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Toll‐like receptors 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis
Author(s) -
Williams Brittney,
Neder Jessica,
Cui Ping,
Suen Andrew,
Tanaka Kenichi,
Zou Lin,
Chao Wei
Publication year - 2019
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14543
Subject(s) - sepsis , thromboelastometry , tissue factor , gpvi , coagulopathy , immunology , tlr2 , inflammation , proinflammatory cytokine , platelet , platelet activation , coagulation , biology , chemistry , medicine , tlr4
Background Sepsis is a life‐threatening condition often manifested as marked inflammation and severe coagulopathy. Toll‐like receptors ( TLR s) play a pivotal role in inflammation, organ dysfunction and mortality in animal sepsis. Objectives To investigate the role of TLR signaling in mediating sepsis‐induced coagulopathy ( SIC ) in a mouse model. Methods Polymicrobial sepsis was created by cecal ligation and puncture ( CLP ) or fecal slurry peritoneal injection. To quantify global clotting function, two viscoelastic assays were performed with rotational thromboelastometry, and the results were presented as maximum clot firmness ( MCF ): ( a ) EXTEM to test tissue factor ( TF )‐initiated clot formation; and ( b ) FIBTEM to test EXTEM in the presence of a platelet inhibitor, cytochalasin D. Plasma coagulation factors were quantified with ELISA . TF gene expression and protein expression were determined with real‐time quantitative reverse transcription PCR and flow cytometry, respectively. Results Between 4 and 24 hours after CLP surgery, wild‐type mice showed significant MCF reduction in both EXTEM and FIBTEM tests. This was accompanied by marked thrombocytopenia and a significant increase in the levels of plasminogen activator inhibitor‐1, plasma TF , and D‐dimer. In comparison, TLR 2 −/− and TLR 7 −/− CLP mice showed preserved MCF and platelet counts, and near‐normal plasma TF levels. Bone marrow–derived macrophages treated with a TLR 2 agonist Pam3cys‐Ser‐(Lys)4 (Pam3cys) or a TLR 7 agonist (R837) showed marked increases in TF gene expression and protein expression. Micro RNA ‐146a, a newly identified proinflammatory mediator that is upregulated during sepsis, induced TF production via a TLR 7‐dependent mechanism. Conclusions Murine sepsis leads to an increased procoagulant response, thrombocytopenia, and global coagulopathy. TLR 2 and TLR 7 play an important role in procoagulant production and in SIC .