Staphylococcus aureus-induced complement activation promotes tissue factor-mediated coagulation

Skjeflo, E. W., Christiansen, D., Fure, H., Ludviksen, J. K., Woodruff, T. M., Espevik, Terje, Nielsen, E. W., Brekke, O. L. and Mollnes, T. E. (2018) Staphylococcus aureus-induced complement activation promotes tissue factor-mediated coagulation. Journal of Thrombosis and Haemostasis, 16 5: 905-918. doi:10.1111/jth.13979


Author Skjeflo, E. W.
Christiansen, D.
Fure, H.
Ludviksen, J. K.
Woodruff, T. M.
Espevik, Terje
Nielsen, E. W.
Brekke, O. L.
Mollnes, T. E.
Title Staphylococcus aureus-induced complement activation promotes tissue factor-mediated coagulation
Formatted title
Staphylococcus aureus-induced complement activation promotes tissue factor-mediated coagulation
Journal name Journal of Thrombosis and Haemostasis   Check publisher's open access policy
ISSN 1538-7836
1538-7933
Publication date 2018-02-13
Year available 2018
Sub-type Article (original research)
DOI 10.1111/jth.13979
Open Access Status Not yet assessed
Volume 16
Issue 5
Start page 905
End page 918
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Subject 2720 Hematology
Abstract There is extensive cross-talk between the complement system, the Toll-like receptors (TLR) and hemostasis. Consumptive coagulopathy is a hallmark of sepsis and often mediated through increased tissue factor (TF) expression.

To study the relative roles of complement, TLRs and TF in Staphylococcus aureus (S. aureus)-induced coagulation.

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 and factor XIIa with peptide inhibitors, CD14, TLR2, and TF with neutralizing antibodies, and TLR4 with eritoran. Complement activation was measured by ELISA. Coagulation was measured by prothrombin fragment 1+2 (PTF1.2) using ELISA, and TF mRNA, monocyte surface expression and functional activity using qPCR, flow cytometry and ELISA, respectively.

All three strains generated substantial and statistically significant amounts of C5a, TCC, PTF1.2, TF mRNA, TF surface expression on monocytes and TF functional activity. Inhibition of C5 cleavage most efficiently inhibited (P < 0.05) 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 CD14 or TLR2, but not TLR4. TF blocking significantly (P < 0.05) reduced PTF1.2 levels to baseline levels.

S. aureus-induced coagulation in human whole blood was mainly due to C5a-induced mRNA upregulation, monocyte TF expression and plasma TF activity, thus underscoring complement as a key player in S. aureus-induced coagulation. This article is protected by copyright. All rights reserved.
Formatted abstract
Background: There is extensive cross-talk between the complement system, the Toll-like receptors (TLR) and hemostasis. Consumptive coagulopathy is a hallmark of sepsis and often mediated through increased tissue factor (TF) expression.

Objectives: To study the relative roles of complement, TLRs and TF in Staphylococcus aureus (S. 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 and factor XIIa with peptide inhibitors, CD14, TLR2, and TF with neutralizing antibodies, and TLR4 with eritoran. Complement activation was measured by ELISA. Coagulation was measured by prothrombin fragment 1+2 (PTF1.2) using ELISA, and TF mRNA, monocyte surface expression and functional activity using qPCR, flow cytometry and ELISA, respectively.

Results: All three strains generated substantial and statistically significant amounts of C5a, TCC, PTF1.2, TF mRNA, TF surface expression on monocytes and TF functional activity. Inhibition of C5 cleavage most efficiently inhibited (P < 0.05) 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 CD14 or TLR2, but not TLR4. TF blocking significantly (P < 0.05) reduced PTF1.2 levels to baseline levels.

Conclusions: S. aureus-induced coagulation in human whole blood was mainly due to C5a-induced mRNA upregulation, monocyte TF expression and plasma TF activity, thus underscoring complement as a key player in S. aureus-induced coagulation.
Keyword Staphylococcus aureus
Bacteremia
Blood coagulation
Complement system proteins
Tissue factor
Toll-like receptor
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 602699
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
 
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Created: Wed, 21 Feb 2018, 11:08:43 EST