Thromb Haemost 2012; 108(06): 1077-1088
DOI: 10.1160/TH12-07-0496
Review Article
Schattauer GmbH

The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors

A systematic review and meta-analysis
Danka J.F. Stuijver
1   Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Bregje van Zaane
1   Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Erica Romualdi
3   Department of Clinical Medicine, University of Insubria, Varese, Italy
,
Dees P.M. Brandjes
1   Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Victor E.A. Gerdes
1   Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands
2   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Alessandro Squizzato
3   Department of Clinical Medicine, University of Insubria, Varese, Italy
› Author Affiliations
Further Information

Publication History

Received: 18 July 2012

Accepted: 10 August 2012

Publication Date:
30 November 2017 (online)

Summary

Several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess;however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo. Data sources included MEDLINE (2006–2012), EMBASE (2006–2012), and reference lists. The sources were combined with our previous search containing studies from 1980–2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random-effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross-sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis.

 
  • References

  • 1 Squizzato A, Romualdi E, Buller HR. et al. Clinical review: Thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab 2007; 92: 2415-2420.
  • 2 Vescovi PP, Favaloro EJ, Lippi G. et al. The spectrum of coagulation abnormalities in thyroid disorders. Semin Thromb Hemost 2011; 37: 7-10.
  • 3 Arnaout MA, Awidi AS, el-Najdawi AM. et al. Arginine-vasopressin and endothelium-associated proteins in thyroid disease. Acta Endocrinol 1992; 126: 399-403.
  • 4 Dorr M, Robinson DM, Wallaschofski H. et al. Low serum thyrotropin is associated with high plasma fibrinogen. J Clin Endocrinol Metab 2006; 91: 530-534.
  • 5 Erem C, Ersoz HO, Karti SS. et al. Blood coagulation and fibrinolysis in patients with hyperthyroidism. J Endocrinol Invest 2002; 25: 345-350.
  • 6 Li Y, Chen H, Tan J. et al. Impaired release of tissue plasminogen activator from the endothelium in Graves’ disease - indicator of endothelial dysfunction and reduced fibrinolytic capacity. Eur J Clin Invest 1998; 28: 1050-1054.
  • 7 Lippi G, Franchini M, Targher G. et al. Hyperthyroidism is associated with shortened APTT and increased fibrinogen values in a general population of unselected outpatients. J Thromb Thrombolysis 2009; 28: 362-365.
  • 8 Ozcan MA, Comlekci A, Demirkan F. et al. Plasma levels of free tissue factor pathway inhibitor in patients with various thyroid disorders. Thromb Res 2003; 110: 243-247.
  • 9 van Zaane B, Squizzato A, Debeij J. et al. Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study. J Thromb Haemost 2011; 9: 1816-1824.
  • 10 van Tulder MW, Assendelft WJ, Koes BW. et al. Method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group for Spinal Disorders. Spine 1997; 22: 2323-2330.
  • 11 Verhagen AP, de Vet HC, de Bie RA. et al. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 1998; 51: 1235-1241.
  • 12 Wells G, Shea B, O’Connell D. et al. Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses 2011. http://www.ohrica/programs/clnical_epidemiology/oxford.asp
  • 13 Higgins JP, Green S.. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011) The Cochrane Collaboration. Available at: http://www.cochrane-handbook.org. Wiley, Oxford UK:
  • 14 Lipsey MW, Wilson DB. Procedures for computing effect sizes values from eligible study reports. Practical meta-analysis: Sage Publications Ltd; 2000: 172-206
