Thyroid Dysfunction and Hemostasis: An Issue Still Unresolved

ABSTRACT

Thyroid hormones exert various effects on the hemostatic system, as documented by the fact that subclinical or overt thyroid dysfunctions may be associated with hypocoagulable or hypercoagulable states. In this review, the hemostatic balance (primary hemostasis, coagulation factors, and fibrinolytic system) in different thyroid disorders is analyzed from a laboratory, pathogenic, and clinical point of view. Although limited, the published studies suggest that patients with hyperthyroidism or subclinical hypothyroidism have an increased thrombotic risk, whereas patients with overt hypothyroidism have a bleeding tendency. Further trials on larger series of patients are needed to confirm these preliminary findings and to elucidate the pathogenic mechanisms regulating the complex interaction between thyroid disorders and hemostasis.

KEYWORDS

Thyroid - hemostasis - bleeding - thrombosis - hypothyroidism - hyperthyroidism

REFERENCES

• 1 Squizzato A, Romualdi E, Büller H R, Gerdes V EA. Clinical review: thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review.  J Clin Endocrinol Metab. 2007;  92 2415-2420
• 2 Simone J V, Abildgaard C F, Schulman I. Blood coagulation in thyroid dysfunction.  N Engl J Med. 1965;  273 1057-1061
• 3 Myrup B, Bregengård C, Faber J. Primary haemostasis in thyroid disease.  J Intern Med. 1995;  238 59-63
• 4 Hofbauer L C, Heufelder A E. Coagulation disorders in thyroid diseases.  Eur J Endocrinol. 1997;  136 1-7
• 5 Squizzato A, Gerdes V EA, Ageno W, Büller H R. The coagulation system in endocrine disorders: a narrative review.  Intern Emerg Med. 2007;  2 76-83
• 6 Franchini M. Hemostasis and thyroid diseases revisited.  J Endocrinol Invest. 2004;  27 886-892
• 7 Marongiu F, Cauli C, Mariotti S. Thyroid, hemostasis and thrombosis.  J Endocrinol Invest. 2004;  27 1065-1071
• 8 Ford H C, Carter J M. Haemostasis in hypothyroidism.  Postgrad Med J. 1990;  66 280-284
• 9 Erem C, Kavgaci H, Ersöz H O et al.. Blood coagulation and fibrinolytic activity in hypothyroidism.  Int J Clin Pract. 2003;  57 78-81
• 10 Dalton R G, Dewar M S, Savidge G F et al.. Hypothyroidism as a cause of acquired von Willebrand's disease.  Lancet. 1987;  1 1007-1009
• 11 Thornton J G, Parapia L A, Minford A MB. Hypothyroidism and von Willebrand's disease.  Lancet. 1987;  1 1314-1315
• 12 Nitu-Whalley I C, Lee C A. Acquired von Willebrand syndrome—report of 10 cases and review of the literature.  Haemophilia. 1999;  5 318-326
• 13 Michiels J J, Schroyens W, Berneman Z, van der Planken M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine.  Clin Appl Thromb Hemost. 2001;  7 113-115
• 14 Attivissimo L A, Lichtman S M, Klein I. Acquired von Willebrand's syndrome causing a hemorrhagic diathesis in a patient with hypothyroidism.  Thyroid. 1995;  5 399-401
• 15 Blesing N E, Hambley H, McDonald G A. Acquired von Willebrand's disease and hypothyroidism: report of a case presenting with menorrhagia.  Postgrad Med J. 1990;  66 474-476
• 16 Bruggers C S, McElligott K, Rallison M L. Acquired von Willebrand disease in twins with autoimmune hypothyroidism: response to desmopressin and L-thyroxine therapy.  J Pediatr. 1994;  125(6 Pt 1) 911-913
• 17 Levesque H, Borg J Y, Cailleux N et al.. Acquired von Willebrand's syndrome associated with decrease of plasminogen activator and its inhibitor during hypothyroidism.  Eur J Med. 1993;  2 287-288
• 18 Aylesworth C A, Smallridge R C, Rick M E, Alving B M. Acquired von Willebrand's disease: a rare manifestation of postpartum thyroiditis.  Am J Hematol. 1995;  50 217-219
• 19 Tjan-Heijnen V CG, Harthoorn-Lasthuizen E J, Kurstjens R MA, Koolen M I. A patient with postpartum primary hypothyroidism and acquired von Willebrand's disease.  Neth J Med. 1994;  44 91-94
• 20 Franchini M, de Gironcoli M, Lippi G et al.. Efficacy of desmopressin as surgical prophylaxis in patients with acquired von Willebrand disease undergoing thyroid surgery.  Haemophilia. 2002;  8 142-144
