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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3388-3396
Formation of the Antithrombin Heterodimer In Vivo and the Onset of
Thrombosis
Aiwu Zhou,
James A. Huntington, and
Robin W. Carrell
From the University of Cambridge Department of Haematology, Cambridge
Institute for Medical Research, Cambridge, UK.
Antithrombin is shown to undergo a slow spontaneous conversion to
its inactive latent conformation with readily discernible amounts
present in plasma on incubation at 37°C for 72 hours. More rapid
conversion occurs on incubation of isolated antithrombin at 41°C or
50°C, but the appearance on electrophoresis of free latent
antithrombin is preceded by the formation, in reciprocal proportions,
of a new slow band. This slow component is shown to be a heterodimer of
active and latent antithrombin. It can be isolated as a single stable
band either by incubation of antithrombin or by mixing equimolar
proportions of active and latent antithrombin under the same conditions
that give overnight crystallization of the active/latent antithrombin
heterodimer. Similarly, equimolar addition of latent antithrombin to
plasma results electrophoretically in a quantitative shift to the
slower heterodimer mobility. Clinically, the presence of latent
antithrombin is potentially deleterious, because its linkage to form
the heterodimer results in inactivation of the otherwise normal
molecule linked to the latent antithrombin. In the case of
 -antithrombin, because the dimer readily dissociates, there is only
a 11% additive loss of activity, but with  -antithrombin the dimer
appears more stable, with the additive loss of activity from the normal
component being 21%, increasing to 33% on stabilization of the
dimer with heparin. This linked and selective loss of activity of
-antithrombin provides an explanation for the unexpected severity of
thrombotic episodes in heterozygotes with conformationally unstable antithrombins.
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