  • 15 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188.
  • 16 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-748.
  • 17 Burggraaf J, Lalezari S, Emeis JJ. et al. Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol. Thyroid 2001; 11: 153-160.
  • 18 Coban E, Aydemir M, Yazicioglu G. et al. Endothelial dysfunction in subjects with subclinical hyperthyroidism. J Endocrinol Invest 2006; 29: 197-200.
  • 19 Erem C. Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity. Clin Endocrinol (Oxf) 2006; 64: 323-329.
  • 20 Graninger W, Pirich KR, Speiser W. et al. Effect of thyroid hormones on plasma protein concentrations in man. J Clin Endocrinol Metab 1986; 63: 407-411.
  • 21 Liu L, Wang X, Lin Z. et al. Elevated plasma levels of VWF:Ag in hyperthyroidism are mediated through beta-adrenergic receptors. Endocr Res 1993; 19: 123-133.
  • 22 Marongiu F, Conti M, Mameli G. et al. Fibrinogen and fibrinolytic activity in hyperthyroidism before and after antithyroid treatment. J Endocrinol Invest 1988; 11: 723-725.
  • 23 Marongiu F, Conti M, Murtas ML. et al. Activation of blood coagulation and fibrinolysis in Graves’ disease. Horm Metab Res 1991; 23: 609-611.
  • 24 Marongiu F, Conti M, Murtas ML. et al. Anticardiolipin antibodies in Grave’s disease: relationship with thrombin activity in vivo. Thromb Res 1991; 64: 745-749.
  • 25 Morishita E, Hashimoto T, Asakura H. et al. Increased plasma levels of free tissue factor pathway inhibitor in patients with Graves’ disease. Thromb Haemost 1998; 79: 919-923.
  • 26 Myrup B, Bregengard C, Faber J. Primary haemostasis in thyroid disease. J Intern Med 1995; 238: 59-63.
  • 27 Rogers JS, Shane SR, Jencks FS. Factor VIII activity and thyroid function. Ann Intern Med 1982; 97: 713-716.
  • 28 Rosc D, Zastawna E, Drewniak W. et al. Plasminogen activators (tissue type t-PA, urokinase type u-PA) and plasminogen activators inhibitors (PAI-1) in Graves disease. Med Sci Monit 1998; 4: 975-978.
  • 29 Wahrenberg H, Wennlund A, Hoffstedt J. Increased adipose tissue secretion of interleukin-6, but not of leptin, plasminogen activator inhibitor-1 or tumour necrosis factor alpha, in Graves’ hyperthyroidism. Eur J Endocrinol 2002; 146: 607-611.
  • 30 Mousa SS, Davis FB, Davis PJ. et al. Human platelet aggregation and degranulation is induced in vitro by L-thyroxine, but not by 3,5,3’-triiodo-L-thyronine or diiodothyropropionic acid (DITPA). Clin Appl Thromb Hemost 2010; 16: 288-293.
  • 31 Olukman O, Sahin U, Kavakli T. et al. Investigation of acquired von Willebrand Syndrome in children with hypothyroidism: reversal after treatment with thyroxine. J Pediatr Endocrinol Metab 2010; 23: 967-974.
  • 32 Yong PH, Junit SM, Harun F. et al. Patients with congenital hypothyroidism demonstrate different altered expression of plasma fibrinogen and haptoglobin polypeptide chains. Clin Biochem 2006; 39: 126-132.
  • 33 Nowicki TS, Moscatello AL, Shin E. et al. The urokinase plasminogen activator system in metastatic papillary thyroid carcinoma: a potential therapeutic target. J Clin Endocrinol Metab 2011; 96: 3062-3064.
  • 34 Reinke CE, Hadler RA, Karakousis GC. et al. Does the presence of thyroid cancer increase the risk of venous thromboembolism in patients undergoing thyroidectomy?. Surgery 2011; 150: 1275-1285.
  • 35 Ulisse S, Baldini E, Sorrenti S. et al. High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillary thyroid carcinoma. J Clin Endocrinol Metab 2011; 96: 504-508.
  • 36 Akinci B, Comlekci A, Yener S. et al. Thrombin activatable fibrinolysis inhibitor antigen levels are inversely correlated with plasminogen activator inhibitor-1 antigen levels in hyperthyroid patients. Endocr J 2007; 54: 593-599.
