title: Reduced plasminogen binding and delayed activation render γ'-fibrin more resistant to lysis than γA-fibrin.
abstract: Fibrin (Fn) clots formed from γ'-fibrinogen (γ'-Fg), a variant with an elongated γ-chain, are resistant to lysis when compared with clots formed from the predominant γA-Fg, a finding previously attributed to differences in clot structure due to delayed thrombin-mediated fibrinopeptide (FP) B release or impaired cross-linking by factor XIIIa. We investigated whether slower lysis of γ'-Fn reflects delayed plasminogen (Pg) binding and/or activation by tissue plasminogen activator (tPA), reduced plasmin-mediated proteolysis of γ'-Fn, and/or altered cross-linking. Clots formed from γ'-Fg lysed more slowly than those formed from γA-Fg when lysis was initiated with tPA/Pg when FPA and FPB were both released, but not when lysis was initiated with plasmin, or when only FPA was released. Pg bound to γ'-Fn with an association rate constant 22% lower than that to γA-Fn, and the lag time for initiation of Pg activation by tPA was longer with γ'-Fn than with γA-Fn. Once initiated, however, Pg activation kinetics were similar. Factor XIIIa had similar effects on clots formed from both Fg isoforms. Therefore, slower lysis of γ'-Fn clots reflects delayed FPB release, which results in delayed binding and activation of Pg. When clots were formed from Fg mixtures containing more than 20% γ'-Fg, the upper limit of the normal level, the delay in lysis was magnified. These data suggest that circulating levels of γ'-Fg modulate the susceptibility of clots to lysis by slowing Pg activation by tPA and provide another example of the intimate connections between coagulation and fibrinolysis.
authors.affiliation: From the Departments of Medicine, the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada.
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Kim
authors.affiliation: the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada Biomedical Sciences, and.
authors.forename: Trang T
authors.initials: TT
authors.lastname: Vu
authors.affiliation: From the Departments of Medicine, the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Leslie
authors.affiliation: From the Departments of Medicine, the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Stafford
authors.affiliation: From the Departments of Medicine, the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Fredenburgh
authors.affiliation: From the Departments of Medicine, the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario L8L 2X2, Canada Biomedical Sciences, and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4L8 and weitzj@taari.ca.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D001777:Blood Coagulation; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D005345:Fibrinopeptide B / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism
chemical_list: D005345:Fibrinopeptide B; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D013917:Thrombin; D005341:Fibrinolysin
keywords: Enzyme Kinetics; Fibrinogen; Fibrinolysis; Plasminogen; Tissue Plasminogen Activator (tPA); γ′-Fibrinogen