Fluctuations in Thyroid Hormone Levels During Initial Treatment for Differentiated Thyroid Carcinoma are Associated with Changes in Hemostasis: A Prospective Cohort Study

Background: During treatment for differentiated thyroid carcinoma (DTC), patients go from euthyroidism to severe hypothyroidism to subclinical hyperthyroidism induced by thyroid hormone suppression therapy (THST). Severe hypothyroidism may induce a tendency toward bleeding, whereas hyperthyroidism is thrombogenic. Therefore, treatment for DTC may increase the risk of bleeding during thyroid hormone withdrawal, and thrombosis during THST. This study aims to provide prospective analysis of changes in the hemostatic system from euthyroidism to hypothyroidism, and during THST, in patients treated for DTC. Methods: This is a secondary study in a larger Dutch prospective cohort. Consecutive samples were obtained from 20 patients (18 female [90%]; median age 48 [interquartile range 35.8-56.5] years) throughout their treatment for DTC during euthyroidism (n = 5), severe hypothyroidism (n = 20), and THST (n = 20). We measured selected hemostatic proteins and C-reactive protein (CRP), performed functional tests of hemostasis (a thrombin generation test and a plasma-based clot lysis test), and assessed markers of in vivo activation of hemostasis (thrombin-antithrombin complexes, plasmin-antiplasmin [PAP] complexes, and D-dimer levels). Results: During hypothyroidism, the majority of measured parameters did not change. During THST, plasma levels of nearly all measured hemostatic proteins were higher than during hypothyroidism. Additionally, CRP significantly increased from 1.3 (0.5-3.3) to 3.2 (1.3-5.1) mg/L during THST (p < 0.01). Ex vivo thrombin generation increased from 626.0 (477.0-836.3) to 876.0 (699.0-1052.0) nM × min (p = 0.02), and ex vivo clot lysis time increased from 60.6 (55.6-67.4) to 76.0 (69.7-95.0) minutes during THST (p < 0.01). PAP levels reduced from 266.5 (211.8-312.0) to 192.0 (161.0-230.0) μg/L during THST (p < 0.01); other markers of in vivo activation of coagulation remained unaffected. Conclusions: During THST-induced hyperthyroidism, a shift toward a more hypercoagulable and hypofibrinolytic state occurred. However, in vivo activation of hemostasis did not increase. The rise in CRP levels suggests the presence of a low-grade inflammation in patients during THST. Both a hypercoagulable and hypofibrinolytic state and a low-grade inflammation are associated with an increased risk of cardiovascular diseases (CVD). Therefore, the subtle changes found during THST could potentially play a role in the pathogenesis of CVD as observed in DTC patients. Clinical Trial Registration: This study is part of a larger clinical trial registered at the Netherlands Trial Register (NTR ID 7228).