Effects of thyroid function on hemostasis, coagulation, and fibrinolysis: A mendelian randomization study

Christina Ellervik*, Samia Mora, Aleksander Kus, Bjørn Asvold, Eirini Marouli, Panos Deloukas, Rosalie B.T.M. Sterenborg, Alexander Teumer, Stephen Burgess, Maria Sabater-Lleal, Jennifer Huffman, Andrew D. Johnson, David Alexandre Trégouet, Nicolas L. Smith, Marco Medici, Paul S. DeVries, Daniel I. Chasman, Alisa D. Kjaergaard

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. Methods: In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N = 134,641), normal-range thyrotropin (TSH; N = 54,288) and free thyroxine (fT4) (N = 49,269), hyperthyroidism (N = 51,823), and thyroid peroxidase antibody positivity (N = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (N = 2583–120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided p < 0.05 was nominally significant, and p < 0.0011[ = 0.05/(5 exposures · 9 outcomes)] was Bonferroni significant for the main MR analysis. Results: Genetically increased TSH was associated with decreased VWF [b(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [b(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [b(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [b(SE) = 0.012(0.004), p = 0.006] and increased FVIII [b(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [b(SE) = -0.009(0.024), p = 0.024] and increased TPA [b(SE) = 0.022(0.008), p = 0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive. Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.

Original languageEnglish
Pages (from-to)1305-1315
Number of pages11
JournalThyroid
Volume31
Issue number9
Early online date1 Jul 2021
DOIs
Publication statusPublished - 7 Sept 2021

Bibliographical note

Funding Information:
M.S.-L. is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. S.M. was funded by the National Heart, Lung, and Blood Institute (NHLBI) grant K24HL136852. A.D.J. is supported by the National Heart, Lung, and Blood Institute Intramural funding. P.S.D.V was supported by the American Heart Association grant number 18CDA34110116 and NHLBI grants R01HL141291, R01HL139553, and R01HL134894. The CHARGE Hemostasis Working Group is partially funded by NHLBI grants HL134894 and HL139553. D.-A.T. is partially supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX.

Publisher Copyright:
© Mary Ann Liebert, Inc.

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