Abstract 292: Platelet Hyperreactivity Characterization by Aggregation and RNA-seq Informs Cardiovascular Risk

Abstract

Background: Patients with peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular and limb events (MACLE), many of which are platelet mediated. In this study, we investigated the association between platelet hyperreactivity and 30-day MACLE in patients undergoing lower extremity revascularization (LER) and derived and validated a gene signature of platelet hyperreactivity. Methods: Patients with symptomatic PAD undergoing LER were recruited into the Platelet Activity and Cardiovascular Events in PAD (PACE-PAD) study. Platelet RNA was collected and platelet aggregation to 0.4 μM epinephrine was measured by light transmission aggregometry (LTA) immediately prior to LER. Patients were followed for 30 days post-procedure MACLE. Integration of platelet RNA-seq and aggregation responses was used to generate a P latelet R eactivity E xpre S ion S ignature ( PRESS ) geneset. Results: A total of 289 patients were included (mean [SD] age 70 [11] years; 94 [33%] female). Patients with platelet hyperreactivity (>60% agg) had an increased incidence of 30-day MACLE post-LER (37.2% vs. 15.3%, P<0.01; adjusted hazard ratio [aHR] 2.80, 95% CI 1.5 to 5.1, P=0.002), which persisted across age, sex, race/ethnicity, antiplatelet therapy, and clinical risk categories. We derived and validated a platelet hyperreactivity geneset, PRESS, that associates with incident cardiac and limb events and can discriminate platelet hyperreactivity across disease states ( Fig. 1 ). Conclusion: Platelet hyperreactivity measured before LER was independently associated with 30 day MACLE. Our transcriptomic signature of platelet hyperreactivity, PRESS, accurately identified patients with hyperreactive platelets. Use of our PRESS geneset as a diagnostic tool of platelet hyperreactivity opens the possibility of personalized intervention approaches to prevent platelet-mediated complications.