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Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis: A Mendelian Randomization Study.

Accepted version
Peer-reviewed

Type

Article

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Authors

Ellervik, Christina  ORCID logo  https://orcid.org/0000-0002-3088-4375
Mora, Samia 
Marouli, Eirini 

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 [β(SE) = -0.020(0.006), p = 0.001] and with decreased fibrinogen [β(SE) = -0.008(0.002), p = 0.001]. Genetically increased fT4 was associated with increased VWF [β(SE) = 0.028(0.011), p = 0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [β(SE) = 0.012(0.004), p = 0.006] and increased FVIII [β(SE) = 0.013(0.005), p = 0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [β(SE) = -0.009(0.024), p = 0.024] and increased TPA [β(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.

Description

Keywords

coagulation, fibrinolysis, hemostasis, hyperthyroidism, hypothyroidism, thyroid hormone, thyroid peroxidase antibody, thyrotropin, Autoantibodies, Biomarkers, Blood Coagulation, Blood Coagulation Factors, Blood Coagulation Tests, Case-Control Studies, Fibrinolysis, Genetic Predisposition to Disease, Genome-Wide Association Study, Hemostasis, Humans, Hyperthyroidism, Hypothyroidism, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Thyrotropin, Thyroxine, von Willebrand Factor

Journal Title

Thyroid

Conference Name

Journal ISSN

1050-7256
1557-9077

Volume Title

31

Publisher

Mary Ann Liebert Inc

Rights

All rights reserved
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (None)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)