This project concerns one aspect of control of the hemostatic (and thrombotic) processes at the molecular level. Specifically, the project focuses on the effects which plasma fibronectin may have in regulating the formation and degradation of fibrin. Fibrin is the end product of the coagulation process; its formation is essential for normal hemostasis, and it plays a significant role in the pathogenesis of both venous and arterial thrombosis. Fibrin formation is also the essential reason for the existence of the fibrinolytic system, in which it is both the surface on which plasmin generation occurs and also the primary substrate of plasmin. Fibronectin is a plasma protein which has several potential points for interaction and regulation in these important processes. Fibronectin may modulate the rate at which fibrin forms and thus affect several steps in fibrin formation (e.g., cleavage of fibrinopeptide B, lateral aggregation, branchpoint formation). Fibronectin may also affect the rate and extent of covalent crosslinking of fibrin by plasma transglutaminase. The type of fibrin which is formed will determine its susceptibility to plasmin. In addition fibronectin may affect fibrinolysis directly by modulating either the rate of plasminogen activation or plasmin inhibition by 2-antiplasmin. Fibronectin may also be important in the process of fibrin retraction and in initiating coagulation events on the surface of damaged endothelium. The experiments in this proposal are designed to test these possibilities.
The specific aims of the project are (1) to determine the effects of fibronectin on fibrin clot structure, including polymerization rate and rate of crosslinking; (2) to determine the effects of fibronectin and fibronectin fragments on fibrin degradation; (3) to characterize the Ca ion binding properties of fibronectin; (4) to study the binding of plasma fibronectin to damaged endothelial cells in tissue culture model systems; (5) to investigate the possible regulatory role of fibronectin in fibrin clot retraction; (6) to prepare monoclonal antibodies to fibronectin which inhibit specific functional properties of fibronectin. All of these experiments will aid in delineating mechanisms which control and modulate the blood coagulation process.
| Carr Jr, M E; Gabriel, D A; McDonagh, J (1987) Influence of factor XIII and fibronectin on fiber size and density in thrombin-induced fibrin gels. J Lab Clin Med 110:747-52 |
