Fibrinolytic

Aplastic anemia and leukemia are not the only health effects ascribed to benzene exposure. A number of recent studies have associated benzene exposure with chromosomal changes (aberrations) (118). Other studies have shown abnormalities in porphyrin metabolism and decrease in leucocyte alkaline phosphatase activity in apparendy healthy workers exposed to 10—20 ppm benzene (119,120). Increases in leukoagglutinins, as well as increases in blood fibrinolytic activity, have also been reported and are believed to be responsible for the persistent hemorrhages in chronic benzene poisoning (121,122). 

Plasma Inhibitors, In Vivo Anticoagulants. Fourteen naturally occurring compounds that normally exert an inhibiting effect on the activity of coagulation, platelet function, and fibrinolytic activity and complement systems have been identified within the circulating blood. 

The plasminogen molecule contains several sites that specifically bind a number of antifibrinolytic amino acids, such as lysine [56-87-1] and S-aminocaproic acid [60-32-2] (EACA). These sites are known as lysine binding sites (LBS), and are localized mainly to the A or heavy chain of the molecule. One is located in K4 and at least one more is in K1 through K3. One LBS, which is beheved to reside in Kl, has a stronger affinity for EACA, whereas the others have a weaker affinity. The LBS are important for the interaction of plasminogen with several components of the endogenous fibrinolytic system. 

Fig. 4. Fibrinolytic system where SCUPA is single-chain urokinase plasminogen activator rTPA is recombinant tissue plasminogen activator APSAC is acylated plasminogen streptokinase activator complex SK is streptokinase and UK is urokinase.

Inhibitors of Fibrinolysis. Inhibitors of the fibrinolytic system are either endogenous naturally occurring inhibitors or modulators or... 

Several synthetic amino acids (63—65) have been identified that excite inhibition of the fibrinolytic system (Table 8). 

Streptokinase. The fibrinolytic activity of streptokinase, isolated from strains of hemolytic Streptococci, was first demonstrated in 1933 (63). Streptokinase is a secreted protein product inasmuch as filtrates free of demonstrable bacteria were found to dissolve fibrin clots with rapidity. 

Coagulation summarizes the mechanisms involved in stopping bleeding due to an injured or defective vessel wall. Coagulation is characterized by procoagulatory and anticoagulatory factors that are in balance under normal conditions. Vessel injuries are occluded by the coagulation system and spontaneous vessel occlusions dissolved by the fibrinolytic cascade. 

Therapeutically t-PA and urokinase are the most important drugs for fibrinolytic therapy (myocardial infarction, stroke, massive pulmonary embolism). This treatment is associated with an enhanced risk of bleeding complications. 

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. 

The fibrinolytic reactions are controlled by endogenous blood plasma inhibitors as well [3]. 

Fibrinolytics. Figure 2 Various fibrin structures for plasmin. Fibrinogen (Fg) is converted to fibrin (F) by thrombin (T), and thrombin can also convert factor XIII (XIII) to activated factor XIII (Xllla). The latter produces crosslinks between fibrins (FxxF) and also may crosslink fibrin with a2-plasmin inhibitor (FxxFxxPI). The efficiency of digestion of these plasmin substrates by plasmin, resulting in the soluble fibrin degradation products (FDP), is different. The amount of FDP formed in time is expressed in arbitrary units. 

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. 

Fibrinolytics. Figure 4 Inactivation of plasmin by a2-plasmin inhibitor Effect of fibrin. The inactivation rate of free plasmin is very rapid (the second order rate constant k 430 104M-1s-1), while of fibrin bound plasmin is slow (the second order rate constant k 1 104M"1s"1). Inactivation of plasmin in the figure is shown in arbitrary units. Abbreviations plasmin (P), fibrin (F). 

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). 

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