Endpoint: mixed — in vitro/mouse platelet mechanism (surrogate) + prospective cohort predicting incident thrombotic events (hard).
Proposes a second, non-atherosclerotic mechanistic route for TMAO harm: direct enhancement of platelet hyperreactivity and thrombosis potential. TMAO exposure augmented sub-maximal agonist-stimulated platelet activation via increased intracellular Ca2+ release; dietary choline/TMAO feeding, germ-free mice, and microbiota transplantation in mice all reproduced heightened thrombosis potential. In the same >4,000-subject cohort used in Tang 2013 (this pool), plasma TMAO independently predicted incident thrombotic events (MI, stroke) over 3 years.
relevance_note: gives TMAO a distinct candidate mechanism (pro-thrombotic, not just pro-atherogenic) and reproduces the prospective TMAO→events link. Data-basis note: shares the Cleveland Clinic angiography-referral cohort with Tang 2013 (this pool) — likely correlated, not independent, evidence for the events association.