The Anticoagulant and Antithrombotic Mechanisms of Heparin

Abstract

The molecular basis for the anticoagulant action of heparin lies in its ability to bind to and enhance the inhibitory activity of the plasma protein antithrombin against several serine proteases of the coagulation system, most importantly factors IIa (thrombin), Xa and IXa. Two major mechanisms underlie heparin's potentiation of antithrombin. The conformational changes induced by heparin binding cause both expulsion of the reactive loop and exposure of exosites of the surface of antithrombin, which bind directly to the enzyme target; and a template mechanism exists in which both inhibitor and enzyme bind to the same heparin molecule. The relative importance of these two modes of action varies between enzymes. In addition, heparin can act through other serine protease inhibitors such as heparin co-factor II, protein C inhibitor and tissue factor plasminogen inhibitor. The antithrombotic action of heparin in vivo, though dominated by anticoagulant mechanisms, is more complex, and interactions with other plasma proteins and cells play significant roles in the living vasculature.

Biochemical and functional characterization of glycosaminoglycans released from degranulating rat peritoneal mast cells: Insights into the physiological role of endogenous heparin

“…Whilst the structural basis of the anticoagulant activity of heparin is well understood (reviewed in 11), the exact structural requirements for the majority of the anti-inflammatory effects of heparin remain to be fully determined. The ability of heparin to interact with a wide variety of proteins can vary from strongly sequence specific, such as the binding of antithrombin, to relatively non-specific, in part due to the size and polyanionic nature of the molecule (18,19). In this regard, it is important to consider that commercially-available heparin, which is usually extracted from porcine intestinal mucosa, is standardized only for its anticoagulant activity, which depends heavily on the presence of the high affinity antithrombin-binding pentasaccharide (18).…”

“…The ability of heparin to interact with a wide variety of proteins can vary from strongly sequence specific, such as the binding of antithrombin, to relatively non-specific, in part due to the size and polyanionic nature of the molecule (18,19). In this regard, it is important to consider that commercially-available heparin, which is usually extracted from porcine intestinal mucosa, is standardized only for its anticoagulant activity, which depends heavily on the presence of the high affinity antithrombin-binding pentasaccharide (18). Therefore, any biological activity confined to other polysaccharide sequences contained within the heparin structure may not necessarily correlate with the total amount of material present in the resultant heterogenous mixture, and may even be fractionated out by the current techniques for preparing heparin commercially as an anticoagulant.…”

Hemostatic Effect of Ethanol Extract of Piper betle, Linn Leaves to Male Mice

“…This is because heparin initially worked on for 20-60 minutes after injected. Intravenous heparin injection is done to ensure that the hemostatic effects of ethanol extract of betel leaves are not from hemostatic effects that come from the body of mice (Gray, Hogwood & Mulloy, 2012).…”

“…Heparin is one type of anticoagulant medication to prevent blood clotting by inhibiting the formation of blood clotting factors, then increase the effect of antithrombin III. The increasing antithrombin III can cause the inactivation of thrombin, thus preventing the conversion of fibrinogen into fibrin (Gray et al, 2012). Table 1 shows that the average bleeding time of mice before treatment, the negative control group is 325.5 seconds, positive control group is 336.75 seconds, ethanol extract of betel leaves 1% group is 318.5 seconds, ethanol extract of betel leaves 5% group is 323.5 seconds, ethanol extract of betel leaves 10% group is 355.5, ethanol extract of betel leaves 15% group is 335 seconds, and ethanol extract of betel leaves 20% group is 340 seconds.…”

“…Heparin which injected intravenously to provided enough hemorrhage effect demonstrated with average bleeding time is six times greater than normal bleeding time. The aim of heparin's injection in this study was to eliminate the bias of clotting factors in the body of mice (Greene et al, 2010;Gray et al, 2012).…”