Document Detail

Antithrombin-TRI (Ala382 to Thr) causing severe thromboembolic tendency undergoes the S-to-R transition and is associated with a plasma-inactive high-molecular-weight complex of aggregated antithrombin.
MedLine Citation:
PMID:  7734359     Owner:  NLM     Status:  MEDLINE    
An antithrombin (AT) variant Ala382 to Thr (AT-TRI) was identified by mass spectrometric techniques. The variant behaved as a substrate rather than a thrombin inhibitor, but, contrary to previously described P12 AT variants, AT-TRI, expressed as a heterozygous dominant trait, caused severe thromboembolic tendency beginning in their teens in affected members of an English family. In addition, it underwent the S-to-R conformational state transition as evidenced by an increased resistance to thermal denaturation on active centre cleavage, but did not react with a monoclonal antibody, 4C9, directed against a neoepitope that is present on complexed and cleaved normal AT. Antithrombin-TRI, in plasma, was also associated with an abnormal high molecular weight (M(r)) 194,000) component composed of non-covalently-linked antithrombin molecules. This component (D194) showed low affinity for heparin and was devoid of antithrombin progressive activity. D194, isolated by ammonium sulphate precipitation and three chromatographic steps (heparin Sepharose, ion exchange and immunoaffinity), migrated as a single band of M(r) 60,000 on SDS-PAGE under both reducing and non-reducing conditions and was recognized by monospecific anti-human antithrombin antibodies, but did not immunoreact with antibodies raised against a number of proteins including albumin and thrombin. The above data and the fact that the 15 N-terminal amino acids of this M(r) 60,000 band were identical to that of normal antithrombin indicated that the inactive D194 component was composed of aggregated antithrombin molecules, possibly antithrombin trimers. In conclusion, early adulthood severe thromboembolic tendency, failure to expose the 4C9 epitope, and presence of aggregated AT molecules in the plasma are characteristic features of AT-TRI not previously described in other ALA-382 THR mutations.
V S Lindo; V V Kakkar; M Learmonth; E Melissari; F Zappacosta; M Panico; H R Morris
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of haematology     Volume:  89     ISSN:  0007-1048     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-06-02     Completed Date:  1995-06-02     Revised Date:  2009-09-29    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  589-601     Citation Subset:  IM    
Thrombosis Research Institute, London.
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MeSH Terms
Amino Acid Sequence
Antibodies, Monoclonal
Antithrombins / chemistry,  genetics*,  isolation & purification
Blotting, Western
Cyanogen Bromide
Disease Susceptibility
Electrophoresis, Polyacrylamide Gel
Hot Temperature
Mass Spectrometry
Middle Aged
Molecular Sequence Data
Molecular Weight
Point Mutation*
Protein Denaturation
Thrombosis / blood,  genetics*
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antithrombins; 506-68-3/Cyanogen Bromide
Comment In:
Br J Haematol. 1996 May;93(2):253-7   [PMID:  8639413 ]

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