The effect of changes in thyroxine and thyroid-stimulating hormone levels on the coagulation system.

Abstract

Introduction: Thyroid dysfunction is known to affect levels of factor VIII, von Willebrand factor and fibrinogen. Although altered coagulation parameters are related to levels of thyroid hormone, this is possibly partially mediated by thyroid stimulating hormone (TSH). Our aim was to examine the effect of TSH and free thyroxine (FT4) on coagulation factors, with a focus on factor VIII (FVIII), von Willebrand factor (VWF) and fibrinogen. Methods: In patients successfully treated for well-differentiated thyroid carcinoma, either levothyroxine was withdrawn for 4 weeks (n=11) or recombinant TSH was administered (n=17) to stimulate thyroglobulin production. We measured levels of FVIII, VWF and fibrinogen, besides prothrombin, factor VII, factor IX, antithrombin, protein C and S, prothrombin fragment 1+2 and thrombin-antithrombin complex on two different occasions. Results: In patients who changed from hypothyroidism to a slightly hyperthyroid state, a rise in FVIII (+39.1 U/dL), VWF (+32.0 U/dL), and fibrinogen (+0.6 g/L) was found. In patients in whom stable FT4 levels accompanied rising levels of TSH, no effect on coagulation parameters was observed. Conclusions: The results of our study suggest that increasing levels of free thyroxine are associated with a rise in FVIII, VWF, and fibrinogen levels. This shift is not mediated by TSH. Introduction Thyroid dysfunction is known to affect the coagulation system. In patients with overt hypothyroidism, an increased bleeding time, prolonged prothrombin time and activated partial thromboplastin time, as well as decreased levels of factor VIII (FVIII), fibrinogen and von Willebrand factor (VWF) have been observed, occasionally leading to a bleeding tendency, similar to acquired von Willebrand’s disease. After adequate suppletion with levothyroxine, these coagulation factors return to normal levels. In hyperthyroidism, elevated levels of VWF and fibrinogen have consistently been observed. These changes in coagulation parameters may have clinical implications, such as an increased risk of venous thrombosis in hyperthyroidism. Although the altered coagulation parameters are related to levels of thyroid hormone, it is possible that the effect on coagulation is either completely or partially mediated by thyroid stimulating hormone (TSH, or thyrotropin). We set out to examine and disentangle the effect of changes in TSH and serum free thyroxine (FT4) levels on FVIII, VWF and fibrinogen, which are the coagulation factors for which an effect of thyroid hormones is best documented. In addition, we studied other coagulation factors to explore whether they were influenced by FT4 and TSH levels. We had the opportunity to study the separate effects of these hormones in two series of patients successfully treated for well-differentiated thyroid carcinoma. For follow-up, serum thyroglobulin (TG) level is used as a tumour marker. To assess serum thyroglobulin levels in a maximally stimulated condition, high levels of TSH are induced. This can be achieved either by withdrawal of levothyroxine for several weeks, or by the administration of recombinant human TSH (rhTSH) while continuing levothyroxine treatment. Measuring coagulation factors at different stages in both TG stimulating protocols can provide clues whether changes in levels of FT4 or TSH affect the coagulation system. Materials and Methods Study population Patients successfully treated for differentiated thyroid carcinoma by surgery and radioactive iodine ablation of the residual thyroid gland were derived from a larger study on the influence of thyroid hormone on metabolism and gene expression in relation to heart rate and blood pressure. Prior to a TSH-stimulated diagnostic protocol, consisting of either thyroxine withdrawal or recombinant TSH injection, patients from the Department of Endocrinology of the Leiden University Medical Centre, Leiden, the Netherlands (a tertiary referral centre for differentiated thyroid carcinoma) were asked to participate in the study. In all patients, successful treatment was defined as the absence of measurable serum TG levels during TSH stimulation and negative total-body scintigraphy. Patients with a haemoglobin level below 7.1 mmol/L, recent blood donation, diabetes mellitus, a body mass index above 35 kg/m, pregnancy, or other endocrine disorders, as well as postmenopausal women were excluded, in addition to patients using any drugs known to influence coagulation. In total, 12 patients undergoing thyroxine withdrawal and 17 patients receiving rhTSH were eligible for the present analysis.