Heparin is a potent anticoagulant belonging to the family of highly sulfated glycosaminoglycans, primarily extracted from animal tissues. It plays a central role in the prevention and treatment of thrombotic disorders through its interactions with plasma proteins involved in the coagulation cascade.
Chemical Structure
Heparin is composed of repeating disaccharide units consisting of uronic acid, predominantly iduronic acid (IdoA) with 2-O-sulfation, and N-sulfated glucosamine (GlcNS), which is frequently 6-O-sulfated. This structure results in a molecular weight ranging from 3 to 30 kDa, with most commercial preparations averaging 12–15 kDa. A distinctive pentasaccharide sequence within the polymer specifically binds antithrombin III (AT). The high density and precise positioning of sulfate groups, combined with a flexible helical conformation, enable strong and selective protein interactions.
Biosynthesis and Relationship to Heparan Sulfate
The biosynthesis of heparin closely resembles that of heparan sulfate (HS) but results in a significantly higher degree of sulfation. Synthesis initiates in the Golgi apparatus with the attachment of a xylose residue to serine residues of core proteins, followed by chain elongation mediated by EXT and EXTL enzymes. Subsequent modifications include N-sulfation by NDST enzymes, O-sulfation by HS2ST, HS6ST, and HS3ST, and epimerization of glucuronic acid to iduronic acid. Predominantly produced by mast cells, heparin contains densely sulfated NS-domains, such as IdoA2S–GlcNS6S, at much higher frequencies than tissue-derived HS.
Mechanism of Action
Heparin exerts its anticoagulant activity by binding to antithrombin through its specific pentasaccharide sequence, inducing a conformational change that markedly accelerates antithrombin-mediated inhibition of thrombin (factor IIa) and factor Xa by up to 1000-fold. Longer heparin chains are capable of simultaneously binding antithrombin and thrombin, forming a ternary complex that further enhances inhibition. This mechanism primarily suppresses fibrin formation without directly affecting platelet function, distinguishing heparin from direct oral anticoagulants.
