J Thromb Haemost. 2026 Oct 30:S1538-7836(26)00687-2. doi: 10.1016/j.jtha.2026.10.019. Online ahead of print.
ABSTRACT
BACKGROUND/AIMS: Bloodstream Staphylococcus aureus infections activate the host's thromboinflammatory response. Staphylocoagulases (Coa and vWbp) are virulence factors that manipulate the host coagulation system that may influence downstream neutrophil responses. We therefore investigated how coagulase-host interactions influence neutrophil activation, neutrophil extracellular trap (NET) formation, and systemic thromboinflammation.
METHODS: Human neutrophils were stimulated with methicillin-resistant S. aureus (MRSA) USA300 wild-type (WT) or coagulase-deficient (ΔcoaΔvwb) strains, and functional activation was analyzed by flow cytometry. NET formation was evaluated from bacteria that had been pre-incubated with fibrinogen, prothrombin, or both. We modeled sepsis in C57BL/6J mice by intravenous injection of WT or ΔcoaΔvwb MRSA. Responses in peripheral blood (differential counts, thromboinflammatory parameters), and hepatic immunothrombosis were examined at timepoints before mice reached moribundity.
RESULTS: MRSA induced rapid neutrophil activation, characterized by CD11b conformational activation and robust degranulation, independent of coagulase expression. USA300 WT, but not ΔcoaΔvwb, strains triggered NET formation that was enhanced by fibrinogen and not by staphylothrombin alone or S. aureus-generated fibrin. This was independent of CD11b activation or degranulation. In vivo, coagulases were associated with early increase of acute-phase reactants, including fibrinogen, von Willebrand factor, and interleukin-6. In the liver, coagulases promoted early neutrophil recruitment and altered thrombus composition, reflected by an increase in VWF-rich thrombi at day 4.
CONCLUSIONS: Fibrinogen amplifies S. aureus-induced NET formation through mechanisms potentially linked to coagulase expression but independent of canonical neutrophil activation pathways. Staphylocoagulases predominantly enhance early inflammatory and endothelial responses without driving sustained coagulation activation, indicating a temporally restricted role in shaping thromboinflammation.
PMID:42962971 | DOI:10.1016/j.jtha.2026.10.019