| For nearly 6 decades scientists have been identifying and defining the many roles of the blood serine protease Factor XII (FXII) in vitro and in vivo. Each year we gain new information about this elusive protein, however conflicts still exist over the importance of FXII in human disease states. Factor XII participates in coagulation, fibrinolysis, renin-angiotensin, and immune system responses making it an integral part of mammalian life. Animal models offer the best way to study the importance of a factor in vivo, however only two readily available FXII deficient models exist, i.e. the gene-manipulated mouse and our cats. This work characterizes the origin of the genetic defect causing FXII deficiency in a colony of domestic cats, and investigates in vivo acute responses to intravascular and intradermal (extravascular) injury. Ultimately we aim to provide a well defined animal model for therapeutic targeting strategies, and gain new insights into the importance of FXII in cellular and extracellular interactions.;Chapter 1 provides a comprehensive overview of the biological features of FXII: its importance as a central player in coagulation, fibrinolysis, complement activation, the innate immune system, and vascular repair; its molecular and genetic structure and cellular interactions; and the attributed pathophysiology derived from human and mouse studies. Chapter 2 details the feline FXII gene and the mutation discovered in our colony along with protein studies to confirm our findings.;Vascular injury and associated fibrinolytic and inflammatory response studies comprise Chapter 3. We found that FXII procoagulant activity is not necessary to initiate clotting and to form stable thrombi upon an initial venous or arterial injury. However, FXII appears to aid in clot stability following a second intravascular injury 48 hours later on the contralateral veins. Inflammatory mediators are also significantly reduced in FXII deficient animals. Chapter 4 addresses the role of FXII in recruiting inflammatory cells to a site of heme-induced skin injury. Our studies explore a new method of nitric-oxide driven innate immune response, finding significantly fewer inflammatory cell infiltrates in FXII deficient cats. Chapter 5 offers future studies to pursue with this model based on results of these dissertation findings. |