  • 37 Akinci B, Demir T, Comlekci A. et al. Effect of levothyroxine suppression therapy on plasma thrombin activatable fibrinolysis inhibitor antigen levels in benign thyroid nodules. Med Princ Pract 2011; 20: 23-28.
  • 38 Brona A, Bohdanowicz-Pawlak A, Jedrzejuk D. et al. Fibrinogen and D-dimers levels in patients with hyperthyroidism before and after radioiodine therapy. Endokrynol Pol 2011; 62: 409-415.
  • 39 Coban E, Aydemir M. Levels of plasma fibrinogen and D-dimer in subjects with subclinical hyperthyroidism. Med Sci Monit 2008; 14: CR42-CR46.
  • 40 Demir T, Akinci B, Comlekci A. et al Levothyroxine (LT4) suppression treatment for benign thyroid nodules alters coagulation. Clin Endocrinol 2009; 71: 446-450.
  • 41 Erem C, Ucuncu O, Yilmaz M. et al. Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hyperthyroidism. Endocrine 2009; 36: 473-478.
  • 42 Homoncik M, Gessl A, Ferlitsch A. et al. Altered platelet plug formation in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 2007; 92: 3006-3012.
  • 43 Mohamed-Ali MS, Ahmed RO. Coagulation profiles in hypothyroid and hyperthyroid female patients in Sudan. Saudi Med J 2008; 29: 1289-1293.
  • 44 Rogers JS, Shane SR. Factor VIII activity in normal volunteers receiving oral thyroid hormone. J Lab Clin Med 1983; 102: 444-449.
  • 45 Franchini M, Lippi G, Manzato F. et al. Thyroid-associated autoimmune coagulation disorders. J Thromb Thrombolysis 2010; 29: 87-91.
  • 46 Hoylaerts MF, Thys C, Arnout J. et al. Recurrent arterial thrombosis linked to autoimmune antibodies enhancing von Willebrand factor binding to platelets and inducing Fc gamma RII receptor-mediated platelet activation. Blood 1998; 91: 2810-2817.
  • 47 Niessen RW, Pfaffendorf BA, Sturk A. et al. The influence of insulin, beta-estradiol, dexamethasone and thyroid hormone on the secretion of coagulant and anticoagulant proteins by HepG2 cells. Thromb Haemost 1995; 74: 686-692.
  • 48 Shih CH, Chen SL, Yen CC. et al. Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins. Endocrinology 2004; 145: 2804-2814.
  • 49 Paggi A, Caccavo D, Ferri GM. et al. Anticardiolipin antibodies in autoimmune thyroid diseases. Clin Endocrinol 1994; 40: 329-333.
  • 50 Thomas DP, Roberts HR. Hypercoagulability in venous and arterial thrombosis. Ann Intern Med 1997; 126: 638-644.
  • 51 Danescu LG, Badshah A, Danescu SC. et al. Venous thromboembolism in patients hospitalized with thyroid dysfunction. Clin Appl Thromb Hemost 2009; 15: 676-680.
  • 52 Debeij J, Dekkers O, Asvold B. et al. Increased levels of free thyroxine and risk of venous thrombosis in a large population-based prospective study. J Thromb Haemost 2012; 10: 1539-1546.
  • 53 Kootte RS, Stuijver DJ, Dekkers OM. et al. The incidence of venous thromboembolism in patients with overt hyperthyroidism: A retrospective multicentre cohort study. Thromb Haemost 2012; 107: 417-422.
  • 54 Lin HC, Yang LY, Kang JH. Increased risk of pulmonary embolism among patients with hyperthyroidism: A 5-year follow-up study. J Thromb Haemost 2010; 8: 2176-2181.
  • 55 Ramagopalan SV, Wotton CJ, Handel AE. et al. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: Record-linkage study. BMC Med 2011; 9: 1.
  • 56 van Zaane B, Squizzato A, Huijgen R. et al. Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: A case-control study. Blood 2010; 115: 4344-4349.
  • 57 Zoller B, Li X, Sundquist J, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: A nationwide follow-up study from Sweden. Lancet 2012; 379: 244-249.
  • 58 Franchini M, Lippi G, Targher G. Hyperthyroidism and venous thrombosis: a casual or causal association? A systematic literature review. Clin Appl Thromb Hemost 2011; 17: 387-392.