期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-018-22156-5
关键词
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资金
- Swedish Medical Research Council [2012-3685, 2016-01104, 2017-01621]
- Crafoordska stiftelsen
- Einar och Inga Nilssons stiftelse
- Harald och Greta Jaenssons stiftelse
- Greta och Johan Kocks stiftelser
- Froken Agnes Nilssons stiftelse
- Franke och Margareta Bergqvists stiftelse for framjande av cancerforskning
- Magnus Bergvalls stiftelse
- Mossfelts stiftelse
- Nanna Svartz stiftelse
- Ruth och Richard Julins stiftelse
- Svenska Lakaresallskapet
- Allmana sjukhusets i Malmo stiftelse for bekampande av cancer
- MAS fonder
- Foundation for Strategic Research (SSF)
- Malmo University Hospital
- Lund University
- Swedish Research Council [2017-01621, 2016-01104] Funding Source: Swedish Research Council
- Vinnova [2017-01621, 2016-01104] Funding Source: Vinnova
Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation ( TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps ( NETs) and/or microparticles ( MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture ( CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation.
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