Vitamin K-dependent blood clotting changes in female rats treated with oestrogens

Hexoestrol, diethylstilboestrol and ethinyloestradiol administered orally at a dose of 60 mg/kg/day to groups of five rats caused decreases in vitamin K-dependent blood clotting as measured by the Thrombotest reaction. These changes were self-limiting over a twenty-day study period and were not associated with external signs of bleeding. Pretreatment with testosterone and vitamin K1 did not significantly affect the clotting changes, but the antioestrogen clomiphene citrate exacerbated these, in several cases to lethal effect. Death was associated with haemorrhage. Hexoestrol-treated rats receiving clomiphene citrate in a sub-experiment did not show the increase in liver weight seen in animals given hexoestrol alone. In another sub-experiment, the level of clotting factor VII activity in the plasma of rats receiving hexoestrol at 60 mg/kg/day for four days was shown to be about half that of controls. There was probably no abnormal clotting inhibitor activity. It was deduced that the reduction in factor VII activity was more likely to be due to a decrease in synthesis as a result of liver dysfunction than changes in vitamin K availability. Clomiphene citrate may exacerbate the liver-dependent clotting disorders induced by oestrogens by preventing an adaptive increase in liver mass. It is concluded that the rat is a poor model species for investigating the blood clotting disorders seen in humans treated with oestrogens.