Proposed mechanisms of the protective action of ASA against S aureus sepsis-induced hepatic thrombosis. Once in the blood, circulating S aureus triggers an immunothrombotic cascade resulting in intravascular coagulation and occlusion of liver sinusoids. Circulating S aureus activates neutrophils and platelets through direct physical interactions (eg, via toll-like receptors and other pattern-recognition receptors) and secretion of immunomodulatory proteins, thus stimulating neutrophil-platelet reciprocal activating interactions. These interactions lead to the release of neutrophil elastase (NE) and cathepsin-G (CG) by neutrophils (PN), as well as to PAD4-dependent formation of procoagulant NETs. Together with nucleosomes, free and NETs-associated NE and CG enhance tissue factor- and factor XII-dependent coagulation, by degrading the tissue factor pathway inhibitor. Intravascular fibrin deposits and NETs help to capture and kill circulating S aureus, while at the same time, they promote liver injury and dysfunction by occluding sinusoids. Depending on the timing of administration, treatment with ASA can prevent thrombosis in sinusoids and associated liver injury by acting on at least 3 possible levels: (1) prevention of NETosis through inhibition of neutrophil-platelet interactions and reciprocal activation, (2) inhibition of S aureus–induced platelet aggregation, and (3) inhibition of platelet incorporation and aggregation on preformed prothrombotic NETs. The antibacterial action of “non-NETotic” neutrophils and other immune cells like Kupffer cells (KC) helps minimize the impact of ASA treatment on bacterial elimination.