• 21 Franchini M, Zugni C, Veneri D et al.. High prevalence of acquired von Willebrand's syndrome in patients with thyroid diseases undergoing thyroid surgery.  Haematologica. 2004;  89 1341-1346
• 22 Franchini M, Veneri D, Lippi G. Analysis of thyroid hormone status in 131 consecutive individuals with low von Willebrand factor levels.  Thromb Haemost. 2005;  93 392-393
• 23 Farid N R, Griffiths B L, Collins J R, Marshall W H, Ingram D W. Blood coagulation and fibrinolysis in thyroid disease.  Thromb Haemost. 1976;  35 415-422
• 24 Marongiu F, Conti M, Murtas M L, Mameli G, Sorano G G, Martino E. Activation of blood coagulation and fibrinolysis in Graves' disease.  Horm Metab Res. 1991;  23 609-611
• 25 Erem C, Ersöz H O, Karti S S et al.. Blood coagulation and fibrinolysis in patients with hyperthyroidism.  J Endocrinol Invest. 2002;  25 345-350
• 26 Hymes K, Blum M, Lackner H, Karpatkin S. Easy bruising, thrombocytopenia, and elevated platelet immunoglobulin G in Graves' disease and Hashimoto's thyroiditis.  Ann Intern Med. 1981;  94 27-30
• 27 Lamberg B A, Kivikangas V, Pelkonen R, Vuopio P. Thrombocytopenia and decreased life-span of thrombocytes in hyperthyroidism.  Ann Clin Res. 1971;  3 98-102
• 28 Kurata Y, Nishioeda Y, Tsubakio T, Kitani T. Thrombocytopenia in Graves' disease: effect of T3 on platelet kinetics.  Acta Haematol. 1980;  63 185-190
• 29 Panzer S, Haubenstock A, Minar E. Platelets in hyperthyroidism: studies on platelet counts, mean platelet volume, 111-indium-labeled platelet kinetics, and platelet-associated immunoglobulins G and M.  J Clin Endocrinol Metab. 1990;  70 491-496
• 30 Marshall J S, Weisberger A S, Levy R P. Coexistent idiopathic thrombocytopenic purpura and hyperthyroidism.  Ann Intern Med. 1967;  67 411-414
• 31 Adrouny A, Sandler R M, Carmel R. Variable presentation of thrombocytopenia in Graves' disease.  Arch Intern Med. 1982;  142 1460-1464
• 32 Pinals R S, Tomar R H, Haas D C, Farah R. Graves' disease, myasthenia gravis, and purpura.  Ann Intern Med. 1977;  87 250
• 33 Yamaguchi K, Ookubo Y, Matsuda H, Suzaki K, Fukushima H, Uzawa H. Idiopathic thrombocytopenic purpura subsequent to Graves' disease and insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 1987;  3 233-237
• 34 Lio S, Albin M, Girelli G et al.. Abnormal thyroid function test results in patients with Fisher-Evans syndrome.  J Endocrinol Invest. 1993;  16 163-167
• 35 Crabtree G R, Lee J C, Cornwell III G G. Letter: autoimmune thrombocytopenia purpura and Hashimoto's thyroiditis.  Ann Intern Med. 1975;  83 371-372
• 36 Ho S L, Shah M, Williams A C. Idiopathic thrombocytopenic purpura and autoimmune thyroiditis in a patient with myasthenia gravis.  Muscle Nerve. 1992;  15 966-967
• 37 Segal B M, Weintraub M I. Hashimoto's thyroiditis, myasthenia gravis, idiopathic thrombocytopenic purpura.  Ann Intern Med. 1976;  85 761-763
• 38 Cordiano I, Betterle C, Spadaccino C A, Soini B, Girolami A, Fabris F. Autoimmune thrombocytopenia (AITP) and thyroid autoimmune disease (TAD): overlapping syndromes?.  Clin Exp Immunol. 1998;  113 373-378
• 39 Hofbauer L C, Spitzweg C, Schmauss S, Heufelder A E. Graves disease associated with autoimmune thrombocytopenic purpura.  Arch Intern Med. 1997;  157 1033-1036
• 40 Zeigler Z R, Hasiba U, Lewis J H, Vagnucci A H, West V A, Bezek E A. Hemostatic defects in response to aspirin challenge in hypothyroidism.  Am J Hematol. 1986;  23 391-399
• 41 Hellem A J, Segaard E, Solem J H. The adhesiveness of human blood platelets and thyroid function.  Acta Med Scand. 1975;  197 15-17
• 42 Edson J R, Fecher D R, Doe R P. Low platelet adhesiveness and other hemostatic abnormalities in hypothyroidism.  Ann Intern Med. 1975;  82 342-346
• 43 Palareti G, Biagi G, Legnani C et al.. Association of reduced factor VIII with impaired platelet reactivity to adrenalin and collagen after total thyroidectomy.  Thromb Haemost. 1989;  62 1053-1056
• 44 Egeberg B O. Influence of thyroid function on the blood clotting system.  Scand J Clin Lab Invest. 1963;  15 1-7
• 45 Rogers II J S, Shane S R, Jencks F S. Factor VIII activity and thyroid function.  Ann Intern Med. 1982;  97 713-716
