The main physiological inhibitors of the coagulation proteases are members of the serpin family, e.g. antithrombin (AT, previously known as antithrombin III or ATIII), heparin cofactor II (HCII), protease nexin 1 (PN1), alpha-1-antitrypsin (α1AT) and protein C inhibitor (PCI). With the exeption of α1AT, all are activated by glycosaminoglycans, such as heparin. The serpin mechanism of inhibition is well characterised, with formation of an initial recognition complex followed by a rapid serpin conformational change that traps and deforms the protease as a covalent acyl-enzyme intermediate.
Alpha-2-Macroglobulin (a2M) is a general inhibitor that has the ability to inhibit proteases from all classes. The mechanism involves protease cleavage of a bait region initiating a large conformational change that effectively traps the protease in a molecular cage.