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We have examined radioiodinated fibrinogen prepared at high levels of iodination as an agent for improved in vivo thrombus detection. Fibrinogen containing 25, 50, and 100 atoms of iodine per molecule is prepared by an electrolytic procedure and is compared with conventional radiolabeled fibrinogen (less than 0.5 iodine atom per molecule) prepared by the iodine monochloride method. The level of iodination has little effect on the isotopic clottability of the product, but its degree of aggregation and its rate of blood clearance in experimental animals is strongly dependent on iodination level. Isotopic thrombus: blood ratios obtained in recently induced thrombi with the 25 atom per molecule preparation average about 50:1, twice as high as the ratios obtained with conventionally labeled fibrinogen.

We have investigated the in vivo behavior of 99mTc-fibrinogen, prepared by a mild and efficient electrolytic method employing tin electrodes. The clearance mechanisms of this agent were studied, and its efficacy for imaging deep-vein thrombi in dogs with an Anger camera was determined. The 99mTc-fibrinogen preparations, which are stable in vitro, undergo partial rapid exchange of the technetium with other plasma proteins and with anions of the blood buffer system in vivo, resulting in an early drop in the percent of radioactivity associated with clottable protein. However, very little or no oxidation to pertechnetate occurs. The nonclottable material is much more rapidly cleared from the blood than the remaining 99mTc-fibrinogen, and the proportion of clottable protein activity increases with time. The fraction of 99mTc-fibrinogen that remains intact in vivo is biologically active and will incorporate into thrombi. Higher thrombus-to-blood activity ratios are obtained with 99mTc-fibrinogen than with radioidinated fibrinogen when both agents are injected into dogs 4 hr after induction of femoral vein thrombosis. Clearly delineated images of the thrombi are obtained, beginning about 2.5 hr after injection. Thus, 99mTc-fibrinogen may be of clinical use as a thrombus-imaging agent in patients under-going active thrombosis, especially in regions of high blood pool.

The uptake of radiolabeled fibrinogen in canine thrombi was determined at varying times after thrombus induction by electric current. The greatest thrombus/blood ratio was achieved when fibrinogen was administered 4 hr after thrombus induction but definite thrombus fibrinogen uptake was still observed when the tracer was administered up to 72 hr after thrombus induction. There was continued fibrinogen accumulation despite a decrease in weight of older thrombi suggesting that net thrombus propagation is not necessary for labeled fibrinogen uptake. Our results suggest that the fibrinogen uptake test may be useful for the diagnosis of deep vein thrombosis for several days after the onset of thrombosis.

A method for producing protein-iodination-grade 123I suitable for use with a compact bio-medical cyclotron is reported. The preparation of highly iodinated fibrinogen (25 123I atoms per molecule) is described, and its successful use as a thrombus-imaging agent in experimental animals is reported. This new agent clears from the blood faster than conventional radioiodinated fibrinogen and gives higher thrombus-to-blood activity ratios. Thus, the detection of deep-vein thrombi in areas of large blood pool is enhanced, and images can be obtained sooner after administration of the radiopharmaceutical. Induced 4--8-hr-old femoral-vien thrombi in dogs can be well visualized with a scintillation camera as early as 4 hr and as late as 15 hr after administration of 1 mCi of 123I-labeled highly iodinated fibrinogen.