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Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin Foley, Jonathan H.; Walton, Bethany L.; Aleman, Maria M.; O'Byrne, Alice M.; Lei, Victor; Harrasser, Micaela; Foley, Kimberley A.; Wolberg, Alisa Sue; Conway, Edward M.
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, clotweight 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
Item Metadata
| Title |
Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin
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| Creator | |
| Publisher |
EBioMedicine
|
| Date Issued |
2016-02-06
|
| Description |
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, clotweight 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
|
| Subject | |
| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2017-01-31
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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| DOI |
10.14288/1.0305008
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| URI | |
| Affiliation | |
| Citation |
Foley JH, Walton BL, Aleman MM, et al. Complement activation in arterial and venous thrombosis is mediated by plasmin. EBioMedicine. 2016;5:175-182.
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| Publisher DOI |
10.1016/j.ebiom.2016.02.011.
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International