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Plasma-antithrombin-III (AT-III) concentrations were measured throughout therapy in 24 patients receiving continuous intravenous heparin infusion and in 2 patients treated with repeated intravenous heparin injections. In all patients, including 1 with congenital AT-III deficiency, heparin therapy was associated with a considerable progressive reduction in AT-III-binding capacity and antigenic protein. The net individual decrease in plasma-AT-III was 0-31 +/- 0-05 units/ml (normal plasma-AT-III was 1-00 units/ml) or 9-5 +/- 2-0 mg/dl and the decrease was independent of initial concentration. Plasma-AT-III returned to normal two to three days after heparin was stopped. There was no decrease in plasma-AT-III after a single dose of intravenous heparin. When present in blood for long periods heparin significantly reduced AT-III, the proteinase inhibitor that is responsible for the anticoagulant effect of this drug. The finding is very relevant to the interpretation of clinical data in patients treated with heparin and suggests that AT-III depletion may underly the thromboembolic complications sometimes encountered during heparin therapy.

A procedure is described for performing a functional assay of serum antithrombin activity. The method consists of adding serum to a thrombin solution and measuring, after a fixed incubation time, the residual thrombin activity on a substrate plasma. The mean serum antithrombin activity found in 96 healthy blood donors using this procedure was 109.5% (range 82%-160%). The method was linear over an activity range between 30.5% and 176%, was significantly correlated with antithrombin-III protein concentration determined by radial immunodiffusion (r = 0.86, P less than 0.01), and showed good reproducibility (coefficient of variation 2.7%). On account of its simplicity and precision this functional assay should be of considerable use in evaluating hypercoagulability.