Clinical Drug Investigation

, Volume 37, Issue 10, pp 929–936 | Cite as

Assessment of the Impact of l-Thyroxine Therapy on Bleeding Risk in Patients Receiving Vitamin K Antagonists

  • Farès Moustafa
  • Rémi Malhomme
  • Bruno Pereira
  • Alain Barres
  • Jennifer Saint-Denis
  • Frederic Dutheil
  • Marie Batisse
  • Jeannot Schmidt
Original Research Article



Several studies have suggested a link exists between l-thyroxine and the coagulation system, and, according to some drug interaction studies, l-thyroxine can potentiate the effect of warfarin. This study sought to assess whether thyroid hormone therapy could impact the risk of bleeding in patients receiving vitamin K antagonists (VKAs).


We conducted a monocentric, retrospective study on prospectively collected data from consecutive patients enrolled in the Registry of patient with AntiThrombotic agents admitted to an Emergency Department (RATED) database, and compared the hemorrhage rates (both major and nonmajor) of patients receiving treatment with and without l-thyroxine. Propensity score matching analysis was performed to reduce the differences between patients receiving l-thyroxine and those not receiving l-thyroxine in order to reassess bleeding outcomes in patients receiving VKAs.


From January 2014 to June 2015, 1454 patients receiving VKAs were recruited into the RATED database. Overall, 187 patients (12.8%) received l-thyroxine. Patients receiving l-thyroxine were more likely to be female than those not receiving l-thyroxine (78.1 vs. 55%) and more likely to exhibit hypertension (65.5 vs. 55.7%; p = 0.015), but less likely to have history of myocardial infarction (9.6 vs. 16.6%; p = 0.022) or higher creatinine levels (96.1 vs. 112.1 μmol/L; p = 0.04). After propensity score matching, bleeding outcomes were not significantly different between patients receiving l-thyroxine and those not receiving l-thyroxine.


Our study revealed no evidence that l-thyroxine could increase bleeding risk in patients receiving VKAs. However, physicians must be aware that patients with thyroid disease receiving VKA therapy could have other drug interactions, particularly with amiodarone therapy. number




All authors had full access to all study data (including statistical reports and tables) and bear responsibility for data integrity and accuracy. In addition, all authors were involved in the critical revision of the manuscript with regard to its primary intellectual content, and approved the final version submitted for publication.

Author Contributions

FM contributed to the design, analysis and interpretation of data, collected patients, and wrote the article. RM contributed to the interpretation of data, collected patients, and approved the final version of the article. BP contributed to statistical analysis and interpretation of data, and approved the final version of the article. AB contributed to the extraction of data and approved the final version of the article. JS-D contributed to the interpretation of data, collected patients, and approved the final version of the article. FD contributed to the interpretation of data, collected patients, and approved the final version of the article. MB contributed to the interpretation of data and approved the final version of the article. JS contributed to the design, analysis and interpretation of data, collected patients, and approved the final version of the article.

Compliance with Ethical Standards

Conflict of interest

Dr. Moustafa has served as a consultant for Bayer HealthCare Pharmaceuticals and Sanofi, has been a speaker for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Daiichi-Sankyo and Sanofi, and has received grants from Sanofi, Bayer HealthCare, and LFB. Dr. Schmidt has received payments for board membership from Bayer, Daichi, Lilly, and Pfizer, as well as personal compensation from Biomerieux, Bohringer Ingelheim, Sanofi, and Novartis. Rémi Malhomme, Bruno Pereira, Alain Barres, Jennifer Saint-Denis, Frederic Dutheil, and Marie Batisse have no conflicts of interest relevant to the contents of this paper.


No specific grants were received from any funding agency in the public, commercial, or not-for-profit sectors for this research.


