Antithrombin ‘DREUX’ (Lys114Glu): A Variant with Complete Loss of Heparin Affinity

Alec Mushunje; Aiwu Zhou; James A. Huntington; Jacqueline Conard; Robin W. Carrell

doi:10.1055/s-0037-1613235

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 88(03): 436-443
DOI: 10.1055/s-0037-1613235

Review Article

Schattauer GmbH

Antithrombin ‘DREUX’ (Lys114Glu): A Variant with Complete Loss of Heparin Affinity

Alec Mushunje^*

¹Department of Haematology, University of Cambridge, Cambridge, Institute of Medical Research, Hills Road, Cambridge, UK

,

Aiwu Zhou^*

¹Department of Haematology, University of Cambridge, Cambridge, Institute of Medical Research, Hills Road, Cambridge, UK

,

James A. Huntington

¹Department of Haematology, University of Cambridge, Cambridge, Institute of Medical Research, Hills Road, Cambridge, UK

,

Jacqueline Conard

¹Department of Haematology, University of Cambridge, Cambridge, Institute of Medical Research, Hills Road , ambridge, UK Hemost asis and Thrombosis Unit, Hôtel-Dieu, Paris, France

,

Robin W. Carrell

¹Department of Haematology, University of Cambridge, Cambridge, Institute of Medical Research, Hills Road, Cambridge, UK

› Institutsangaben

Abstract

Summary

Here we report the finding of a new natural antithrombin mutation that confirms the critical contribution of lysine 114 to the binding of the core heparin pentasaccharide, with the replacement of lysine 114 by glutamate causing a complete loss in affinity. The variant was identified in a father and son, the father having been investigated for an episode of cerebral ischaemia associated with hypercholesterolaemia. The variant forms SDS-stable complexes with activated factor X (fXa) and its thermal stability and rate of factor Xa inhibition in the absence of heparin are identical to those of normal antithrombin. Normal antithrombin binds to the high affinity heparin pentasaccharide with a Kd of 1nM, as detected by a 45% change in intrinsic fluorescence, resulting in a 230-fold increase in rate of factor Xa inhibition. However, no change in fluorescence was detected for the variant when titrated with heparin or the heparin pentasaccharide, nor was there detectable activation towards factor Xa, indicating a complete loss of heparin binding.

Keywords

Antithrombin - heparin - thrombosis - mutant - serpin

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References
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