Hemostatic and Fibrinolytic Abnormalities in Endocrine Diseases: A Narrative Review

ABSTRACT

This review summarizes current knowledge of the effects of polycystic ovary syndrome, Cushing's syndrome, thyrotoxicosis, hypothyroidism, primary hyperparathyroidism, acromegaly, hypopituitarism, and growth hormone deficiency on coagulation and fibrinolysis. Several abnormalities of the coagulation-fibrinolytic system have been described among patients affected by these endocrine disorders. Although further larger studies are needed to provide more definitive information, clinically overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine diseases appear to be associated with a thrombotic tendency. The disorders of coagulation and fibrinolysis observed in these endocrine pathologies usually range from mild to moderate and, rarely, to potentially severe laboratory abnormalities (e.g., bleeding diathesis in overt hypothyroidism mainly due to an acquired von Willebrand's syndrome type 1), are reversible after pharmacologic treatment of the hormonal dysfunction, and are usually of limited consequence in clinical practice. Nevertheless, the prompt recognition of potentially severe disorders of blood coagulation is mandatory for the correct management of these patients.

KEYWORDS

Endocrine diseases - coagulation - fibrinolysis - hemostatic disorders - coagulation disorders

REFERENCES

• 1 Kannel W B. Overview of hemostatic factors involved in atherosclerotic cardiovascular disease.  Lipids. 2005;  40(12) 1215-1220
• 2 Davì G, Patrono C. Platelet activation and atherothrombosis.  N Engl J Med. 2007;  357(24) 2482-2494
• 3 Fay W P, Garg N, Sunkar M. Vascular functions of the plasminogen activation system.  Arterioscler Thromb Vasc Biol. 2007;  27(6) 1231-1237
• 4 Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;  122(6) 727-735
• 5 Mina A, Favaloro E J, Koutts J. Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review.  Semin Thromb Hemost. 2007;  33(8) 798-809
• 6 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.  Semin Thromb Hemost. 2009;  35(3) 277-287
• 7 Norman R J, Dewailly D, Legro R S, Hickey T E. Polycystic ovary syndrome.  Lancet. 2007;  370(9588) 685-697
• 8 Meyer C, McGrath B P, Teede H J. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease.  J Clin Endocrinol Metab. 2005;  90(10) 5711-5716
• 9 Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.  Clin Endocrinol (Oxf). 2000;  52(5) 595-600
• 10 Yildiz B O, Haznedaroğlu I C, Kirazli S, Bayraktar M. Global fibrinolytic capacity is decreased in polycystic ovary syndrome, suggesting a prothrombotic state.  J Clin Endocrinol Metab. 2002;  87(8) 3871-3875
• 11 Kelly C J, Lyall H, Petrie J R et al.. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome.  J Clin Endocrinol Metab. 2002;  87(7) 3287-3290
• 12 Atiomo W U, Bates S A, Condon J E, Shaw S, West J H, Prentice A G. The plasminogen activator system in women with polycystic ovary syndrome.  Fertil Steril. 1998;  69(2) 236-241
• 13 Erdoğan M, Karadeniz M, Alper G E et al.. Thrombin-activatable fibrinolysis inhibitor and cardiovascular risk factors in polycystic ovary syndrome.  Exp Clin Endocrinol Diabetes. 2008;  116(3) 143-147
• 14 Adali E, Yildizhan R, Kurdoglu M, Bugdayci G, Kolusari A, Sahin H G. Increased plasma thrombin-activatable fibrinolysis inhibitor levels in young obese women with polycystic ovary syndrome.  Fertil Steril. 2009;  , April 13 (Epub ahead of print)
• 15 Mak W, Dokras A. Polycystic ovarian syndrome and the risk of cardiovascular disease and thrombosis.  Semin Thromb Hemost. 2009;  35 613-620
• 16 Orme S M, McNally R J, Cartwright R A, Belchetz P E. United Kingdom Acromegaly Study Group . Mortality and cancer incidence in acromegaly: a retrospective cohort study.  J Clin Endocrinol Metab. 1998;  83(8) 2730-2734
• 17 Bates A S, Van't Hoff W, Jones J M, Clayton R N. An audit of outcome of treatment in acromegaly.  Q J Med. 1993;  86(5) 293-299
• 18 Bogazzi F, Battolla L, Spinelli C et al.. Risk factors for development of coronary heart disease in patients with acromegaly: a five-year prospective study.  J Clin Endocrinol Metab. 2007;  92(11) 4271-4277
• 19 Landin-Wilhelmsen K, Tengborn L, Wilhelmsen L, Bengtsson B A. Elevated fibrinogen levels decrease following treatment of acromegaly.  Clin Endocrinol (Oxf). 1997;  46(1) 69-74
