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Staphylococcus aureus‐ induced complement activation promotes tissue factor‐mediated coagulation
Author(s) -
Skjeflo E. W.,
Christiansen D.,
Fure H.,
Ludviksen J. K.,
Woodruff T. M.,
Espevik T.,
Nielsen E. W.,
Brekke O. L.,
Mollnes T. E.
Publication year - 2018
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.13979
Subject(s) - tissue factor , tlr2 , complement component 5 , coagulation , complement system , complement receptor 1 , immunology , thromboplastin , complement factor i , cd14 , receptor , staphylococcus aureus , microbiology and biotechnology , biology , flow cytometry , antibody , tlr4 , medicine , inflammation , biochemistry , bacteria , genetics
Essentials Complement, Toll‐like receptors and coagulation cross‐talk in the process of thromboinflammation. This is explored in a unique human whole‐blood model of S. aureus bacteremia. Coagulation is here shown as a downstream event of C5a‐induced tissue factor (TF) production. Combined inhibition of C5 and CD14 efficiently attenuated TF and coagulation.Summary Background There is extensive cross‐talk between the complement system, the Toll‐like receptors ( TLR s), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor ( TF ) expression. Objectives To study the relative roles of complement, TLR s and TF in Staphylococcus aureus ‐induced coagulation. Methods Lepirudin‐anticoagulated human whole blood was incubated with the three S. aureus strains Cowan, Wood, and Newman. C3 was inhibited with compstatin, C5 with eculizumab, C5a receptor 1 (C5aR1) and activated factor XII with peptide inhibitors, CD 14, TLR 2 and TF with neutralizing antibodies, and TLR 4 with eritoran. Complement activation was measured by ELISA . Coagulation was measured according to prothrombin fragment 1 + 2 ( PTF 1 + 2 ) determined with ELISA , and TF m RNA , monocyte surface expression and functional activity were measured with quantitative PCR , flow cytometry, and ELISA , respectively. Results All three strains generated substantial and statistically significant amounts of C5a, terminal complement complex, PTF 1 + 2 , and TF m RNA , and showed substantial TF surface expression on monocytes and TF functional activity. Inhibition of C5 cleavage most efficiently and significantly inhibited all six markers in strains Cowan and Wood, and five markers in Newman. The effect of complement inhibition was shown to be completely dependent on C5aR1. The C5 blocking effect was equally potentiated when combined with blocking of CD 14 or TLR 2, but not TLR 4. TF blocking significantly reduced PTF 1 + 2 levels to baseline levels. Conclusions S. aureus ‐induced coagulation in human whole blood was mainly attributable to C5a‐induced m RNA upregulation, monocyte TF expression, and plasma TF activity, thus underscoring complement as a key player in S. aureus ‐induced coagulation.

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