Plasminogen activator inhibitor-1 activity

Levi M, Biemond BJ, VanZonneveld AJ et al. (1992) Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 85 305-312... 

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. 

Inhibits platelet aggregation by increasing levels of cAMP Binds protein C, which is then cleaved by thrombin to yield activated protein C this in combination with protein S degrades factors Va and Villa, limiting their actions Activates plasminogen to plas-min, which digests fibrin the action of t-PA is opposed by plasminogen activator inhibitor- (PAI-1)... 

Plasminogen activator Plasminogen activator inhibitor-1 Tissue inhibitor of metalloproteinase... 

Plasminogen activator inhibitors have been shown to be present in a large variety of different cells and tissues. These inhibitors are thought to play an important role in regulating tissue fibrinolysis. One of these inhibitors has been purified from cultured bovine aortic epithelial cells. This inhibitor has been shown to be a serine protease inhibitor and inhibits the function of two proteolytic enzymes urokinase and tissue plasminogen activator, both of which cleave and activate plasminogen. The mechanism by which this inhibitor functions is very similar to that described above with a-l-PI. Thus, the inhibitor forms a binary complex with the proteolytic enzyme and thereby inhibits its activity. Again in a situation comparable to that with a-l-PI, it was found that when the purified bovine aortic epithelial inhibitor was exposed to Al-chlorosuccinimide,... 

PAI Plasminogen activator inhibitor PA-IgG Platelet associated immunoglobulin G PAM Pulmonary alveolar macrophages... 

DVT, deep vein thrombosis HIT, heparin-induced thrombocytopenia PAI-I, plasminogen activator inhibitor PE, pulmonary embolism SERM, selective estrogen receptor modulator VTE, venous thromboembolism. 

BMI body mass index PAI-1 plasminogen activator inhibitor-1... 

ACE-I, angiotensin-converting enzyme inhibitor ARB, angiotensin receptor blocker INR, International Normalized Ratio IV, intravenous t-PA, tissue plasminogen activator. 

Fio. 3. The intrinsic and extrinsic cascade fibrinolytic systems. activation H, inhibition t-PA, tissue plasminogen activator PAI, plasminogen activator inhibitor a2-M, a2-macroglobulin a2-AP, a2-antiplasmin. 

The antithrombotic factors produced by endothelial cells are thrombomodulin (TM) and protein S (PS), components of the vitamin K-dependent protein C (PC) anticoagulant pathway, inhibiting F-Va-F-Villa (E15) tissue plasminogen activator (tPA), responsible for fibrinolysis (N2, LI8) and the lipoprotein-associated coagulation inhibitor (LACI), which inhibits F-VIIa-TF complex and F-Xa (B51). 

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