• 20 Erem C, Nuhoglu I, Kocak M et al.. Blood coagulation and fibrinolysis in patients with acromegaly: increased plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI), and an inverse correlation between growth hormone and TFPI.  Endocrine. 2008;  33(3) 270-276
• 21 Wildbrett J, Hanefeld M, Fücker K et al.. Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I.  Exp Clin Endocrinol Diabetes. 1997;  105(6) 331-335
• 22 Tomlinson J W, Holden N, Hills R K West Midlands Prospective Hypopituitary Study Group et al. Association between premature mortality and hypopituitarism.  Lancet. 2001;  357(9254) 425-431
• 23 Elhadd T A, Abdu T A, Clayton R. Hypopituitarism and atherosclerosis.  Ann Med. 2001;  33(7) 477-485
• 24 Johansson J O, Landin K, Tengborn L, Rosén T, Bengtsson B A. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults.  Arterioscler Thromb. 1994;  14(3) 434-437
• 25 Johansson J O, Landin K, Johannsson G, Tengborn L, Bengtsson B A. Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.  Thromb Haemost. 1996;  76(3) 422-428
• 26 Kvasnicka J, Marek J, Kvasnicka T et al.. Increase of adhesion molecules, fibrinogen, type-1 plasminogen activator inhibitor and orosomucoid in growth hormone (GH) deficient adults and their modulation by recombinant human GH replacement.  Clin Endocrinol (Oxf). 2000;  52(5) 543-548
• 27 Elhadd T A, Abdu T A, Oxtoby J et al.. Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency.  J Clin Endocrinol Metab. 2001;  86(9) 4223-4232
• 28 Sesmilo G, Biller B M, Llevadot J et al.. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial.  Ann Intern Med. 2000;  133(2) 111-122
• 29 Devin J K, Blevins Jr L S, Verity D K et al.. Markedly impaired fibrinolytic balance contributes to cardiovascular risk in adults with growth hormone deficiency.  J Clin Endocrinol Metab. 2007;  92(9) 3633-3639
• 30 Serri O, St-Jacques P, Sartippour M, Renier G. Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy.  J Clin Endocrinol Metab. 1999;  84(1) 58-63
• 31 Sartorio A, Cattaneo M, Bucciarelli P et al.. Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly.  Exp Clin Endocrinol Diabetes. 2000;  108(7) 486-492
• 32 Sesmilo G, Miller K K, Hayden D, Klibanski A. Inflammatory cardiovascular risk markers in women with hypopituitarism.  J Clin Endocrinol Metab. 2001;  86(12) 5774-5781
• 33 Abdu T A, Elhadd T A, Buch H, Barton D, Neary R, Clayton R N. Recombinant GH replacement in hypopituitary adults improves endothelial cell function and reduces calculated absolute and relative coronary risk.  Clin Endocrinol (Oxf). 2004;  61(3) 387-393
• 34 Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: The association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship?.  J Clin Endocrinol Metab. 2007;  92(7) 2421-2429
• 35 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(11) 832-845
• 36 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(7) 2415-2420
• 37 Franchini M, Montagnana M, Manzato F, Vescovi P P. Thyroid dysfunction and hemostasis: an issue still unresolved.  Semin Thromb Hemost. 2009;  35(3) 288-294
• 38 Franchini M, Lippi G, Manzato F, Vescovi P P. Thyroid-associated autoimmune coagulation disorders.  J Thromb Thrombolysis. 2009;  , March 10 (Epub ahead of print)
• 39 Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism.  J Clin Endocrinol Metab. 2007;  92(8) 3006-3012
• 40 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(2) 153-160
• 41 Horne III M K, Singh K K, Rosenfeld K G et al.. Is thyroid hormone suppression therapy prothrombotic?.  J Clin Endocrinol Metab. 2004;  89(9) 4469-4473
• 42 Demir T, Akinci B, Comlekci A et al.. Levothyroxine suppression treatment for benign thyroid nodules alters coagulation.  Clin Endocrinol (Oxf). 2009;  71(3) 446-450
• 43 Erem C, Ersoz H O, Karti S S et al.. Blood coagulation and fibrinolysis in patients with hyperthyroidism.  J Endocrinol Invest. 2002;  25(4) 345-350
• 44 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(4) 593-599
• 45 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(3) 323-329
• 46 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(3) 362-365
• 47 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(2) 131-137
• 48 Coban E, Yazicioglu G, Ozdogan M. Platelet activation in subjects with subclinical hypothyroidism.  Med Sci Monit. 2007;  13 CR211-214
