Evaluation of platelet dependent thrombosis and the role of dual antiplatelet therapy on blood thrombogenicity in patients with type 2 diabetes mellitus and coronary artery disease

Abstract

Evaluation of platelet dependent thrombosis and the role of dual antiplatelet therapy on blood thrombogenicity in patients with type 2 diabetes mellitus and coronary artery disease The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing. Recurrent thrombotic events and cardiac mortality are higher in T2DM. Aims: My overall aim was to identify abnormalities in blood thrombogenicity in T2DM and assess the response to dual antiplatelet therapy. Hypotheses: Study 1 ACS study: Patients with T2DM have increased blood thrombogenicity following non ST-elevation acute coronary syndromes (NSTE-ACS). Study 2 CAD study (double blinded RCT): Addition of clopidogrel to standard treatment will reduce blood thrombogenicity in T2DM and stable coronary artery disease (CAD). Methods: Study 1 ACS study: Eighty patients (40 with T2DM) with troponin positive NSTE-ACS on aspirin and clopidogrel underwent thrombogenicity studies. Study 2 CAD study: Ninety patients with T2DM and proven but stable CAD were randomised to either clopidogrel 75 mg od or placebo and were studied at base line and one week after therapy. I performed i) Badimon chamber study, ii) thromboelastography, iii) VerifyNow® aggregometry, iv) scanning electron microscopy (SEM), v) Multiplate® aggregometry, vi) biomarkers of platelet reactivity assays and vii) serum pro-inflammatory cytokines assays. Results: In T2DM patients with NSTE-ACS, there was higher thrombus area compared to non-diabetic patients. Diabetic thrombus showed lower viscoelastic tensile ii strength and was more resistant to autolysis. On SEM, fibrin fibres in diabetic thrombus were thinner, with higher lateral interlinkage and mesh-like organisation. Thrombus correlated inversely with the rate of thrombus retraction. P selectin, CD40 ligand and inflammatory cytokines were higher in T2DM. Clopidogrel decreased thrombus area in stable CAD patients with T2DM, lowered platelet content of thrombus and increased fibrin diameter and density. Fibrin fibre diameter correlated negatively with shear elastic force of the thrombus. In a post hoc analysis, thrombus area of non diabetic ACS patients’ was similar to that of T2DM patients with stable CAD. Thrombus area and point of care tests showed no correlation. Conclusions: T2DM had higher blood thrombogenicity after NSTE-ACS and platelet dependent thrombus was reduced in stable CAD patients after clopidogrel therapy. Clopidogrel resulted in favourable ultra structural changes to thrombus. Patients with T2DM and stable CAD were “ACS equivalent” and addition of clopidogrel may improve their clinical outcomes. Novel pharmacotherapy to target fibrin and inflammation in T2DM may reduce blood thrombogenicity.