title: Regulation of formation of factor XIIIa by its fibrin substrates.
abstract: Thrombin-catalyzed release of activation peptide (AP) from plasma factor XIII was studied to characterize the regulation of this initial step in the activation of factor XIII zymogen (fibrin-stabilizing factor). High-performance liquid chromatography was used to monitor the kinetics of release of AP. Non-cross-linked polymeric fibrins I and II (polymerized des-A- and des-A,B-fibrinogens), physiological substrates of factor XIIIa, were shown to be potent promoters of thrombin-catalyzed release of activation peptide from factor XIII. These promoters are proposed to act by complexing factor XIII and reducing the apparent Km for thrombin-catalyzed release of AP. Since thrombin-catalyzed release of AP is inefficient in the absence of polymerized fibrin, this mode of regulation should minimize formation of factor XIIIa prior to the formation of its fibrin substrates. The promoting activity of polymeric fibrin was rapidly lost when catalytically competent factor XIIIa was allowed to form. This observation suggested the possibility that factor XIIIa catalyzed cross-linking of fibrin inactivates fibrin as a promoter for the thrombin-catalyzed release of AP from factor XIII. Consistent with this view, the thiol reagent S-methyl methanethiosulfonate inactivated factor XIIIa, blocked cross-linking of fibrin, and protected against loss of its promoter activity. This mode of feedback regulation of the activation process by catalytically active factor XIIIa may serve to ensure against continued generation of factor XIIIa after its fibrin substrates have been cross-linked.
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: T J
authors.initials: TJ
authors.lastname: Janus
authors.forename: L
authors.initials: L
authors.lastname: Lorand
authors.forename: J A
authors.initials: JA
authors.lastname: Shafer
mesh_terms: D002118:Calcium / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005176:Factor XIII / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D008970:Molecular Weight; D013917:Thrombin / Q000378:metabolism; D011503:Transglutaminases
chemical_list: D046911:Macromolecular Substances; D005337:Fibrin; D005176:Factor XIII; D011503:Transglutaminases; D013917:Thrombin; D002118:Calcium