The Immediate and Late Effects of Thyroid Hormone (Triiodothyronine) on Murine Coagulation Gene Transcription

Thyroid dysfunction is associated with changes in coagulation. The aim of our study was to gain more insight into the role of thyroid hormone in coagulation control. C57Black/6J mice received a low-iodine diet and drinking water supplemented with perchlorate to suppress endogenous triiodothyronine (T(3)) and thyroxine (T(4)) production. Under these conditions, the impact of exogenous T(3) on plasma coagulation, and hepatic and vessel-wall-associated coagulation gene transcription was studied in a short- (4 hours) and long-term (14 days) setting. Comparing euthyroid conditions (normal mice), with hypothyroidism (conditions of a shortage of thyroid hormone) and those with replacement by incremental doses of T(3), dosages of 0 and 0.5 μg T(3)/mouse/day were selected to study the impact of T(3) on coagulation gene transcription. Under these conditions, a single injection of T(3) injection increased strongly hepatic transcript levels of the well-characterized T(3)-responsive genes deiodinase type 1 (Dio1) and Spot14 within 4 hours. This coincided with significantly reduced mRNA levels of Fgg, Serpinc1, Proc, Proz, and Serpin10, and the reduction of the latter three persisted upon daily treatment with T(3) for 14 days. Prolonged T(3) treatment induced a significant down-regulation in factor (F) 2, F9 and F10 transcript levels, while F11 and F12 levels increased. Activity levels in plasma largely paralleled these mRNA changes. Thbd transcript levels in the lung (vessel-wall-associated coagulation) were significantly up-regulated after a single T(3) injection, and persisted upon prolonged T(3) exposure. Two-week T(3) administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T(3) has specific effects on coagulation, with Fgg, Serpinc1, Proc, Proz, Serpin10 and Thbd responding rapidly, making these likely direct thyroid hormone receptor targets. F2, F9, F10, F11, F12, Vwf, Tf and Tfpi are late responding genes and probably indirectly modulated by T(3).