A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion

Blood. 2004 May 15;103(10):3783-8. doi: 10.1182/blood-2003-12-4240. Epub 2004 Jan 29.


Human alpha2-antiplasmin (alpha2AP), also known as alpha2-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms of alpha2AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-alpha2AP, and a 452-residue version with Asn as the N-terminus, Asn-alpha2AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-alpha2AP to yield Asn-alpha2AP and have named it antiplasmin-cleaving enzyme (APCE). APCE is similar in primary structure and catalytic properties to membrane-bound fibroblast activation protein/seprase for which a physiologic substrate has not been clearly defined. We found that Asn-alpha2AP becomes cross-linked to fibrin by activated factor XIII approximately 13 times faster than native Met-alpha2AP during clot formation and that clot lysis rates are slowed in direct proportion to the ratio of Asn-alpha2AP to Met-alpha2AP in human plasma. We conclude that APCE cleaves Met-alpha2AP to the derivative Asn-alpha2AP, 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-alpha2AP could result in a more rapid removal of fibrin by plasmin during atherogenesis, thrombosis, and inflammatory states.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Factor XIIIa / metabolism
  • Fibrin / metabolism*
  • Fibrinolysin / antagonists & inhibitors
  • Fibrinolysis
  • Humans
  • Kinetics
  • Serine Endopeptidases / blood*
  • Serine Endopeptidases / isolation & purification*
  • Serine Endopeptidases / physiology
  • alpha-2-Antiplasmin / metabolism
  • alpha-2-Antiplasmin / physiology*


  • alpha-2-Antiplasmin
  • Fibrin
  • Factor XIIIa
  • Serine Endopeptidases
  • antiplasmin-cleaving enzyme, human
  • Fibrinolysin