High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study

Debeij, J.; Zaane, Bregje van; Dekkers, Olaf M.; Doggen, Catharina Jacoba Maria; Smit, Johannes W. A.; Zanten, Anton P. van; Brandjes, Dees P. M.; Büller, Harry R.; Gerdes, V.E.A.; Rosendaal, F. R.; Cannegieter, Suzanne C.

doi:10.1111/jth.12573

Cited by 43 publications

(49 citation statements)

References 35 publications

(48 reference statements)

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“…In line with the predominantly clinical studies published so far on this topic [81–85], our proteome analysis demonstrated several proteins involved in the coagulation cascade to exhibit FT 4 -associated plasma levels (Fig. 4); these findings have been published separately [86].…”

Section: Resultssupporting

confidence: 86%

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Pietzner

Engelmann

Kacprowski

et al. 2017

BMC Med

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BackgroundDeterminations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model.MethodsA sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure.ResultsDespite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels.ConclusionOur results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0770-8) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 86%

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Pietzner

Engelmann

Kacprowski

et al. 2017

BMC Med

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“…High levels of fT4 were also associated with the risk of VTE, up to an OR of 2.2 (95% CI 1.0-4.6) for levels above 24.4 pmol/L relative to fT4 levels between 15.5 and 18.9 pmol/L. Low TSH levels were also, but less evidently, associated with thrombosis, while there was no association with antiTPO and VTE risk [19].…”

Section: Rycina 3 Wartości Inr Dla Pacjentów Z Niskim Lub Prawidłowymentioning

confidence: 90%

Koncentracja hormonu tyreotropowego jako niezależny czynnik ryzyka żylnych powikłań zakrzepowo-zatorowych bez względu na czynność tarczycy

Kovářová

Koller

Štvrtinová

et al. 2015

Endokrynologia Polska

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Introduction: Thyroid dysfunction has been recognised as playing a role in the coagulation cascade, but the clinical implications of this phenomenon are unclear. The aim of our study was to assess the predictive power of TSH measurement on the presence or absence of venous thromboembolism (VTE). Material and methods: From January 2009 to August 2012, all consecutive patients hospitalised for suspected VTE were included in the study. VTE was confirmed either by pulmonary angiography or compressive ultrasound. We investigated the predictive power of TSH concentration on the risk of VTE in univariate and multivariate analysis including the existing risk factors (age, D-dimer). Results: A total of 232 patients were eligible for final analysis, with a median age of 70 years (IQR 58-80) and male-to-female ratio of 124:108. VTE was confirmed in 124 patients (53.4%). TSH concentration was significantly higher in cases with VTE (median 2.17 vs. 1.76 mIU/L, p = 0.0104), but free T4 concentrations were not found to be significantly different. Receiver operating curve analysis identified the cut-off of TSH > 2.686 mIU/L as a predictor of VTE with the prevalence of VTE 47.1 vs. 66.7% below and above this cut-off, p = 0.011.

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“…The relatively low values of FT 4 in the population undergoing bariatric surgery are striking [median (IQR): 13 (12-14) pmol/l in both cases and controls]. The median FT 4 level in the study of Debeij et al [8] was 17.7 pmol/l, and in the MEGA Study [1], which was a large case-control study investigating risk factors for VTE, the median FT 4 level was 16.6 pmol/l in the controls. The literature about the association between (morbid) obesity and levels of FT 4 is limited, but it seems that lower levels of FT 4 are associated with higher BMI, suggesting that thyroid function (also within the normal range) could be one of several factors acting in concert to determine body weight in a population [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indicated that thyroid hormone also influences the hemostatic balance and that these changes are associated with a risk of venous thromboembolism (VTE) or bleeding. Higher plasma levels of free thyroxine (FT 4 ) have been associated with an increased VTE risk [1,2,3]. Conversely, lower levels of FT 4 seem to be associated with a bleeding tendency [4,5].…”

Section: Introductionmentioning

confidence: 99%

Plasma Levels of Free Thyroxine and Risk of Major Bleeding in Bariatric Surgery

et al. 2016

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Background: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT₄) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT₄ within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. Methods: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1:4. We evaluated the association between preoperative FT₄ levels and the risk of major bleeding by logistic regression. Results: Seventy-two cases(2.5%) withmajor bleeding were identified and 288 controls were selected. The median plasma level of FT₄ was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT₄ on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT₄ level <11 pmol/l, 1.03 (0.49-2.18) for patients with an FT₄ level <12 pmol/l, and 1.12 (0.65-1.94) for patients with an FT₄ level <13 pmol/l as compared to patients with FT₄ values greater than or equal to these cutoff levels. Interpretation: We did not observe an increased risk of major bleeding with low levels of FT₄ in patients undergoing bariatric surgery.

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High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study

Cited by 43 publications

References 35 publications

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Koncentracja hormonu tyreotropowego jako niezależny czynnik ryzyka żylnych powikłań zakrzepowo-zatorowych bez względu na czynność tarczycy

Plasma Levels of Free Thyroxine and Risk of Major Bleeding in Bariatric Surgery

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