title: Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin.
abstract: Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin-antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clot weight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis, we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolution.
authors.affiliation: Centre for Blood Research, Department of Medicine, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, LSC4306, Vancouver V6T 1Z3, Canada; Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom; Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London, United Kingdom.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Foley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 819 Brinkhous-Bullitt Building, CB# 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Walton
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 819 Brinkhous-Bullitt Building, CB# 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aleman
authors.affiliation: Centre for Blood Research, Department of Medicine, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, LSC4306, Vancouver V6T 1Z3, Canada.
authors.forename: Alice M
authors.initials: AM
authors.lastname: O'Byrne
authors.affiliation: Centre for Blood Research, Department of Medicine, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, LSC4306, Vancouver V6T 1Z3, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Lei
authors.affiliation: Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Micaela
authors.initials: M
authors.lastname: Harrasser
authors.affiliation: Cancer Care and Epidemiology, Queen's Cancer Research Institute, Queen's University, Kingston, Canada.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Foley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 819 Brinkhous-Bullitt Building, CB# 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Centre for Blood Research, Department of Medicine, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, LSC4306, Vancouver V6T 1Z3, Canada.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000187:drug effects / Q000276:immunology; D001158:Arteries / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D015926:Complement C3a / Q000096:biosynthesis / Q000276:immunology; D015936:Complement C5a / Q000096:biosynthesis / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000276:immunology; D015951:Factor Xa / Q000276:immunology / Q000378:metabolism; D005341:Fibrinolysin / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D010447:Peptide Hydrolases / Q000187:drug effects / Q000276:immunology; D010960:Plasminogen Activators / Q000008:administration & dosage; D013917:Thrombin / Q000276:immunology / Q000378:metabolism; D020246:Venous Thrombosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: D015938:Complement Membrane Attack Complex; C046193:antithrombin III-protease complex; D015926:Complement C3a; D015936:Complement C5a; D000990:Antithrombin III; D010447:Peptide Hydrolases; D010960:Plasminogen Activators; D013917:Thrombin; D015951:Factor Xa; D005341:Fibrinolysin
keywords: Complement; FDP, fibrin degradation product; FeCl3, ferric chloride; Fibrinolysis; IL-8, interleukin-8; IVC, inferior vena cava; Leukocytes; MAC, membrane attack complex; MCP1-1, monocyte chemoattracant protein-1; NETs, neutrophil extracellular traps; PAR1, protease activated receptor 1; PPACK, Phe-Pro-Arg-chloromethylketone; R751, arginine 751; TAT, thrombin antithrombin; Thrombin; Thrombosis; VFKck, Val-Phe-Lys-chloromethylketone; VWF, von Willebrand factor; tPA, tissue-type plasminogen activator