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Pathway Description
Heparin
Homo sapiens
Physiological Pathway
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given intravenously or by injection under the skin.[2] Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines. Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin itself does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin, factor Xa and other proteases. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. 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. The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.
References
Heparin References
"Heparin Sodium". The American Society of Health-System Pharmacists. Archived from the original on 27 January 2016.
Alquwaizani M, Buckley L, Adams C, Fanikos J: Anticoagulants: A Review of the Pharmacology, Dosing, and Complications. Curr Emerg Hosp Med Rep. 2013 Apr 21;1(2):83-97. doi: 10.1007/s40138-013-0014-6. Print 2013 Jun.
Pubmed: 23687625
Warnock LB, Huang D: Heparin.
Pubmed: 30855835
Chuang YJ, Swanson R, Raja SM, Olson ST: Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence. Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin. J Biol Chem. 2001 May 4;276(18):14961-71. doi: 10.1074/jbc.M011550200. Epub 2001 Feb 7.
Pubmed: 11278930
Bjork I, Lindahl U: Mechanism of the anticoagulant action of heparin. Mol Cell Biochem. 1982 Oct 29;48(3):161-82. doi: 10.1007/BF00421226.
Pubmed: 6757715
Petitou M, Herault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM: Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature. 1999 Apr 1;398(6726):417-22. doi: 10.1038/18877.
Pubmed: 10201371
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