Plasminogen inhibitors

Secretion of tissue plasminogen activator by cultured endothelial cells increases within an hour after exposure to arterial levels of shear stress [11], while secretion of the related inhibitor (plasminogen inhibitor-1) by the same cells is unaffected by shear forces over the physiological range. 

Sequences have been determined for plasminogen and bovine Factor XII, and they are not homologous with the other serine proteases. The amino-terminal sequence of Factor XII is homologous, however, with the active site of several naturally occurring protease inhibitors (11). 

Although the precise mechanism of plasminogen activation is unknown, three principal theories have developed based on studies of the in vitro activation of native human plasminogen. Activation of native Glu-plasminogen in the absence of any plasmin inhibitor yields Lys —plasmin plus the so-called pre-activation peptides (PAP) formed by cleavage at LySg2 S E3 Activation takes place by a two-step mechanism in... 

The high affinity LBS is involved in the interaction of plasminogen with fibrin, a2-antiplasmin, and a plasmin inhibitor called histidine-rich glycoprotein. It has been observed that plasminogen activation takes place on the surface of fibrin and that a2-antiplasmin competitively inhibits the plasminogen—fibrin interaction at the high affinity LBS. 

Mottonen, J., et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature 355 270-273, 1992. 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

Since plasmin in free form (not bound to fibrin) is extremely and rapidly inactivated by the inhibitor system (Fig. 4), plasminogen activators are used for treatment of thrombosis. Under such a condition, if plasmin is formed by the activators (especially by tPA) at the site of fibrin, the bound form can degrade fibrin because it is protected against the inhibitor system. In the medical practice, mainly two endogenous plasminogen activators, tPA and uPA, and one exogenous, the streptokinase (SK) are used [1,4]. 

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). 

Figure 51-7. Scheme of sites of action of streptokinase, tissue plasminogen activator (t-PA), urokinase, plasminogen activator inhibitor, and Kj-antiplasmin (the last two proteins exert inhibitory actions). Streptokinase forms a complex with plasminogen, which exhibits proteolytic activity this cleaves some plasminogen to plasmin, initiating fibrinolysis. 

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