Origin of the gender differences of the natural resistance to antivitamin K anticoagulants in rats

Sébastien Lefebvre (1) , Benoit Rannou (1) , Stéphane Besse (1) , Etienne Benoit (1) , Virginie Lattard (1)

1 RS2GP - Rongeurs Sauvages, Risques Sanitaires et Gestion des Populations - UR 1233

Vitamin K antagonists (VKA) are used either in human medicine to prevent thromboembolic disorders oras rodenticides for pest control management. In rodents, female rats are described to be more tolerant tothe action of vitamin K antagonists than males. Nevertheless, the mechanism of this greatest tolerance isstill unknown and this study aims to identify the origin of this greatest tolerance after VKAadministration. Therefore, difethialone, one of the most powerful VKA was used in this study.A possible difference in the pharmacokinetics of difethialone between males and females wasfirstinvestigated. The determination of the pharmacokinetic parameters allowed to exclude a pharmacokineticorigin of the greatest tolerance of females to VKA. Thus, a natural resistance to difethialone of theliver VKOR activity, which is the target of VKA, was thus explored in females. The determination of Kitowards difethialone in liver microsomes allowed to also exclude this hypothesis. Therefore, equipmentin vitamin K-dependent clotting factors and properties of vitamin K-dependent clotting factors wereexplored. Basal activity of clotting factors VII and X were found significantly higher in females ofrespectively 43% and 21%. Moreover, after VKA administration, half-lives of clotting factors II and X werefound significantly longer in females of respectively 27% and 10% and a lag time of 4 h before thebeginning of the decay of factor VII was observed only in females after difethialone administration. Thegreater tolerance of female rats to VKA is thus due a stronger basal pool of vitamin K-dependent clottingfactors VII and X and to a slower decline of vitamin K-dependent clotting factors II, VII and X after VKAadministration.

Mots clés: vitamin K antagonist; Difethialone; susceptibility; rat; gender differences; Sex & gender; Rattus norvegicus; Coagulation; Coagulation Cascade; Clotting factor activity; Clotting Time CT

Domaines: Médecine vétérinaire et santé animale; Biochimie [q-bio.BM]; Ecotoxicologie; Toxicologie et chaîne alimentaire

Sébastien Lefebvre, Benoit Rannou, Stéphane Besse, Etienne Benoit, Virginie Lattard. Origin of the gender differences of the natural resistance to antivitamin K anticoagulants in rats. Toxicology, 2016, 344, pp.34-41. ⟨10.1016/j.tox.2016.02.002⟩. ⟨hal-01503380⟩