ABSTRACT
It is estimated that plasma proteinase inhibitors constitute some 10% of the total plasma proteins.1 Most of the proteinase inhibitors inhibit serine proteinase such as thrombin and are known by the collective term serpins (serine proteinase inhibitors).2,3 Serpins are considered to have a common reaction mechanism that can be considered as a stabilized acyl-enzyme intermediate.4 While the formation of an enzyme-inhibitor complex is reversible to the point of the formation of this intermediate, progression through the complete reaction results in the transition of the inhibitor from a virgin or native state to a modi€ed form which is inactive.5 A partial list of human plasma proteinase inhibitors is presented in Table 7.1. This list may be incomplete as new inhibitors continue to be discovered and the physiological relevance of others has not been €rmly established.6-8 It is of some interest that Laskowski and Kato commented some 30 years ago4 that the precise physiological function of inhibitors is not known. Two plasma proteinase inhibitors-antithrombin (SERPINC1; earlier known as antithrombin III) and α-antiproteinase inhibitor (SERPINA1; earlier known as α-1-antitrypsin)—are of signi€cant importance, as biopharmaceutical products and their complexes with proteases such as thrombin-antithrombin9 are valuable biomarkers. Other plasma proteinase inhibitors, such as tissue factor pathway inhibitor (TFPI)10,11 and C1 esterase inhibitor,12,13 are also of interest as commercial products, but do not have the project maturity of antithrombin and α-1-antitrypsin. One of the major advantages of inhibitors such as antithrombin is that they are biological buffers that react with enzymes such as thrombin in an equilibrium reaction similar to that of a substrate and enzymes; thus, it is most unlikely that hemorrhagic events are of importance as adverse events. Other inhibitors are heparin cofactor II, α2-macroglobulin, and α2-antiplasmin (SERPINF2 will also be discussed). Finally, both antithrombin and α1-antitrypsin have potentially important functions tangential to their function as inhibitors, while the antiprotease function of α2-macroglobulin may be truly secondary to other activities.
