Heparin activates antithrombin anticoagulant function by generating new interaction sites (exosites) for blood clotting proteinases.

The plasma protein, antithrombin, and its polysaccharide activator, heparin, are essential anticoagulant regulators of blood clotting proteinases that are critical for maintaining hemostasis. Heparin activates antithrombin both by inducing conformational changes in the protein that specifically enhances factor Xa binding and by providing a surface to promote thrombin or factor Xa binding alongside antithrombin in a ternary bridging complex. Although x-ray structures of antithrombin, free and complexed with heparin, have suggested that exposure of a reactive proteinase binding loop is a key feature of conformational activation, mutagenesis of reactive loop residues indicates that the function of this structural change is not to present an optimal loop sequence to target clotting proteinases. Rather, the reactive loop sequence provides only the minimal requirements for recognition by either thrombin or factor Xa, and heparin activation enhances antithrombin recognition by these proteinases through the presentation of exosites outside of the reactive loop. These and other findings suggest that the reactive loop sequence of antithrombin was designed not for optimal recognition by procoagulant proteinases but rather to prevent recognition by the anticoagulant proteinase, activated protein C, thus ensuring that antithrombin functions as an effective anticoagulant.