Antithrombin III activation

Protein C, protein S, antithrombin III, activated protein C resistance, lipoprotein(a) anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation 20210a... 

The excess vessel wall fibrin accumulation and atherosclerosis seen as a long-term complication of diabetes may well result from the glycosylation-induced inhibition in fibrinogen (fibrin)-plasmin degradative function and heparin-catalyzed antithrombin III activity. 

B31. Brownlee, M., Vlassara, H., and Cerami, A., Inhibition of heparin-catalyzed antithrombin III activity by nonenzymatic glycosylation Possible role in fibrin deposition in diabetes. Diabetes 33, 532-535 (1984). 

C7. Ceriello, A., Decreased antithrombin III activity in diabetes may be due to nonenzymatic glycosylation. Thromh. IIaenw.sta.sis 50, 633-634 (1983). 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

The endogenous activity of antithrombin III is gready potentiated by the presence of acidic proteoglycans such as heparin (Chapter 48). These bind to a specific cationic site of antithrombin III, inducing a conformational change and promoting its binding to... 

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

Antithrombin III. AT-III administration holds some promise because it inhibits a number of activated coagulation factors F-XIa, F-IXa, F-Xa, and thrombin. There are, however, no data to support the use of heparin. Although a... 

Nesheim M., Blackburn M. N., Lawler C. M., Mann K. G. Dependence of antithrombin III and thrombin binding stoichiometries and catalytic activity on the molecular weight of affinity purified heparin. J Biol Chem 1986 261,3214-21. 

Heparin and X Activates antithrombin III, inhibitor of thrombin and factor X... 

Pharmacology The antithrombotic activity is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. 

Mechanism of action Potentiates anti-protease activity of antithrombin III Inhibits vitamin K epoxide reductase... 

Heparin binds to antithrombin III and induces a conformational change that accelerates the interaction of antithrombin III with the coagulation factors. Heparin also catalyzes the inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent the formation of free thrombin than are needed to inhibit the protease activity of clot-bound thrombin. Inhibition of free thrombin is the basis of low-dose prophylactic therapy. 

Low-molecular-weight fragments produced by chemical depolymerization and extraction of standard heparin consist of heterogeneous polysaccharide chains of molecular weight 2,000 to 9,000. The LMWH molecules contain the pentasaccharide sequence necessary for binding to antithrombin III but not the 18-saccharide sequence needed for binding to thrombin. Compared to standard heparin, LMWH has a 2- to 4-fold greater antifactor Xa activity than antithrombin activity. 

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