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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2696-2706
RAPID COMMUNICATION
Antithrombins Wibble and Wobble (T85M/K): Archetypal Conformational
Diseases With In Vivo Latent-Transition, Thrombosis, and Heparin
Activation
N.J. Beauchamp,
R.N. Pike,
M. Daly,
L. Butler,
M. Makris,
T.R. Dafforn,
A. Zhou,
H.L. Fitton,
F.E. Preston,
I.R. Peake, and
R.W. Carrell
From the Division of Molecular and Genetic Medicine, University of
Sheffield, Royal Hallamshire Hospital, Sheffield, UK; and the
Department of Haematology, University of Cambridge, MRC Centre,
Cambridge, UK.
The inherent variability of conformational diseases is demonstrated
by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the
main  -sheet of the molecule and its replacement, by the polar
lysine, in antithrombin Wobble, resulted in a plasma deficiency of
antithrombin with an uncharacteristically severe onset of thrombosis at
10 years of age, whereas the replacement of the same residue by a
nonpolar methionine, antithrombin Wibble, gave near-normal levels of
plasma antithrombin and more typical adult thromboembolic disease.
Isolated antithrombin Wibble had a decreased thermal stability (Tm
56.2, normal 57.6°C) but was fully stabilized by the heparin
pentasaccharide (Tm 71.8, normal 71.0°C), indicating that the prime
abnormality is a laxity in the transition of the main sheet of the
molecule from the 5- to 6-stranded form, as was confirmed by the ready
conversion of antithrombin Wibble to the 6-stranded latent form on
incubation. That this transition can occur in vivo was shown by the
finding of nearly 10% of the proband's plasma antithrombin in the
latent form and also, surprisingly, of small but definitive amounts of
latent antithrombin in normal plasma. The latent transition will be
predictably accelerated not only by gross mutations, as with
antithrombin Wobble, to give severe episodic thrombosis, but also
by milder mutations, as with antithrombin Wibble, to trigger thrombosis
in the presence of other predisposing factors, including the
conformational stress imposed by the raised body temperatures of
fevers. Both antithrombin variants had an exceptional (25-fold)
increase in heparin affinity and this, together with an increased
inhibitory activity against factor Xa, provides evidence of the direct
linkage of A-sheet opening to the conformational basis of heparin
binding and activation.
© 1998 by The American Society of Hematology.
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