title: Coagulation factor XIIIa is inactivated by plasmin.
abstract: Coagulation factor XIIIa (FXIIIa) is a transglutaminase that covalently cross-links fibrin and other proteins to fibrin to stabilize blood clots and reduce blood loss. A clear mechanism to describe the physiological inactivation of FXIIIa has been elusive. Here, we show that plasmin can cleave FXIIIa in purified systems and in blood. Whereas zymogen FXIII was not readily cleaved by plasmin, FXIIIa was rapidly cleaved and inactivated by plasmin in solution (catalytic efficiency = 8.3 × 10(3) M(-1)s(-1)). The primary cleavage site identified by mass spectrometry was between K468 and Q469. Both plasma- and platelet-derived FXIIIa were susceptible to plasmin-mediated degradation. Inactivation of FXIIIa occurred during clot lysis and was enhanced both in plasma deficient in fibrinogen and in plasma treated with therapeutic levels of tissue plasminogen activator. These results indicate that FXIIIa activity can be modulated by fibrinolytic enzymes, and suggest that changes in fibrinolytic activity may influence cross-linking of blood proteins.
authors.affiliation: Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Woosuk S
authors.identifier: http://orcid.org/0000-0001-5074-6423
authors.initials: WS
authors.lastname: Hur
authors.affiliation: Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Nima
authors.initials: N
authors.lastname: Mazinani
authors.affiliation: Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: X J David
authors.initials: XJ
authors.lastname: Lu
authors.affiliation: Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Britton
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: James R
authors.initials: JR
authors.lastname: Byrnes
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Alisa S
authors.identifier: http://orcid.org/0000-0002-2845-2303
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Kastrup
mesh_terms: D005176:Factor XIII / Q000737:chemistry / Q000378:metabolism*; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism*; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D059748:Proteolysis; D010959:Tissue Plasminogen Activator / Q000737:chemistry / Q000378:metabolism
chemical_list: D005176:Factor XIII; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin