Nascent fibrin that is formed on release of fibrinopeptide A by thrombin is carried in a soluble, monomeric form reversibly complexed with fibrinogen in blood. Rapid clearance of this fibrin from the circulation appears to depend on a recently identified receptor-mediated mechanism for endocytotic uptake by phagocytic cells. The clearance of fibrin prior to its incorporation into tightly bound aggregates is suggested to be of critical importance in reducing dependence on thrombolytic pathways for its removal. There are indications that specific uptake of fibrinogen monomer involves the aggregation site that is blocked by fibrinopeptide A in the parent fibrinogen molecule. Continued studies are proposed to characterize the fibrin-specific receptors in mouse J774A.1 and human U-937 macrophage/monocyte cell lines which bind monomer and NDSK preparations of fibrin with specificities identical to peritoneal macrophages. These studies will be aided by highly selective modifications of fibrin and fibrin derivatives for specific affinity labelling and isolation of the receptors. New interrelationships between dissociability of fibrin complexes and receptor mediated clearance provide insights into biologic significances of fibrinopeptide B release and the cross-linking that occur toward end stages of fibrin formation. Hypotheses pertaining to fibrin assembly and its metabolism will be detailed through direct analysis of equilibria in fibrin/fibrinogen interactions, coupled interactions with fibrinogen dimer and effects on fibrin clearance, and identification of critical epitopes functioning in fibrin assembly and cellular uptake. Cross-lined fibrin complexes and degradation products corresponding to pre-and post-thrombus products can be readily differentiated and subclassified from immunoelectrophoretic analysis of plasma and serum. Both families of derivatives have been found consistently elevated in patients with claudication from peripheral arterial thromboembolism, and the levels of these fibrinogen derivatives do not change substantially during or after catheter-directed thrombolysis with tissue-plasminogen activator. Their persistence without substantial change in course of treatment prompts a hypothesis that the localized arterial emboli were symptomatic of a more extensive, possibly systemic coagulopathic process. Similar fibrinogen derivatives have been found to be pathognomonic for departure from a benign to a malignant form of experimental hypertension in rats. The proposed studied address precise characterization of the derivatives by immunochemical and direct amino aid sequencing methods, analysis of their disparate clearance mechanisms, and a new approach to assessing fibrinogen turnover. Focused study of these patients will provide criteria for identifying subjects with a predisposition to intravascular coagulation.
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