VKORC1 mutations detected in patients resistant to vitamin K antagonists are not all associated with a resistant VKOR activity
Article first published online: 12 DEC 2012
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 10, Issue 12, pages 2535–2543, December 2012
How to Cite
HODROGE, A., MATAGRIN, B., MOREAU, C., FOUREL, I., HAMMED, A., BENOIT, E. and LATTARD, V. (2012), VKORC1 mutations detected in patients resistant to vitamin K antagonists are not all associated with a resistant VKOR activity. Journal of Thrombosis and Haemostasis, 10: 2535–2543. doi: 10.1111/jth.12019
- Issue published online: 12 DEC 2012
- Article first published online: 12 DEC 2012
- Accepted manuscript online: 5 OCT 2012 11:36AM EST
- Received 5 March 2012, accepted 1 October 2012
- anticoagulant resistance;
- catalytic properties;
- Vitamin K antagonists;
Summary. Background: The VKORC1 gene codes for the VKORC1 enzyme, which is responsible for the reduction of vitamin K epoxide into vitamin K. VKORC1 enzyme is the target of vitamin K antagonists (VKA). Twenty-eight rare single mutations in the VKORC1 coding sequence have been reported from resistant patients receiving unusually high doses of VKA to achieve therapeutic anticoagulation.
Objectives: It has been suggested that these mutations are responsible for the resistant phenotype, while biochemical consequences of these mutations on the VKORC1 enzyme have not yet been evaluated. Therefore, the aim of this study was to investigate the causality of the VKORC1 mutations in the resistance phenotype.
Methods: Wild-type VKORC1 and its spontaneous mutants were expressed in Pichia pastoris and susceptibility to VKA was assessed by the in vitro determination of kinetic and inhibition constants.
Results and Conclusions: The in vitro analysis revealed that six mutations only (A26P, A41S, V54L, H68Y, I123N and Y139H) were associated with increase in Ki, suggesting their involvement in the resistance phenotype observed in patients. A41S and H68Y led to selective resistance, respectively, to indane-1,3-dione and 4-hydroxycoumarine derivatives. The other mutations did not increase the Ki. Furthermore, 10 mutations (S52L, S52W, W59L, W59R, V66M, V66G, G71A, N77S, N77T and L128R) led to an almost complete loss of activity. These results suggest the existence of other resistance mechanisms.