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Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin
Jonathan H Foley1, Bethany L Walton2, Maria M Aleman2
1Centre 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.
Ebiomedicine
|April 15, 2016
Summary
Plasmin, an enzyme involved in blood clot breakdown, generates complement component C5a during thrombosis. This links blood clot formation to the immune response, potentially offering new therapeutic targets.
Area of Science:
- Immunology
- Hematology
- Complement System
Background:
- Thrombosis involves complex interactions between coagulation, fibrinolysis, and innate immunity.
- Leukocyte recruitment, crucial in thrombosis, is partly mediated by complement factors C3a and C5a.
- Mechanisms of C3a/C5a generation during thrombosis remain largely unstudied.
Purpose of the Study:
- To investigate the mechanisms of C3a and C5a generation during thrombosis.
- To explore the role of plasmin in activating complement component C5 during thrombus formation.
Main Methods:
- Murine venous and arterial thrombosis models were utilized.
- Levels of thrombin-antithrombin complexes, C3a, C5a, and clot weight were measured.
- In vitro assays assessed the catalytic efficiency of plasmin, thrombin, and factor Xa in C5a generation.
- Functional membrane attack complex (MAC) assembly was evaluated.
- Plasminogen activator administration was used in an arterial thrombosis model.
Main Results:
- Thrombin-antithrombin complexes did not strongly correlate with C3a/C5a levels, suggesting thrombin is not central to their production.
- Clot weight showed a strong correlation with C5a levels, indicating thrombosis-triggered processes enhance C5a generation.
- Plasmin demonstrated high catalytic efficiency in generating C5a, comparable to known C5 convertases.
- Plasmin-activated C5 formed a functional MAC.
- Administration of plasminogen activator increased C5a levels in an arterial thrombosis model.
Conclusions:
- Plasmin plays a significant role in bridging thrombosis and the immune response by generating C5a.
- Plasmin-mediated C5 activation leads to the assembly of the membrane attack complex (MAC).
- These findings suggest novel therapeutic strategies targeting plasmin to modulate thrombosis and immune responses.
Keywords:
ComplementFDP, fibrin degradation productFeCl3, ferric chlorideFibrinolysisIL-8, interleukin-8IVC, inferior vena cavaLeukocytesMAC, membrane attack complexMCP1-1, monocyte chemoattracant protein-1NETs, neutrophil extracellular trapsPAR1, protease activated receptor 1PPACK, Phe-Pro-Arg-chloromethylketoneR751, arginine 751TAT, thrombin antithrombinThrombinThrombosisVFKck, Val-Phe-Lys-chloromethylketoneVWF, von Willebrand factortPA, tissue-type plasminogen activator
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