Combined deficiency of coagulation factor V and coagulation factor VIII is another inherited bleeding disease under study in our lab. We have recently found that about a quarter of these patients carry a mutation in a different gene, presumably another critical component of this same protein-manufacturing machinery. These findings offer new insight into the process by which these two clotting factors are made in the body, as well as the general processes of protein synthesis and export. The fibrinolytic system, the body's mechanism for breaking down blood clots, is delicately balanced with the system that forms blood clots. Overactivity of either system results in uncontrolled bleeding or uncontrolled blood clotting.
Plasminogen activators are the proteins that turn on the fibrinolytic system.
We are using transgenic approaches to study the function of the PAIs and several closely related clotting factors in a mouse model system. This work has unmasked previously unappreciated roles of these proteins in the blood clotting system and in the response of the body to various types of injury, including infection and cancer progression. By mixing these mice with other mice genetically predisposed to diseases of the blood vessels, we are investigating the roles of these proteins in the development of atherosclerosis, the underlying cause of heart attack and stroke. These studies may provide valuable new information about how these common human diseases develop, as well as suggesting new approaches to therapy.