• 46 Rogers II J S, Shane S R. Factor VIII activity in normal volunteers receiving oral thyroid hormone.  J Lab Clin Med. 1983;  102 444-449
• 47 Nordoy A, Vik-Mo H, Berntsen H. Haemostatic and lipid abnormalities in hypothyroidism.  Scand J Haematol. 1976;  16 154-160
• 48 Gullu S, Sav H, Kamel N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism.  Eur J Endocrinol. 2005;  152 355-361
• 49 Meiklejohn D J, Watson H G. Acquired haemophilia in association with organ-specific autoimmune disease.  Haemophilia. 2001;  7 523-525
• 50 Marongiu F, Cauli C, Mameli G, Usai B, Mariotti S. Apathetic Graves' disease and acquired hemophilia due to factor VIIIc antibody.  J Endocrinol Invest. 2002;  25 246-249
• 51 Sievert R, Goldstein M L, Surks M I. Graves' disease and autoimmune factor VIII deficiency.  Thyroid. 1996;  6 245-247
• 52 Chadarevian R, Bruckert E, Ankri A, Beucler I, Giral P, Turpin G. Relationship between thyroid hormones and plasma D-dimer levels.  Thromb Haemost. 1998;  79 99-103
• 53 Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A, Turpin G. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism.  J Clin Endocrinol Metab. 2001;  86 732-737
• 54 Müller B, Tsakiris D A, Roth C B, Guglielmetti M, Staub J J, Marbet G A. Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease.  Eur J Clin Invest. 2001;  31 131-137
• 55 Marongiu F, Biondi G, Conti M et al.. Is a hypercoagulable state present in hypothyroidism?.  Thromb Haemost. 1992;  67 729
• 56 Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism.  J Clin Endocrinol Metab. 2007;  92 3006-3012
• 57 Burggraaf J, Lalezari S, Emeis J J et al.. Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol.  Thyroid. 2001;  11 153-160
• 58 Morikawa Y, Morikawa A, Makino I. Relationship of thyroid states and serum thrombomodulin (TM) levels in patients with Graves' disease: TM, a possible new marker of the peripheral activity of thyroid hormones.  J Clin Endocrinol Metab. 1993;  76 609-614
• 59 Hak A E, Pols H A, Visser T J, Drexhage H A, Hofman A, Witteman J C. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.  Ann Intern Med. 2000;  132 270-278
• 60 Özcan M A, Cömlekçi 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
• 61 Loeliger E A, Esch B. The biological disappearance rate of prothrombin, factors VII, IX and X from plasma in hypothyroidism, hyperthyroidism and during fever.  Thromb Diath Haemorrh. 1964;  10 267-277
• 62 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. 2008;  , September 12 (Epub ahead of print)
• 63 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
• 64 Cantürk Z, Cetinarslan B, Tarkun I, Cantürk N Z, Ozden M, Duman C. Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism.  Thyroid. 2003;  13 971-977
• 65 Li Y, Chen H, Tan J, Wang X, Liang H, Sun X. 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
• 66 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
• 67 Chadarevian R, Bruckert E, Giral P, Turpin G. Relationship between thyroid hormones and fibrinogen levels.  Blood Coagul Fibrinolysis. 1999;  10 481-486
• 68 Grant P J, Medcalf R L. Hormonal regulation of haemostasis and the molecular biology of the fibrinolytic system.  Clin Sci (Lond). 1990;  78 3-11
• 69 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
• 70 Polikar R, Burger A G, Scherrer U S, Nicod P. The thyroid and the heart.  Circulation. 1993;  87 1435-1441
• 71 Woeber K A. Thyrotoxicosis and the heart.  N Engl J Med. 1992;  327 94-98
• 72 Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease.  Endocrine. 2004;  24 1-13
• 73 Mariotti S, Cambuli V M. Cardiovascular risk in elderly hypothyroid patients.  Thyroid. 2007;  17 1067-1073
• 74 Duntas L H, Wartofsky L. Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?.  Thyroid. 2007;  17 1075-1084
• 75 Singh S, Duggal J, Molnar J, Maldonado F, Barsano C P, Arora R. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis.  Int J Cardiol. 2008;  125 41-48
• 76 Ochs N, Auer R, Bauer D C et al.. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.  Ann Intern Med. 2008;  148 832-845