The immediate and late effects of thyroid hormone (triiodothyronine) on murine coagulation gene transcription.

Salam Salloum-Asfar,Pieter H Reitsma,Anita Boelen,Bart J M Van Vlijmen,Eliseo A Eugenin

doi:10.1371/journal.pone.0127469

Abstract

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 (T3) and thyroxine (T4) production. Under these conditions, the impact of exogenous T3 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 T3, dosages of 0 and 0.5 μg T3/mouse/day were selected to study the impact of T3 on coagulation gene transcription. Under these conditions, a single injection of T3 injection increased strongly hepatic transcript levels of the well-characterized T3-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 T3 for 14 days. Prolonged T3 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 T3 injection, and persisted upon prolonged T3 exposure. Two-week T3 administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T3 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 T3.

Highlights

Abnormalities of blood coagulation are common in patients with thyroid dysfunctions
As expected deprivation of thyroid hormone coincided with a dramatic significant reduction of hepatic transcript levels of deiodinase type 1 (Dio1), a well-characterized thyroid hormone response gene (Table 2)
For a selected panel of coagulation genes, thyroid hormone deprivation resulted in marked increases in coagulation transcript levels as compared to normal conditions

Summary

Introduction

Abnormalities of blood coagulation are common in patients with thyroid dysfunctions. In general, hyperthyroidism is associated with a hypercoagulable state and increased risk for venous thrombosis [1,2]. The severity of the disorder determines whether the coagulation profile is shifted towards an anticoagulant or procoagulant state as subclinical hypothyroidism is associated with hypercoagulation whereas patients with overt hypothyroidism have a bleeding tendency [3,4]. Experimental evidence regarding the mechanisms by which thyroid hormones modulate blood coagulation is more limited, and consists mainly of in vitro data showing that triiodothyronine (T3) is able to modulate transcript levels of FGG, factor (F) 2, F10 and SERPINC1, genes encoding fibrinogen-γ, FII, FX and antithrombin respectively [8,9,10]. In vivo studies with thyroid hormone receptor knock-out mice identified Fgg to be modulated by T3, whereas T3 administration in thyroidectomized rats was able to increase Fga (encoding fibrinogen-α), F2 and F10 mRNA levels [6,10]

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