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Semin Thromb Hemost 2021; 47(06): 654-661
DOI: 10.1055/s-0040-1722270
Review Article

Use of Glucocorticoids and Risk of Venous Thromboembolism: A Narrative Review

Chiara Simion
1   Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Elena Campello
1   Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Elisa Bensi
2   Division of Geriatrics, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Andrea Bellio
2   Division of Geriatrics, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Anna Pontarin
2   Division of Geriatrics, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Luca Spiezia
1   Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
,
Paolo Simioni
1   Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
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Abstract

Glucocorticoids are potent anti-inflammatory agents that are widely used for the treatment of many inflammatory, autoimmune, and neoplastic disorders. However, their beneficial effect is associated with several side effects, including an increased risk of cardiovascular complications, such as myocardial infarction and stroke. Whether their use also contributes to a procoagulant state, and therefore increases the risk of venous thromboembolism (VTE), is still a matter of debate. As an increased risk of venous thrombotic events is described in patients with Cushing's syndrome, which is characterized by endogenous hypercortisolism, it is reasonable to speculate that the chronic administration of glucocorticoids may induce a hypercoagulable state. However, it seems virtually impossible to separate the role of the drug from the underlying condition, which itself predisposes to the development of VTE. Actually, some evidence suggests that the use of exogenous glucocorticoids for the treatment of underlying disease and its exacerbations may further amplify the risk of VTE. Moreover, a procoagulant state has also been reported in healthy participants receiving oral glucocorticoids versus placebo. We have performed a concise narrative review on available data on the influence of exogenous glucocorticoids on hemostasis and their clinical impact on the risk of VTE.

Keywords

exogenous hypercortisolism - hypercoagulability - inflammation - steroids - thrombosis


