Circulating Tissue Factor: Characterization and Interactions with Factor IX

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DESCRIPTION (provided by applicant): Tissue factor (TF) is an integral membrane glycoprotein that initiates the coagulation cascade after exposure to blood components. In classical models, TF is constitutively expressed in epithelia and vascular adventitial cells so as to create a "hemostatic envelope" around but separated from blood. However, endothelial cells and hematopoietic cells can express TF especially after inflammatory stimuli, and it has been postulated that activation of circulating TF is important for clot propagation. We have used a Tie2-Cre transgene to excise a floxed Tf allele to generate mice in which hematopoietic and endothelial cell Tf has been ablated ('Tf hem/endo knockout"). Data using such mice suggest that endothelial and hematopoietic Tf is necessary for disseminated intravascular coagulation in mouse models of endotoxemia. However, the normal role of endothelial and hematopoietic TF in homeostasis and in inflammatory states is unknown. We shallask: Specific Aim 1. Is endothelial and hematopoietic TF important for hemostasis and thrombosis? In Tf hem/endo knockout mice, we will assess ablation of circulating TF by quantitative RT- PCR for Tf mRNA. Hemostasis and thrombosis will be tested in mice using well-validated protocols. Specific Aim 2. Does induction of endothelial and hematopoietic TF by inflammatory stimuli promote hemostasis and thrombosis? We will induce TF mRNA expression via exposure to endotoxin and then examine bleeding times and thrombosis. Enhanced hemostasis and/or thrombosis would support the hypothesis that endothelial and hematopoietic TF may provide a link between inflammation and thrombosis. Specific Aim 3. Might mice lacking factor IX provide a sensitized system in which we might detect normal roles for circulating TF? We will test the hypothesis that these systems are partially redundant by examining hemostasis and thrombosis in mice that lack both circulating TF and factor IX. Our study seeks to define the role of circulating TF, which is increased in important human inflammatory disease states, and its interaction with the intrinsic coagulation pathway. These studies may provide attractive therapeutic targets for treatment of these inflammatory states.