Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin
| Autor: | Bethany L. Walton, Kimberley Foley, Maria M. Aleman, Edward M. Conway, Jonathan H. Foley, Alisa S. Wolberg, Micaela Harrasser, Victor Lei, Alice M. O'Byrne |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmin medicine.medical_treatment PPACK Phe-Pro-Arg-chloromethylketone Complement Pathway Alternative lcsh:Medicine Complement C3-C5 Convertases 030204 cardiovascular system & hematology tPA tissue-type plasminogen activator 0302 clinical medicine Leukocytes Fibrinolysin Complement Activation Complement component 5 IL-8 interleukin-8 TAT thrombin antithrombin lcsh:R5-920 Fibrinolysis Thrombin Complement C5 Complement C4 hemic and immune systems General Medicine Complement C3 Complement C2 Complement C9 3. Good health Complement C6 Venous thrombosis Coagulation Complement C3b MAC membrane attack complex lcsh:Medicine (General) FDP fibrin degradation product medicine.drug Research Paper circulatory and respiratory physiology VWF von Willebrand factor NETs neutrophil extracellular traps Complement Activating Enzymes Complement chemical and pharmacologic phenomena General Biochemistry Genetics and Molecular Biology 03 medical and health sciences IVC inferior vena cava medicine R751 arginine 751 Humans Thrombus MCP1-1 monocyte chemoattracant protein-1 business.industry lcsh:R FeCl3 ferric chloride Thrombosis medicine.disease Complement system 030104 developmental biology VFKck Val-Phe-Lys-chloromethylketone Immunology business Complement membrane attack complex PAR1 protease activated receptor 1 |
| Zdroj: | EBioMedicine, Vol 5, Iss C, Pp 175-182 (2016) EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | 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. Highlights • Thrombin is not a major direct contributor to C5a generation during venous thrombosis in mice. • Plasmin, a protease generated in response to thrombin generation and fibrin deposition, efficiently cleaves C5 to C5a. • In an arterial thrombosis model, administration of a plasminogen activator augments C5a plasma levels. • Plasmin participates in immunothrombosis, liberating chemotactic C5a and inducing assembly of the procoagulant C5b-9. Venous and arterial thrombosis are major causes of death and morbidity. Leukocytes are early and active participants in thrombus formation, recruited partly by complement factor C5a. We examined how C5a is generated in the setting of thrombosis. In venous thrombosis in mice, we show that thrombin, a key clot-promoting enzyme, is not a major contributor to C5a generation. Rather, plasmin, a fibrinolytic enzyme formed in response to thrombin generation and clot formation, efficiently generates C5a. The findings were validated in an arterial thrombosis model in mice. These insights may be valuable in developing therapeutic strategies to limit thrombus formation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|