Molecular forms of fibrin are carried as soluble complexes with fibrinogen in blood, and the level and composition of these complexes reflect pro-coagulant activity in vivo. The proposed studies are directed to (1) bring to a conclusion a quest for a rapid and economical means for surveillance of the level, the fibrinopeptide content, and the degree of cross-linking of the complexes as indicators of both the nature and the degree of coagulopathic processes contributing to thrombosis and necrotizing vascular disease in patients, (2) establish by electron microscopy the routes and limiting conditions for transendothelial transport and clearance of fibrin, (3) characterize a receptor that is indicated by electron microscopic studies to function in reticuloendothelial clearance of fibrin, and (4) build a general concept of the interrelationship between the order of fibrinopeptide release and its relationship to fibrin aggregation in both physiologic and pathologic aspects of hemostasis. Chromatographic methods for determining composition and special properties of the complexes have now been refined to a degree that will enable 24 analyses to be performed in 4 hours by zonal immobilization on glyoxyl agarose, and this technology will be applied to surveillance of hypercoagulability of surgical patients at risk of deep vein thrombosis and pulmonary artery embolism. Tracking of transendothelial invasion and clearance of fibrin will employ a hemepeptide labeling procedure which recent studies have shown capable of detailing macrophage uptake of the fibrin at the single molecule level of resolution. It is hypothesized in both physical and metabolic studies that the fate of fibrin in the circulation is critically dependent on its dissociabilility as determined by its fibrinopeptide content and cross-linking. Tests of this hypothesis center in part on indications of 1) cooperative binding in monomer association with epitopes unmasked by the release of fibrinopeptides, 2) affinity of reticuloendothelial cell receptors for the same epitope (a circumstance making tight aggregation and rapid clearance of fibrin mutally exclusive phenomena), and 3) the capacity of fibrinogen to facilitate clearance of fibrin by maintaining the fibrin in a dissociable state required for rapid uptake.
NIH ExPorter
NIH ExPorter