  1. 1.
    Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–67.CrossRefPubMedGoogle Scholar
  2. 2.
    Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schunemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):7S–47S.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rubboli A, Becattini C, Verheugt FW. Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy. World J Cardiol. 2011;3:351–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):257S–98S.CrossRefPubMedGoogle Scholar
  5. 5.
    Becattini C, Franco L, Beyer-Westendorf J, Masotti L, Nitti C, Vanni S, et al. Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life. Int J Cardiol. 2017;227:261–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Casais P, Sánchez Luceros A, Meschengieser S, Fondevila C, Santarelli MT, Lazzari MA. Bleeding risk factors in chronic oral anticoagulation with acenocoumarol. Am J Hematol. 2000;63:192–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Klok FA, Hösel V, Clemens A, Yollo WD, Tilke C, Schulman S, et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J. 2016;35:e419S–94S.Google Scholar
  8. 8.
    Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999;159:457–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Ruíz-Giménez N, Suárez C, González R, Nieto JA, Todolí JA, Samperiz AL, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. findings from the RIETE Registry. Thromb Haemost. 2008;100:26–31.PubMedGoogle Scholar
  10. 10.
    Pisters R, Lane DA, Nieuwlaat R, De Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–100.CrossRefPubMedGoogle Scholar
  11. 11.
    Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105:91–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Debeij J, Cannegieter SC, van Zaane B, van Zanten AP, Rosendaal FR, Gerdes VEA, et al. Major haemorrhage during vitamin K antagonist treatment: the influence of thyroid hormone levels. Eur Thyroid J. 2014;3:32–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Squizzato A, Romualdi E, Büller HR, Gerdes VEA. Clinical review: thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab. 2007;92:2415–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A, Gé A, et al. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J Clin Endocrinol Metab. 2016;86:732–7.CrossRefGoogle Scholar
  15. 15.
    Franchini M, Montagnana M, Manzato F, Vescovi PP. Thyroid dysfunction and hemostasis: an issue still unresolved. Semin Thromb Hemost. 2009;35:288–94.CrossRefPubMedGoogle Scholar
  16. 16.
    Debeij J, Cannegieter SC, Van Zaane B, Smit JWA, Corssmit EPM, Rosendaal FR, et al. The effect of changes in thyroxine and thyroid-stimulating hormone levels on the coagulation system. J Thromb Haemost. 2010;8(12):2823–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Yango J, Alexopoulou O, Eeckhoudt S, Hermans C, Daumerie C. Evaluation of the respective influence of thyroid hormones and TSH on blood coagulation parameters after total thyroidectomy. Eur J Endocrinol. 2011;164:599–603.CrossRefPubMedGoogle Scholar
  18. 18.
    Hylek EM. Paracetamol (acetaminophen) and warfarin interaction: unraveling the pivotal role of the vitamin K cycle. Thromb Haemost. 2004;92:672–3.PubMedGoogle Scholar
  19. 19.
    Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e44S–88S.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Erem C, Kavgaci H, Ersöz HO, Hacihasanoglu A, Ukinç K, Karti SS, et al. Blood coagulation and fibrinolytic activity in hypothyroidism. Int J Clin Pract. 2003;57:78–81.PubMedGoogle Scholar
  21. 21.
    Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab. 2007;92:3006–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Marongiu F, Barcellona D, Mameli A, Mariotti S. Thyroid disorders and hypocoagulability. Semin Thromb Hemost. 2011;37:11–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Kellett HA, Sawers JS, Boulton FE, Cholerton S, Park BK, Toft AD. Problems of anticoagulation with warfarin in hyperthyroidism. Q J Med. 1986;58:43–51.PubMedGoogle Scholar
  24. 24.
    Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore). 2004;83:107–13.CrossRefGoogle Scholar
  25. 25.
    Jobski K, Behr S, Garbe E. Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case–control study in a large population-based German database. Eur J Clin Pharmacol. 2011;67:941–51.CrossRefPubMedGoogle Scholar
  26. 26.
    Meegaard PM, Holck LHV, Pottegård A, Madsen H, Hallas J. Excessive anticoagulation with warfarin or phenprocoumon may have multiple causes. Dan Med J. 2012;59(2):A4383.PubMedGoogle Scholar
  27. 27.
    Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–99.CrossRefPubMedGoogle Scholar
  28. 28.
    Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121:948–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Grais IM, Sowers JR. Thyroid and the heart. Am J Med. 2014;127:691–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Palareti G, Cosmi B. Bleeding with anticoagulation therapy: who is at risk, and how best to identify such patients. Thromb Haemost. 2009;102(2):268–78.PubMedGoogle Scholar
  33. 33.
    Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.CrossRefGoogle Scholar
  34. 34.
    Austin PC, Small DS. The use of bootstrapping when using propensity-score matching without replacement: a simulation study. Stat Med. 2014;33:4306–19.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Gasse C, Hollowell J, Meier CR, Haefeli WE. Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin. Thromb Haemost. 2005;94:537–43.PubMedGoogle Scholar
  36. 36.
    Holbrook AM, Pereira JA, Labiris R, Douketis JD, Crowther M, Wells PS. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095–106.CrossRefPubMedGoogle Scholar
  37. 37.
    Pincus D, Gomes T, Hellings C, Zheng H, Paterson JM, Mamdani MM, et al. A population-based assessment of the drug interaction between levothyroxine and warfarin. Clin Pharmacol Ther. 2012;92:766–70.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21:5–11.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Edwin SB, Jennings DL, Kalus JS. An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodarone. J Clin Pharmacol. 2010;50:693–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Comets E, Diquet B, Legrain S, Huisse MG, Godon A, Bruhat C, et al. Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians. Clin Pharmacol Ther. 2012;91:777–86.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Emergency DepartmentClermont-Ferrand University HospitalClermont-FerrandFrance
  2. 2.EA 4679Université Clermont AuvergneClermont-FerrandFrance
  3. 3.Biostatistics Unit, DRCIClermont-Ferrand University HospitalClermont-FerrandFrance
  4. 4.Department of Medical InformationUniversity Hospital of Clermont-FerrandClermont-FerrandFrance
  5. 5.Laboratory of Metabolic Adaptations to Exercise in Physiological and Pathological Conditions (AME2P, EA 3533)Blaise Pascal UniversityClermont-FerrandFrance
  6. 6.School of Exercise ScienceAustralian Catholic UniversityMelbourneAustralia
  7. 7.Department of EndocrinologyCHU Clermont-FerrandClermont-FerrandFrance

Personalised recommendations