Increased tissue factor, MMP-8, and D-dimer expression in diabetic patients with unstable advanced carotid atherosclerosis

Abstract

Advanced atherogenesis is characterized by the presence of markers of enhanced prothrombotic capacity, attenuated fibrinolysis, and by clinical conditions associated with defective coagulation. Diabetes may be associated with enhanced lesion instability and atherosclerotic plaque rupture. Plaques obtained from 206 patients undergoing carotid endarterectomy were divided into diabetic (type 2) and nondiabetic and analyzed by Western blotting and immunohistochemistry to detect tissue factor (TF), metalloproteinases (MMP)-2, -8, -9, and fibrin/fibrinogen related antigens, and in situ zymography to detect MMP activity. Plasma samples were quantified for TF procoagulant activity, C-reactive protein, fibrinogen and D-dimer. Diabetic and symptomatic patients with hypoechogenic plaques had increased plasma TF activity and D-dimer, compared with those with hyperechogenic plaques (p = 0.03, p = 0.007, respectively). Diabetic, symptomatic patients had higher plasma D-dimer levels than asymptomatic patients (p = 0.03). There was a significant correlation between intramural TF levels and D-dimer in diabetic patients with symptomatic disease (p = 0.001, r2 = 0.4). In diabetic patients, plasma fibrinogen levels were higher in patients with hypoechogenic plaques (p = 0.007). Diabetic patients with ulcerated plaques had higher plasma D-dimer and MMP-8 levels than those with fibrous plaques (p = 0.02, p = 0.01, respectively). This data suggests that currently available circulating markers may be clinically useful to select diabetic patients at higher risk of therothrombosis. Increased procoagulant activity in diabetic patients may be linked to increased mural remodeling.