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Thrombin demonstrates a high level of allosteric regulation. [2] Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant. [3]
The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin. [37]
Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate ("minor antithrombin"). [ 5 ] The product encoded by this gene is a serine protease inhibitor which rapidly inhibits thrombin in the presence of dermatan sulfate or heparin.
Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's.
The structure of an antithrombin-thrombin-heparin ternary complex taken from pdb 1TB6. Increased thrombin inhibition requires the minimal heparin pentasaccharide plus at least an additional 13 monomeric units. [33] This is thought to be due to a requirement that antithrombin and thrombin must bind to the same heparin chain adjacent to each other.
Antithrombin (AT), a serine protease inhibitor, is the major plasma inhibitor of coagulation proteases. [15] LMWHs inhibit the coagulation process by binding to AT via a pentasaccharide sequence. This binding leads to a conformational change of AT, increasing the rate at which it inhibits activated factor X . Once dissociated, the LMWH is free ...
Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site. Recombinant thrombin is available as a powder for reconstitution into aqueous solution.
Indirect thrombin inhibitors bind to antithrombin to enhance the rate of inactivation of clotting factors, indirectly inactivating thrombin through actions on antithrombin. [42] Heparin is a widely used anticoagulant. It is administered intravenously (into a vein) or subcutaneously (below the skin).