• 49 Gullu S, Sav H, Kamel N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism.  Eur J Endocrinol. 2005;  152(3) 355-361
• 50 Erikci A A, Karagoz B, Ozturk A et al.. The effect of subclinical hypothyroidism on platelet parameters.  Hematology. 2009;  14(2) 115-117
• 51 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(11) 1341-1346
• 52 Manfredi E, van Zaane B, Gerdes V EA, Brandjes D P, Squizzato A. Hypothyroidism and acquired von Willebrand's syndrome: a systematic review.  Haemophilia. 2008;  14(3) 423-433
• 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(2) 732-737
• 54 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(2) 113-115
• 55 Chadarevian R, Jublanc C, Bruckert E et al.. Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism.  J Endocrinol Invest. 2005;  28(5) 398-404
• 56 Erem C. Coagulation and fibrinolysis in thyroid dysfunction.  Endocrine. 2009;  36(1) 110-118
• 57 Lundgren E, Lind L, Palmér M, Jakobsson S, Ljunghall S, Rastad J. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years.  Surgery. 2001;  130(6) 978-985
• 58 Söreide J A, van Heerden J A, Grant C S, Yau Lo C, Schleck C, Ilstrup D M. Survival after surgical treatment for primary hyperparathyroidism.  Surgery. 1997;  122(6) 1117-1123
• 59 Hedbäck G, Odén A. Persistent disease after surgery for primary hyperparathyroidism: the long-term outcome.  Eur J Endocrinol. 2004;  150(1) 19-25
• 60 Lind L, Jacobsson S, Palmér M, Lithell H, Wengle B, Ljunghall S. Cardiovascular risk factors in primary hyperparathyroidism: a 15-year follow-up of operated and unoperated cases.  J Intern Med. 1991;  230(1) 29-35
• 61 Erem C, Kocak M, Nuhoglu I, Yilmaz M, Ucuncu O. Increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels in patients with primary hyperparathyroidism.  Eur J Endocrinol. 2009;  160(5) 863-868
• 62 Erem C, Kocak M, Hacihasanoglu A, Yilmaz M, Saglam F, Ersoz H O. Blood coagulation, fibrinolysis and lipid profile in patients with primary hyperparathyroidism: increased plasma factor VII and X activities and D-Dimer levels.  Exp Clin Endocrinol Diabetes. 2008;  116(10) 619-624
• 63 Chertok-Shacham E, Ishay A, Lavi I, Luboshitzky R. Biomarkers of hypercoagulability and inflammation in primary hyperparathyroidism.  Med Sci Monit. 2008;  14 CR628-632
• 64 Etxabe J, Vazquez J A. Morbidity and mortality in Cushing's disease: an epidemiological approach.  Clin Endocrinol (Oxf). 1994;  40(4) 479-484
• 65 Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines.  Clin Endocrinol (Oxf). 2004;  61(6) 768-777
• 66 Boscaro M, Sonino N, Scarda A et al.. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing's syndrome.  J Clin Endocrinol Metab. 2002;  87(8) 3662-3666
• 67 Patrassi G M, Dal Bo Zanon R, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state of patients with Cushing's syndrome.  Thromb Haemost. 1985;  54(2) 518-520
• 68 Patrassi G M, Sartori M T, Viero M L, Scarano L, Boscaro M, Girolami A. The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state.  Blood Coagul Fibrinolysis. 1992;  3(6) 789-793
• 69 Fatti L M, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci P M. Markers of activation of coagulation and fibrinolysis in patients with Cushing's syndrome.  J Endocrinol Invest. 2000;  23(3) 145-150
• 70 Terzolo M, Allasino B, Bosio S et al.. Hyperhomocysteinemia in patients with Cushing's syndrome.  J Clin Endocrinol Metab. 2004;  89 3745-3751
• 71 Erem C, Nuhoglu I, Yilmaz M et al.. Blood coagulation and fibrinolysis in patients with Cushing's syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels.  J Endocrinol Invest. 2009;  32(2) 169-174
• 72 Ambrosi B, Sartorio A, Pizzocaro A, Passini E, Bottasso B, Federici A. Evaluation of haemostatic and fibrinolytic markers in patients with Cushing's syndrome and in patients with adrenal incidentaloma.  Exp Clin Endocrinol Diabetes. 2000;  108(4) 294-298
• 73 Van Zaane B, Nur E, Squizzato A et al.. Hypercoagulable state in Cushing's syndrome: a systematic review.  J Clin Endocrinol Metab. 2009;  94(8) 2743-2750
• 74 Tauchmanovà L, Rossi R, Biondi B et al.. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk.  J Clin Endocrinol Metab. 2002;  87(11) 4872-4878
• 75 Arnaldi G, Angeli A, Atkinson A B et al.. Diagnosis and complications of Cushing's syndrome: a consensus statement.  J Clin Endocrinol Metab. 2003;  88(12) 5593-5602