Tissue Factor, a Membrane-associated Marker of Platelet Activation, Predicts 5-year Cardiovascular Mortality in Coronary Artery Disease Patients

Abstract

Thrombotic risk stratification in coronary artery disease (CAD) patients is an unmet need. CAD patients show increased platelet activation, but its prognostic relevance remains unexplored. We aimed to assess the prognostic value of platelet-activation markers on mortality in CAD patients.Surface expression of platelet-associated activated GPIIbIIIa, P-selectin, tissue factor (TF), and platelet-leukocyte aggregate was analyzed in 527 CAD patients (acute coronary syndromes [ACS, n = 149] and chronic coronary syndrome [CCS, n = 378]) by whole-blood flow-cytometry and plasma F1 + 2 by ELISA. With COX regression model 5-year survival analysis from all-cause (AC) and cardiovascular (CV) mortality was performed. Cross-validated cut-off of TF^pos platelets was calculated by Euclidean distance method.AC and CV mortality rates were 9.7 and 6.5%, respectively. Among the biomarkers evaluated, only TF independently predicted AC mortality (hazard ratio [HR] =2.02, p = 0.042) also after adjustment for CAD presentation. ACS and CCS patients with TF^pos platelets >4% (the best cut-off value for all-cause mortality prediction) had the highest levels of F1 + 2 and a worse prognosis for AC and CV mortality (HR = 1.91; p = 0.018 and HR = 2.51; p = 0.005; respectively) than those with <4% TF^pos platelets. Interestingly, patients on dual antiplatelet therapy (n = 246, 46.8%) responder to P2Y₁₂ inhibitors with TF^pos platelets >4% had the highest risk for AC mortality (HR = 4.11; p = 0.0215) and CV mortality (HR = 6.88; p = 0.0408). In these patients, TF^pos platelet levels outperformed a clinical model in CV mortality prediction (net reclassification improvement = 0.436, p < 0.001). Platelet TF predicted AC (HR = 3.03; p = 0.012) and CV mortality (HR = 3.56; p = 0.008) in aspirin-only treated patients also (n = 239, 45.3%).The percentage of circulating TF^pos platelets may serve as an independent predictor of AC and CV mortality in CAD patients on antiplatelet therapy.