A platelet transcriptomic signature of thromboinflammation predicts cardiovascular risk

The CHOlesterol Reduction and Residual Risk in type 2 Diabetes (CHORD) study was a prospective study that investigated the effect of lipid lowering therapieis in participants with LDL-C >100 mg/dL without cardiovascular disease, off all antiplatelet therapy. Individuals with MPA levels, defined as CD14+CD16+ cells, were measured before and after four weeks of lipid lowering therapy. Patients were categorized as MPAhigh or MPAlow based on consistently high or low MPA levels accross timepoints. MPAhigh individuals exhibited an enrichment of immune signaling pathway. We developed a 42/gene Thromboinflammation Platelet Signature (TIPS), which correlated with MPA levels in multiple cohorts. TIPS was significantly elevated in patients with COVID-19 and myocardial infarction and predicted future cardiovascular events in patients who underwent lower extremity revascularization after a median follow-up of 18 months. Notably, TIPS was modifiable by ticagrelor. These findings introduce TIPS as a novel platelet RNA signature that captures platelet-immune activity and offers a promising tool for cardiovascular risk stratification.