ABSTRACT
Fibrin structure contributes to the regulation of the fibrinolytic rate. As the fibrin fiber size is decreased, the fibrinolytic rate also decreases. Fibrin structure was altered by either changing the ratio of thrombin to fibrinogen, i.e. altering the assembly rate or by adding a fibrin assembly inhibitor, iopamidol. Changes in the fibrinolytic rate were followed by measuring the time dependence of the decrease in the fiber mass/length ratio during fibrinolysis. A measure of the overall fibrinolytic rate was determined from the decrease in the mass/length ratio versus time. An 8-fold reduction in the fibrinolytic rate was seen on decreasing the mass/length ratio from 2.7 x 10(12) daltons/cm to 0.5 x 10(12) daltons/cm. It is shown that thin fibrin fibers have a decreased rate of conversion of plasminogen to plasmin by tissue plasminogen activator and that thin fibrin fibers are lysed more slowly than thick fibrin fibers.
Subject(s)
Fibrin/chemistry , Fibrin/metabolism , Fibrinolysis , Amino Acid Sequence , Fibrin/isolation & purification , Fibrinolysin/metabolism , Gels , Humans , Iopamidol/pharmacology , Kinetics , Macromolecular Substances , Molecular Sequence Data , Molecular Weight , Nephelometry and Turbidimetry , Substrate SpecificityABSTRACT
The effect of the radiographic contrast agents, iopamidol and diatrizoate, on fibrin assembly and structure as well as platelet surface charge was studied. Increasing the iopamidol concentration from 0 to 4.5 mM prolongs the fibrin gelation time from 20 to 105 seconds (an anticoagulant effect) and reduces the fibrin fiber mass/length ratio from 3.2 x 10(12) to 0.5 x 10(12) Da/cm (i.e., produces very thin fibrin fibers). Ultraviolet difference spectroscopy of fibrinogen showed both a 15-nm shift in the ultraviolet difference maximum for iopamidol (suggesting binding) and a perturbation of the aromatic amino acid side chain region for fibrinogen (suggesting a conformational change in fibrinogen) as the concentration of iopamidol was increased from 0 to 9 mg/ml. Binding of iopamidol to fibrinogen was also shown by affinity chromatography using a Sepharose-fibrinogen column. Electrophoretic quasi elastic light scattering was used to show platelet interaction with iopamidol as reflected in a reduction in the platelet electrophoretic mobility from 2.0 to 0.5 (microns-cm)/(V-sec) as the concentration of iopamidol was increased from 0 to 4.5 mM. In addition, the ionic radiopaque contrast agent, Renografin, was also studied and found to inhibit fibrin monomer assembly. Although iopamidol is not shown to be thrombogenic, iopamidol does appear to reduce platelet surface charge, bind fibrinogen, and modify fibrin clot structure.
