A novel plasma proteinase potentiates α2-antiplasmin inhibition of fibrin digestion

Human alpha(2)-antiplasmin (alpha(2)AP), also known as alpha(2)-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms Of alpha(2)AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-alpha(2)AP, and a 452-residue version with Asn as the N-terminus, Asn-alpha(2)AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-alpha(2)AP to yield Asn-alpha(2)AP and have named it antiplasmin-cleaving enzyme (APCE). APCE is similar in primary structure and catalytic properties to membranebound fibroblast activation protein/seprase for which a physiologic substrate has not been clearly defined. We found that Asn-alpha(2)AP becomes cross-linked to fibrin by activated factor XIII approximately 13 times faster than native Met alpha(2)AP during clot formation and that clot lysis rates are slowed in direct proportion to the ratio of Asn-alpha(2)AP to Met-alpha(2)AP in human plasma. We conclude that APCE cleaves Met-alpha(2)AP to the derivative Asn- CLAP, which is more efficiently Incorporated into fibrin and consequently makes it strikingly resistant to plasmin digestion. APCE may represent a new target for pharmacologic inhibition, since less generation and incorporation of Asn-alpha(2)AP could result in a more rapid removal of fibrin by plasmin during atherogenesis, thrombosis, and inflammatory states. (C) 2004 by The American Society of Hematology.