The conformational basis of thrombosis.
Antithrombin readily undergoes a spontaneous transition from its active five-stranded form to a six-stranded inactive latent form. The recognition of this change in plasma has been obscured by the immediate linkage of newly formed latent antithrombin to a molecule of active antithrombin to give a dimer with an electrophoretic mobility readily confused with that of native active antithrombin. A new micromethod now allows unequivocal identification of latent antithrombin in whole plasma. This shows that at 37 degrees C some 10% of plasma antithrombin is converted to the latent form in 24 h. The rate of conversion is greatly accelerated at increased temperatures, as occurs in the pasteurisation of plasma concentrates that should now be checked for efficacy. But increased transition also occurs in the plasma at the slightly increased temperatures that accompany incidental infections. This is of particular significance if there is a conformationally unstable variant of antithrombin; here fever can provoke a sudden transition with the onset of a characteristically severe episode of thromboembolism. Such variants are not rare and include those previously classified as pleiotropic. The precise structural pathway, now known with antithrombin, provides a model of the changes occurring in other conformational diseases, including Alzheimer's and the prion dementias.
Carrell
R W
RW
Department of Haematology, University of Cambridge, Wellcome Trust Centre for Molecular Mechanisms in Disease, UK. rwc1000@cam.ac.uk
Huntington
J A
JA
Mushunje
A
A
Zhou
A
A
D000991:Antithrombins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics; D005334:Fever / Q000150:complications; D014644:Genetic Variation; D006801:Humans; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry; D013696:Temperature; D013927:Thrombosis / Q000209:etiology*
D000991:Antithrombins; D015843:Serpins