Heparan sulfate anticoagulant pathway. Anchored by a proteoglycan core to the vessel wall, heparan sulfate binds antithrombin (AT) via a unique pentasaccharide sequence (diamonds) found on 1 to 10% of the glycosaminoglycan side-chains. Key to the high-affinity binding of AT to the pentasaccharide is the 3-O-sulfated glucosamine residue in the middle of the pentasaccharide sequence (red diamond). Once bound, AT undergoes a conformational change at its reactive centre loop that enhances its reactivity with thrombin (IIa), thereby promoting the formation of AT/IIa complexes. Targeted disruption of 3-O-sulfotransferase-1 (3-OST-1) attenuates 3-O-sulfation (in red) of the critical glucosamine residue within the pentasaccharide sequence of heparan sulfate, thereby reducing its capacity to bind AT (inset). Antithrombin affinity is not abolished, however, because 3-OST-6, another 3-O-sulfotransferase isoform, can also generate 3-O-sulfated glucosamine residues.