Heparin-antithrombin complex

Complexation of antithrombin with thrombin (and probably also with other proteinases) occurs by formation of a covalent bond which, by subsequent splitting, produces unaltered proteinase and irreversibly modified antithrombin.405,406 The strength of heparin-antithrombin complexes, as determined by u.v.-difference,405 fluorescence,406,407 af-... 

Heparin is a carbohydrate-based (glycosaminoglycan) anticoagulant associated with many tissues, but mainly found stored intracellularly as granules in mast cells that line the endothelium of blood vessels. Upon release into the bloodstream, heparin binds to and thereby activates an additional plasma protein, namely antithrombin. The heparin-antithrombin complex then binds a number of activated clotting factors (including Ha, IXa, Xa, XIa and Xlla), thereby inactivating them. The heparin now disassociates from the complex and combines with another antithrombin molecule, thereby initiating another turn of this inhibitory cycle. 

In addition, UFH also binds simultaneously to fibrin and thrombin. The heparin-thrombin-fibrin complex lessens the ability of the heparin-antithrombin complex to inhibit thrombin and increases the affinity of thrombin for its fibrin substrate. This results in a protection of fibrin-bound thrombin from inactivation by the heparin-antithrombin complex... 

The degradation of heparin by the reactor is a multistep process. Heparin and the heparin-antithrombin complex must first diffuse from the bulk phase to the surface of the immobilized enzyme particle. The two species diffuse into the agarose particles where they encounter immobilized heparinase. The heparin-anti thrombin complex is assumed to be sterically inhibited from binding to immobilized heparinase, and under these conditions only unbound heparin is enzymatically degraded. As unbound heparin is consumed, heparin dissociates from the heparin-antithrombin complex to generate more free heparin. The breakdown of heparin is given by the following chemical reaction ... 

Within the particle, molar conservation equations are written for heparin (H), octasaccharide (P), antithrombin (A), the heparin-antithrombin complex (AH) and the octasaccharide-antithrombin complex (AP). The... 

Teitel JM, Rosenberg RD. Protection of factor Xa from neutralization by the heparin-antithrombin complex. J Chn Invest 1983 71 1383-1391. 

The anticoagulant effect of UFH is mediated through a specific pentasaccharide sequence on the heparin molecule that binds to antithrombin, provoking a conformational change. The UFH-antithrombin complex is 100 to 1,000 times more potent as an anticoagulant than antithrombin alone. 

Ikada and coworkers also studied the blood compatibility and protein denaturation properties of heparin covalently and ionically bound onto polymer surfaces [513], Both types of bound heparin gave deactivation of the coagulation process. Clotting deactivation was attributed to a heparin/ antithrombin III complex by covalently bound heparin which gave adsorbed protein denaturation and platelet deformation as compared with lack of these features with ionically bound heparin. 

At present, the binary water-soluble preparation of heparin and proteolytic enzymes is being applied for the treatment of thromboses. For instance, injection into the bloodstream of heparin-plasmin complex or a heparin-plasmin-streptokinase preparation leads to the total dissolution of the thrombus, while if introduced separately, heparin and streptokinase do not display the lytic action at all, and plasmin, alone or together with streptokinase, dissolves the thrombus only partially 132>. The treatment of acute thrombophlebitis with trypsin resulted in a full dissolution of the thrombus and in an increase of antithrombin III in the blood 133). Administration of trypsin together with heparin has an effect similar in efficiency to the action of the heparin-plasmin complex 134>. The use of a mix of heparin and urokinase for improving tbrom-boresistance of polymeric materials was also described 13S). These substances were immobilized by preliminary coating of the surface of a polymer with a graphite layer and subsequent adsorption of heparin and the enzyme. 

Converse to UFH, LMWH action is primarily directed against factor Xa, because most of the chains are not sufficiently long to form the ternary complex necessary for the inactivation of thrombin (<50% of the chains contain at least the 18 saccharide units needed for the formation of the ternary heparin-thrombin-antithrombin complex) (Fig. IC). Depending on the LMWH, the antithrombin-anti-Xa activity ratio varies from 1.9 (tinzaparin) to 3.8 (enoxaparin) (2). 

Heparin acts indirectly at multiple points within the coagulation cascade, Its major anticoagulant effect is via interaction with its requisite co-factor, antithrombin III (AT). The heparin-AT complex inactivates factors IXa, Xa, and XIla, and binds thrombin at its active site to prevent the conversion of fibrinogen to fibrin (3). Heparin also prevents fibrin stabilization through the inhibition of fibrin stabilization factor. Heparin has no fibrinolytic activity and therefore is ineffective as a thrombolytic (4,5). 

Inactive factors [Note While the heparin-antithrombin III complex readily inactivates thrombin, the complex of low molecular weight heparin with... 

Reaction susceptible to mi inhibition by heparin- Jjji- antithrombin complex... 

Indirect antithrombins. The action of heparin is complex, and it is sometimes referred to as an indirect-acting antithrombin, in as much as it works indirectly to inhibit the action of thrombin in the coagulation cascade. Dicoumarin anticoagulants, most notably warfarin, also act in an indirect... 

Factors Ila and Xa are the most sensitive to inhibition by the UFH-antithrombin complex. In order to inactivate thrombin, the heparin molecule must form a ternary complex bridging between antithrombin and thrombin (see Fig. 19-5). Only molecules thatcontain more than 18 saccharides are able to bind to both antithrombin and thrombin simultaneously. Smaller heparin molecules cannot facilitate... 

Heparin/antithrombin III complexes react also with various other factors of the coagulation/fibrinolysis cascades... 

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). 

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