OC 57.5 - Platelet Aggregation and Transcriptomic Profiling Informs Perioperative Bleeding Risk

Background: Perioperative bleeding is a common complication during noncardiac surgery and is independently associated with morbidity and all-cause mortality. Mechanisms that predispose individuals to pathologic bleeding are unknown. Given the central role of platelets in hemostasis, pre-operative platelet phenotyping may provide mechanistic insights into dysregulated pathways and identify patients at risk for perioperative bleeding.

Aims: To investigate associations between major perioperative bleeding and 1) pre-operative platelet aggregation and 2) the pre-operative platelet transcriptome in patients undergoing lower extremity revascularization (LER).

Methods: Patients with symptomatic peripheral artery disease undergoing LER were recruited into the Platelet Activity and Cardiovascular Events in PAD (PACE-PAD) study (n=300). Platelet RNA was collected and aggregation to 0.4 µM epinephrine was measured immediately prior to LER. Perioperative major bleeding was defined as both (1) documented bleeding or estimated blood loss of ≥800mL, and (2) transfusion of ≥2 packed red blood cells or hemoglobin decline ≥ 2g/dL.

Results: In PACE-PAD 25% of patients experienced major bleeding. Patients with versus without bleeding were older (75.0 vs. 72.0 y, p=0.02), more often white (63.2% vs. 60.6%, p=0.029), female (47.4% vs. 27.7%, p=0.003), and had a lower BMI (24.9 vs. 26.9, p=0.015). After adjustment for age, sex, race, BMI, and antiplatelet use, platelet aggregation was lower in patients with versus without major bleeding (35.5% vs. 46.8%, adjusted [adj] p=0.05, n=254). The pre-procedure platelet transcriptome of patients who subsequently experienced major bleeding differed from those without bleeding (1774 differentially expressed genes, p< 0.05), with enrichment of pathways associated with activation of immune responses (adjp=2x10-8), secretory granule release (adjp=7x10-8), and G-protein coupled receptor signaling (adjp=4x10-5).

Conclusion(s): Platelet phenotyping (aggregation, transcriptomics) prior to noncardiac surgery can identify patients at risk for perioperative bleeding. These studies provide proof-of-concept that platelet transcriptomics can yield insights into dysfunctional platelet responses that contribute to defective hemostasis and perioperative bleeding.