Thyroid function and cardiovascular disease: the mediating role of coagulation factors.
Open accessAbstract
CONTEXT: Mechanisms linking high and high-normal thyroid function to increased cardiovascular risk remain unclear. Hypothetically, coagulation can play a role. OBJECTIVE: To investigate (i) the association of thyroid function with coagulation factors and (ii) whether coagulation factors mediate the association of thyroid function with cardiovascular disease (CVD). DESIGN AND SETTING: Rotterdam Study, a population-based prospective study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 5918 participants (mean age, 69.1 years), we measured TSH, free T4 (FT4), and coagulation factors [von Willebrand factor antigen (VWF:Ag), ADAMTS13 activity, fibrinogen]. Participants were followed up for the occurrence of cardiovascular events and deaths. Associations of thyroid function with coagulation factors (standardized z scores) and CVD were assessed through linear regression and Cox proportional hazards models, adjusted for potential confounders. We performed causal mediation analyses to evaluate whether the effect of thyroid function on CVD is mediated by coagulation. RESULTS: Higher FT4 levels were associated with higher VWF:Ag (β = 0.34; 95% CI = 0.22, 0.47), lower ADAMTS13 activity (β = -0.22; 95%CI = -0.35, -0.09), and higher fibrinogen (β = 0.26; 95% CI = 0.13, 0.39); 857 incident cardiovascular events and 690 cardiovascular deaths occurred. FT4 levels were positively associated with cardiovascular events and deaths. The effect of FT4 on incident cardiovascular events was minimally mediated by fibrinogen (1.6%) but not by VWF:Ag and ADAMTS13. VWF:Ag and fibrinogen together mediated 10.0% of the effect of FT4 on cardiovascular deaths. CONCLUSIONS: Higher FT4 levels were associated with higher VWF:Ag, lower ADAMTS13 activity, and higher fibrinogen levels, indicating a procoagulant state. VWF:Ag and fibrinogen explained up to 10% of the link between FT4 and CVD.
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- Authors
- Bano, A., Chaker, L., de Maat, M. P. M., Atiq, F., Kavousi, M., Franco, O. H., Mattace-Raso, F. U. S., Leebeek, F. W. G., & Peeters, R. P.
- Affiliations
- University of Bern (CH)
- Erasmus MC (NL)
- Department of Hematology, Erasmus Medical Center, Rotterdam, Netherlands
- Corresponding author
- Leebeek, Frank W G
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2019-04-02
- Volume
- 104
- Issue
- 8
- Pages
- 3203-3212
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2934586764
- Cited by
- 25
- References
- 43
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 8 · 2020: 5 · 2019: 2
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- CSL Behring
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (VENI 91616079)
- Consultant for UniQure and Shire (fees go to the institution), received unrestricted research grants of CSL Behring and Baxalta (Shire), and travel support from Roche
- ZonMw (Zon-MWTOP grant 91212044)
- Erasmus Medical Center Medical Research Advisory Committee grant
- IBSA and Goodlife Fertility
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- thyroid function, cardiovascular disease, coagulation factors, free thyroxine, von Willebrand factor, ADAMTS13, fibrinogen, procoagulant state, mediation analysis, cardiovascular mortality, cardiovascular events
- MeSH terms
- ADAMTS13 Protein, Aged, Aged, 80 and over, Blood Coagulation, Cardiovascular Diseases, Female, Fibrinogen, Humans, Male, Middle Aged, Prospective Studies, Thyroid Gland, Thyroxine, von Willebrand Factor, Proportional Hazards Models
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