Heparin binding to antithrombin III

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. 

In order to make equation 6 more specific it will be assumed that heparin binds to antithrombin III... 

Mechanism Heparin binds to antithrombin III, increasing its serine protease inhibiting activity and resulting in fast inactivation of factors Ila, IXa, Xa, XIa, and XHa. 1 Hepatic synthesis of vitamin K-dependent factors II, VII, IX, X—coumarins prevent y-carboxylation no effect on factors already present. In vivo effects only. 

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. 

Inactive factors 1. Mechanism of action Heparin acts indirectly by binding to antithrombin III to cause a rapid anticoagulant effect. Maximal anticoagulation occurs within minutes after intravenous heparin injection (unlike vitamin K antagonist anticoagulants, such as war-... 

Fondaparinnx is a sjmthetic pentasaccharide that mimics the site of heparin that binds to antithrombin III and inhibits factor Xa activity, which in tnm inhibits thrombin generation. It does not release tissne factor pathway inhibitor. It is nearly completely absorbed after snbcntaneous... 

Appreciable further work on the heparin pentasaccharide has been repo i ed. Compound (4) was synthesized and found to bind to antithrombin (III) with an association constant similar to that of high-affinity heparin. The 3-sulphate (5) is a very potent analogue, but the desulphated compound (6) has none of the biological properties of (4). Other inactive analogues of compound (4) are the compound with B-L-idopyranose 2,6-disulphate in place of the iduronosyl 2-sulphate and the pentasaccharide... 

Rapid I Antithrombin III I plus heparin very slowly. The binding of heparin to antithrombin III produces a conformational change allowing the antithrombin to rapidly combine with and inhibit thrombin except that already bound to fibrin. 

Heparin and heparin-like compounds are available in a variety of molecular weight fractions. The lower molecular weight heparins are not able to bind both antithrombin III and thrombin simultaneously, which is necessary for the inactivation of thrombin. These drugs, consequently, affect the actions of factors lXa and Xa, rather than thrombin. 

Mechanism and effects Regular heparin binds to and activates endogenous antithrombin 111 (ATlIl). The heparin-ATIll complex combines with and inactivates thrombin (activated factor 11) and several other factors, especially factor X. In the presence of heparin, antithrombin III inhibits the coagulation factors approximately 1000-fold faster than in its absence. Low doses of heparin also coat the endothelial walls of vessels and reduce the activation of clotting elements by these cells. Because it acts on preformed blood components, heparin is also active in vitro—almost instantaneously. The action of heparin is monitored with the activated partial thromboplastin time laboratory test (aPTT or PTT). 

Polymeric materials having antithrombogenic activity are very important and their development is expected in the field of artificial organs such as the artificial vessel or the devices for extracorporeal circulation. In previous papers >2 we described that the binding of sulfonate and amino acid sulfamide groups onto cross-linked polystyrene endows these materials with antithrombic activity which requires the presence of a plasma cofactor, antithrombin III. These insoluble materials operate as catalysts of the inactivation of thrombin by its inhibitor as does soluble heparin. The catalytic effect of this mucopolysaccharide was demonstrated to require the formation of complexes between heparin and either antithrombin III or thrombin or both > >. ... 

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