TISSUE FACTOR, THROMBOSIS AND THE ARTERIAL WALL

This is a competitive renewal of a SCOR in Hemostatic and Thrombotic Diseases by a highly-interactive group of investigators at the Mount Sinai School of Medicine. The program is comparised of 5 projects and 3 cores. Findings by the SCOR investigators and other laboratories have established the presence of circulating tissue factor (TF). Our program, in particular has demonstrated that this TF is active and can initiate thrombus formation. The project of Dr. Fuster will measure circulating TF in patients with risk factors for atherosclerosis and thrombosis and will examine the effect of risk factor reduction on TF levels and thrombogenicity. Dr. Fuster has found collaborations with investigators that will provide samples from several important clinical studies. Dr. Nemerson's project will explore the novel finding that leukocytes can transfer TF to the surface of platelets and will attempt to identify the platelet "TF receptor." Based on the finding that large thrombi stain diffusely the TF, Dr. Nemerson will develop mathematical models to examine the diffusion of molecules within the thrombus. Dr. Taubman's project will study the role of smooth muscle cells (SMC) and cardiomyocytes in releasing TF into the microcirculation after angioplasty and myocardial infarction. He will employ pig models of coronary artery injury and infarction and novel transgenic mice in which TF is conditionally knocked out in SMC and cardiomyocytes to examine the role of TF in mediating infarct size and intimal hyperplasia. These closely- linked projects promise to establish new paradigms for TF generation and biology. A second major focus of the SCOR is on platelet-leukocyte interactions. The project of Dr. Harpel will examine the role of I-309, a CC-chemokine, in regulating leukocyte accumulation in arterial injury. His findings that platelets possess I-309 has led to the novel hypothesis that the release of I-309 by platelets accumulating at the site of injury is critical to the early recruitment of leukocytes. He will also examine the role of I-309 in mediating endothelial cell migration and vasculogenesis. Dr. Coller's project will undertake a detailed examination of the interaction between leukocytes and platelets in regulating arterial thrombosis and leukocyte transmigration. His project involves several recently-developed models of thrombosis and novel transgenic animals. In support of this project will be a Pathology Core, a Thrombosis Core.