A. Koneti Rao, MBBS

Molecular Mechanisms in Inherited Disorders of Platelet Signal Transduction. Patients with inherited platelet bleeding disorders are not uncommonly encountered in clinical practice.  However, in the vast majority of these patients, the underlying molecular mechanisms leading to the platelet dysfunction are unknown.  Our studies have focused on platelet signaling processes in these patients and have delineated hitherto undescribed abnormalities in key signaling proteins, including phospholipase C-beta-2, GTP binding protein G-alpha-q and protein kinase-C?theta.   These studies are supported by grant awards from the NIH (NIH HL RO1 HL56724) and the March of Dimes Birth Defects Foundation.  The insights from these studies will lead to better understanding of the normal platelet mechanisms and the identification of novel targets to develop newer antiplatelet agents.

Hyperglycemia, Hyperinsulinemia, and Tissue Factor Pathway of Blood Coagulation. Diabetes mellitus is well-recognized risk factor for cardiovascular disease.  These patients have a high incidence of acute events including heart attacks and strokes.  The impact of hyperglycemia (high blood glucose) and hyperinsulinemia (high blood insulin) on the activation of blood coagulation mechanisms has not been fully clarified.  These studies, performed in collaboration with Dr. Guenther Boden, focus on the activation of the tissue factor pathway induced by hyperglycemia and hyperinsulinemia in healthy subjects and patients with diabetes mellitus.  Studies to date reveal a strong evidence for the activation of tissue factor pathway by both hyperglycemia and hyperinsulinemia, with the highest levels being observed with the combination of both.   Further studies will lead to an understanding of the effect of antithrombotic agents on the expression of tissue factor in diabetes mellitus.  These studies are supported by a NIH- RO1 grant (RO1 DK 58895; PI: Boden; Co-PI Rao).

Impact of Antiplatelet Drugs Aspirin, Clopidogrel and Cilostazol on Platelet Function and Blood Coagulation in Patients with Peripheral Arterial Disease (PAD).   Antiplatelet drugs aspirin, clopidogrel and cilostazol are widely used in the management of patients with PAD, but the effects of these agents when used in combination on platelet function and the blood coagulation system has not been clarified.   Supported by a grant from Pharmaceutical industry, these studies seek to define these effects, including on the tissue factor pathway of blood coagulation.   Our studies suggest that antiplatelet agents inhibit circulating levels of tissue factor, a mechanism hitherto not recognized, and which is likely to contribute to the antithrombotic effects of these agents.