Article Dans Une Revue Pesticide Biochemistry and Physiology Année : 2018

Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats

Résumé

Vitamin K antagonist rodenticide pharmacodynamics (PD) is studied in rodents with traditional laboratory tests. We wondered if thrombin generation test (TGT) could add value. Difethialone (10mg/kg) was administered per os to 97 OFA-Sprague Dawley rats. PD was studied over a 72h-period using the Calibrated Automated Thrombogram on platelet poor plasma before and after intoxication (3 female and 3 male rats for each 13 time points) and TGT parameters were compared with the prothrombin time (PT) and vitamin K dependent factor activities previously reported. Following intoxication, preliminary tests evidenced rapid and full inhibition of thrombin generation triggered with 5 or 20pM human recombinant tissue factor. To study the evolution of TGT parameters following difethialone intake, we adapted the test by complementing intoxicated rat samples with pooled normal rat plasma (3/1, v/v). Adapted TGT confirmed the known higher procoagulant basal level in females compared to males through higher endogenous thrombin potential (ETP) and peak height (PH) (p<0.0001 and p=0.0003, respectively). An exponential model fitted well the PH and ETP decay after intoxication. In contrast to PT, the decreases were observed immediately following VKA intake and had comparable time to halving values: 10.5h (95% CI [8.2; 13.6]) for ETP and 10.4h (95% CI [7.8; 14.1]) for PH. The decrease of FVII and FX preceded that of PH, ETP and FII while FIX decreased later on, contributing to the severe hypo-coagulability. We demonstrated that TGT performed in samples of intoxicated rats complemented with normal plasma is a reliable tool for evaluation of VKA rodenticide PD in rats.

Fichier principal
Vignette du fichier
Jourdi.pdf (652.35 Ko) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)
Licence
Commentaire Mise en page faite par l'auteur à partir de LaTeX
Loading...

Dates et versions

hal-01713957 , version 1 (04-02-2020)

Licence

Identifiants

Citer

Georges Jourdi, Sébastien Lefebvre, Bernard Le Bonniec, Emmanuel Curis, Pascale Gaussem, et al.. Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats. Pesticide Biochemistry and Physiology, 2018, 146, pp.19 - 24. ⟨10.1016/j.pestbp.2018.02.004⟩. ⟨hal-01713957⟩
288 Consultations
507 Téléchargements

Altmetric

Partager

  • More