- plasminogen complex) streptococci protein streptococci plaminogen, which is then cleaved to form plasmin. Plasmin mediate fibrinolysis. Systemic lytic state and immunogenicity may limit its use. Because antistreplase is aheadly lined to plaminogen, the onset of fibrinolytic is faster. These enzymes are not fibrin-specific. 

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