Catabolism and distribution of functionally heterogeneous human antithrombin III

To test the hypothesis that binding to an endogenous heparin-like substance controls breakdown of antithrombin III (ATIII) in vivo, the metabolic behavior of a commercial ATIII concentrate was investigated in three normal volunteers and five subjects with hereditary ATIII deficiency. The concentrate, purified to homogeneity as evidenced by sodium dodecyl sulfate--gel electrophoresis, was a 2:1 mixture of functional ATIII with heparin cofactor activity and dysfunctional ATIII incapable of binding enzymes or heparin. Each subject received intravenously a dose of 75 U/kg of ATIII activity together with iodine 125-labeled tracer. Daily fractional catabolic rates calculated from the three-exponential disappearance curves of plasma radioactivity were similar in all investigated subjects and were within the range obtained in studies using functionally homogeneous tracer. Although all subjects had markedly increased ATIII levels after injection of the concentrate, the relative sizes of their ATIII distribution pools resembled those reported previously for people with normal ATIII concentration. There was, however, a noticeably faster disappearance from plasma of excess functional ATIII compared with that of ATIII antigen, with mean half-lives of 47.5 +/- 9 hours and 62.3 +/- 8 hours, respectively. Assuming that antigenic ATIII represented both functional inhibitor and dysfunctional ATIII incapable of binding heparin, these data are consistent with the supposition that interaction with endogenous heparin or a similar substance may regulate a catabolic pathway marking ATIII for destruction.