Antithrombin III heparin cofactor

Magnusson, S. Primary structure of antithrombin III (Heparin Cofactor). Partial homology between oci antitrypsin and antithrombin-III, in Collen DW, Wiman B, Verstraete M (eds) The Physiological Inhibitions of Blood Coagulation and Fibrinolysis. Amsterdam, The Netherlands, Elsevier/North-Holland Biomedical Press, 1979, p 43. 

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. 

Although the product has proven to be an effective (and relatively inexpensive) anticoagulant, it does suffer from a number of clinical disadvantages, including the need for a cofactor (antithrombin III) and poorly predictable dose responses. Despite such disadvantages, however, heparin still enjoys widespread clinical use. 

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. 

Micromedex, lepirudin directly inhibits all actions of thrombin. It inhibits free and clot-bound thrombin without requiring endogenous cofactors. Lepirudin is not inhibited by platelet factor 4 and acts independently of antithrombin III and heparin cofactor II. It has no direct effect on platelet function, except inhibition of thrombin-induced platelet activation. No physiological inhibitor of lepirudin is known. 

Scully, M. F., Ellis, V., Seno, N., and Kakkar, V. V. (1988). Effect of oversulphated chondroitin and dermatan sulphate upon thrombin and factor Xa inactivation by antithrombin III or heparin cofactor II. Biochem. J. 254,547-551. 

Abildgaard U, Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest I 968 21 89-91. 

Further, it will be assumed that E is proportional to the concentration of the heparin antithrombin III cofactor... 

With heparin farin, whose maximum activity requires 8 to 12 hours). Antithrombin III, sometimes referred to as heparin cofactor, is an... 

In the last several years, it has become known and more appreciated that the in vivo role of heparin as an anticoagulant may be less important as an inhibitor of thrombin and more important as an inhibitor of Factor Xa.8B Actually heparin is not an anticoagulant, but a cofactor for a protein (a8 globulin - antithrombin III) in the plasma that neutralizes Factor Xa or thrombin by molecular combination. Without heparin this neutralization, which is concentration dependent, is slow. In the presence of heparin, it is greatly accelerated. Heparin has no effect on thrombin... 

During blood coagulation either an intrinsic (all blood) system or an extrinsic (tissue juice-lipoprotein) system is activated.. In either case the pathways meet at the activation of Factor X, forming a proteolytic enzyme Factor X. This enzyme in the presence of cofactors (calcium ion, phospholipid and Factor V) will form thrombin from prothrombin. Heparin is a cofactor for a protein called antithrombin III which circulates in the plasma and is an inhibitor of both Factor Xg and thrombin. Antithrombin III neutralizes these 2 enzymes by molecular combination heparin increases the rate of this neutralization. In the past 2 years work has continued on the mechanism of blood coagulation More... 

As noted previously, for heparin to exert its anticoagulant effect, a plasma cofactor, antithrombin III, is needed. It has been proposed that heparin acts as a catalyst to cause a marked increase in the rate of interaction between AT-III and serine proteases like thrombin and Factor Xa (B4). Some uncertainty still exists as to whether the binding of heparin to the inhibitor or the enzyme or to both is the key step (P6). 

The DTIs bind and inactivate both free thrombin and thrombin bound to fibrin. Unlike heparin, DTIs, such as Iepirudin, bivalirudin, argatroban, and ximelagatran, bind directly and reversibly to the active site of thrombin. Unlike the heparins, these inhibitors do not require an activated antithrombin III as a cofactor for their anticoagulant activity. Furthermore, contrary to the heparins. 

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 > >. ... 

Church, FC Meade, JB Treanor, RE Whinna, HC. Antithrombin activity of fucoidan. The interaction of fucoidan with heparin cofactor II, antithrombin III, and thrombin. 

Sinniger, V Tapon-Bretaudie re, J Millieu, C Muller, D Jozefonvicz, J Fischer, A M. Affinity chromatography of sulphated polysaccharides separately fractionated on antithrombin III and heparin cofactor II immobilized on concanavalin A-sepharose. Journal of Chromatography, 1992, 615, 215-223. 

Pizzo SV, Mast AE, Feldman SR, SalvesenG. In vivo catabolism of alphai-antichy-motrypsin is mediated by the serpin receptor which binds alphai-protease inhibitor, antithrombin III and heparin cofactor II. Biochim Biophys Acta 1988 967 158-162. 

---