Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study

Zaane, Bregje van; Squizzato, Alessandro; Debeij, J.; Dekkers, Olaf M.; Meijers, Joost C. M.; Zanten, Anton P. van; Büller, Harry R.; Gerdes, Victor E. A.; Cannegieter, Suzanne C.; Brandjes, Dees P. M.

doi:10.1111/j.1538-7836.2011.04430.x

Cited by 45 publications

(54 citation statements)

References 38 publications

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“…Indeed, it was recently demonstrated by the MEGA study that patients with increased fT 4 levels possess an up to twofold higher risk for venous thrombosis and/or pulmonary embolism [6]. The effect of levothyroxine exposure on coagulation and fibrinolysis has already been addressed specifically in a controlled randomized crossover study in healthy volunteers [7]. Upon increase in free thyroxine, increased levels of procoagulant coagulation factors including FIX were observed, an observation that was confirmed in our study.…”

Section: Discussionsupporting

confidence: 75%

Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study

Engelmann¹,

Bischof²,

Dirk³

et al. 2015

Eur Thyroid J

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Background: Hyperthyroidism is known toinduce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT₄ levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT₄, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.

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Section: Discussionsupporting

confidence: 75%

Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study

Engelmann¹,

Bischof²,

Dirk³

et al. 2015

Eur Thyroid J

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show abstract

“…However, not all details were matching. For example, in contrast to the data of van Zaane et al [7] , levels of von Willebrand factor did not change in our study. The differences observed for specific coagulation factors might reflect different stages of thyrotoxicosis and/or different properties of the assay methods used.…”

Section: Discussioncontrasting

confidence: 56%

“…However, global plasma protein profiling disclosed protein alterations besides the typical proteins studied for the evaluation of coagulation and fibrinolysis [7] . Thus, another interesting finding was the increase in serpin A5 (protein C inhibitor), which is a potent inhibitor of activated protein C [8,9] .…”

Section: Discussionmentioning

confidence: 99%

Effect of experimental thyrotoxicosis onto blood coagulation – A proteomics study

Engelmann

Bischof

Dirk

et al. 2015

Exp Clin Endocrinol Diabetes

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protein abundances and fT 4 levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT 4 , supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.

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“…An alternative explanation is that the observed effect of AIT on stroke was caused by thyroxine treatment because thyroxine can have a procoagulant effect. 34 However, if the observed effect was due to thyroxine, we might expect to have seen the excess stroke risk restricted to the period soon after start of treatment, whereas the risk remained increased 6 to 12 months after diagnosis in our study. Moreover, a thyroxine-mediated effect might also be expected to generate short-term differences in incidence of AF between patients with AIT and individuals without AIT because thyroxine in high doses can induce AF; this was not the case.…”

Section: Discussionmentioning

confidence: 50%

Autoimmune thyroiditis as a risk factor for stroke

Karch

Thomas

2014

Neurology

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Objective:To investigate the effect of autoimmune thyroiditis (AIT) on risk of stroke and to assess whether any increased risk (1) varied by AIT duration, and (2) was independent of classic cardiovascular risk factors.Methods:This was a large historical cohort study using data from The Health Improvement Network Database. Rates of first stroke during follow-up in thyroxine-treated patients with AIT (n = 34,907) were compared with those in matched individuals without AIT (n = 149,632) using random-effects Poisson regression models.Results:There was strong evidence for a slightly increased risk of stroke in patients with AIT (adjusted rate ratio = 1.10, 95% confidence interval: 1.01–1.20). The observed increase was partly independent of cardiovascular risk factors. Higher effect sizes were identified in the first year after AIT diagnosis (rate ratio = 1.33, 95% confidence interval: 1.14–1.56) but not in the long-term, consistent with a residual effect of hypothyroidism.Conclusion:Our results support the hypothesis of a slightly increased risk of stroke in patients with AIT. The higher effect size found soon after AIT diagnosis suggests an increased cardiovascular risk due to thyroid-hormone deficiency rather than a cumulative effect of autoimmune pathology. Better screening and early treatment of patients with asymptomatic hypothyroid AIT could help reduce excess risk of stroke in the first year after diagnosis.

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Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study

Cited by 45 publications

References 38 publications

Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study

Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study

Effect of experimental thyrotoxicosis onto blood coagulation – A proteomics study

Autoimmune thyroiditis as a risk factor for stroke

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