ROLE OF TISSUE FACTOR IN HEMOSTASIS & THROMBOSIS

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Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascades. It plays an essential role in hemostasis. Under pathological conditions, however, aberrant TF expression within the vasculature is associated with thrombosis. The goals of this proposal are to determine the roles of TF in hemostasis and thrombosis. In aim 1, we will determine the relative contribution of monocytes, endothelial cells, and platelets to LPS-induced coagulation in a mouse model. Sepsis is the major cause of death in intensive care units in the United States. In humans, the innate immune system has evolved to sense an infection by detecting small amounts of products from the pathogens, such as LPS. However, an excessive response to the presence of LPS in the blood is associated with disseminated intravascular coagulation (DIG). Monocytes and endothelial cells have been shown to express TF in animal models of endotoxemia and sepsis. More recently, we found that LPS induced TF expression in platelets. In aim 2, we will use both genetic and pharmacologic approaches to investigate the role of the phosphatidylinositol-3-kinase (PI3K)- protein kinase B (Akt) pathway in the suppression of LPS-induced gene expression both in vitro and in vivo. We have found that the PI3K-Akt pathway suppresses LPS induction of TF and inflammatory gene expression in monocytic cells and in endotoxemic mice. Importantly, several agents that reduce both coagulation and inflammation in animal models of endotoxemia and sepsis activate this pathway. In aim 3, we will investigate the role of the extrinsic (TF and FVII) and intrinsic (FXII, FXI, FIX and FVIII) coagulation pathways in tissue-specific hemostasis and wound healing. A recent study showed that expression of high levels of FVIIa in mice leads to premature death due to thrombosis in the heart and lung. We will cross high FVIIa mice with either low TF mice or mice with increased and decreased TF expression in the heart. The phenotypes of the different mice will test the hypothesis that the extrinsic pathways mediates heart-specific hemostasis. RELEVANCE (See instructions): These studies should provide novel insights into the mechanisms of hemostasis and thrombosis that may stimulate the development of novel therapeutic strategies to treat patients with these disorders.