Publication History

Article published online:
23 April 2021

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Ramamoorthy S, Cidlowski JA. Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin North Am 2016; 42 (01) 15-31 , vii
    CrossrefPubMedGoogle Scholar
  • 2 Johannesdottir SA, Horváth-Puhó E, Dekkers OM. et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013; 173 (09) 743-752
    CrossrefPubMedGoogle Scholar
  • 3 van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM 2000; 93 (02) 105-111
    CrossrefPubMedGoogle Scholar
  • 4 Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol 2007; 157 (05) 545-559
    CrossrefPubMedGoogle Scholar
  • 5 van Zaane B, Nur E, Squizzato A. et al. Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors. J Thromb Haemost 2010; 8 (11) 2483-2493
    CrossrefPubMedGoogle Scholar
  • 6 van der Pas R, Leebeek FWG, Hofland LJ, de Herder WW, Feelders RA. Hypercoagulability in Cushing's syndrome: prevalence, pathogenesis and treatment. Clin Endocrinol (Oxf) 2013; 78 (04) 481-488
    Google Scholar
  • 7 Coelho MCA, Santos CV, Vieira Neto L, Gadelha MR. Adverse effects of glucocorticoids: coagulopathy. Eur J Endocrinol 2015; 173 (04) M11-M21
    CrossrefPubMedGoogle Scholar
  • 8 Goodwin JE. Glucocorticoids and the cardiovascular system. Adv Exp Med Biol 2015; 872: 299-314
    CrossrefPubMedGoogle Scholar
  • 9 Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term side effects of glucocorticoids. Expert Opin Drug Saf 2016; 15 (04) 457-465
    CrossrefPubMedGoogle Scholar
  • 10 Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet 2015; 386 (9996): 913-927
    CrossrefPubMedGoogle Scholar
  • 11 Stuijver DJF, van Zaane B, Feelders RA. et al. Incidence of venous thromboembolism in patients with Cushing's syndrome: a multicenter cohort study. J Clin Endocrinol Metab 2011; 96 (11) 3525-3532
    CrossrefPubMedGoogle Scholar
  • 12 Stuijver DJF, Majoor CJ, van Zaane B. et al. Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study. Chest 2013; 143 (05) 1337-1342
    CrossrefPubMedGoogle Scholar
  • 13 Majoor CJ, Sneeboer MMS, de Kievit A. et al. The influence of corticosteroids on hemostasis in healthy subjects. J Thromb Haemost 2016; 14 (04) 716-723
    CrossrefPubMedGoogle Scholar
  • 14 Brotman DJ, Girod JP, Posch A. et al. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Thromb Res 2006; 118 (02) 247-252
    CrossrefPubMedGoogle Scholar
  • 15 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 (06) 768-777
    CrossrefPubMedGoogle Scholar
  • 16 Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol 2016; 4 (07) 611-629
    CrossrefPubMedGoogle Scholar
  • 17 Zilio M, Mazzai L, Sartori MT. et al. A venous thromboembolism risk assessment model for patients with Cushing's syndrome. Endocrine 2016; 52 (02) 322-332
    CrossrefPubMedGoogle Scholar
  • 18 Wagner J, Langlois F, Lim DST, McCartney S, Fleseriu M. Hypercoagulability and risk of venous thromboembolic events in endogenous cushing's syndrome: a systematic meta-analysis. Front Endocrinol (Lausanne) 2019; 9: 805
    CrossrefPubMedGoogle Scholar
  • 19 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
    CrossrefPubMedGoogle Scholar
  • 20 Van Zaane B, Nur E, Squizzato A. et al. Hypercoagulable state in Cushing's syndrome: a systematic review. J Clin Endocrinol Metab 2009; 94 (08) 2743-2750
    CrossrefPubMedGoogle Scholar
  • 21 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. 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
    CrossrefPubMedGoogle Scholar
  • 22 Barbot M, Daidone V, Zilio M. et al. Perioperative thromboprophylaxis in Cushing's disease: what we did and what we are doing?. Pituitary 2015; 18 (04) 487-493
    CrossrefPubMedGoogle Scholar
  • 23 Isidori AM, Minnetti M, Sbardella E, Graziadio C, Grossman AB. Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur J Endocrinol 2015; 173 (03) R101-R113
    CrossrefPubMedGoogle Scholar
  • 24 Ikkala E, Myllylä G, Pelkonen R, Rasi V, Viinikka L, Ylikorkala O. Haemostatic parameters in Cushing's syndrome. Acta Med Scand 1985; 217 (05) 507-511
    CrossrefPubMedGoogle Scholar
  • 25 Patrassi GM, Sartori MT, Viero ML, 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 (06) 789-793
    CrossrefPubMedGoogle Scholar
  • 26 Casonato A, Pontara E, Boscaro M. et al. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing's syndrome. Blood Coagul Fibrinolysis 1999; 10 (03) 145-151
    CrossrefPubMedGoogle Scholar
  • 27 Boscaro M, Sonino N, Scarda A. et al. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing's syndrome. J Clin Endocrinol Metab 2002; 87 (08) 3662-3666
    PubMedGoogle Scholar
  • 28 Kastelan D, Dusek T, Kraljevic I. et al. Hypercoagulability in Cushing's syndrome: the role of specific haemostatic and fibrinolytic markers. Endocrine 2009; 36 (01) 70-74
    CrossrefPubMedGoogle Scholar
  • 29 van der Pas R, de Bruin C, Leebeek FWG. et al. The hypercoagulable state in Cushing's disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J Clin Endocrinol Metab 2012; 97 (04) 1303-1310
    CrossrefPubMedGoogle Scholar
  • 30 Birdwell L, Lodish M, Tirosh A. et al. Coagulation profile dynamics in pediatric patients with cushing syndrome: a prospective, observational comparative study. J Pediatr 2016; 177: 227-231
    CrossrefPubMedGoogle Scholar
  • 31 Manetti L, Bogazzi F, Giovannetti C. et al. Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery. Eur J Endocrinol 2010; 163 (05) 783-791
    CrossrefPubMedGoogle Scholar
  • 32 Chopra A, Kumar R, Kishore K. et al. Effect of glucocorticoids on von Willebrand factor levels and its correlation with von Willebrand factor gene promoter polymorphism. Blood Coagul Fibrinolysis 2012; 23 (06) 514-519
    CrossrefPubMedGoogle Scholar
  • 33 Fatti LM, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci PM. Markers of activation of coagulation and fibrinolysis in patients with Cushing's syndrome. J Endocrinol Invest 2000; 23 (03) 145-150
    CrossrefPubMedGoogle Scholar
  • 34 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 (02) 169-174
    CrossrefPubMedGoogle Scholar
  • 35 Koutroumpi S, Spiezia L, Albiger N. et al. Thrombin generation in Cushing's Syndrome: do the conventional clotting indices tell the whole truth?. Pituitary 2014; 17 (01) 68-75
    CrossrefPubMedGoogle Scholar
  • 36 Tripodi A. Thrombin generation assay and its application in the clinical laboratory. Clin Chem 2016; 62 (05) 699-707
    CrossrefPubMedGoogle Scholar
  • 37 Majoor CJ, Kamphuisen PW, Zwinderman AH. et al. Risk of deep vein thrombosis and pulmonary embolism in asthma. Eur Respir J 2013; 42 (03) 655-661
    CrossrefPubMedGoogle Scholar
  • 38 Chung W-S, Lin C-L, Ho F-M. et al. Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study. Eur Respir J 2014; 43 (03) 801-807
    CrossrefPubMedGoogle Scholar
  • 39 Lippi G, Favaloro EJ. Allergy and Venous Thromboembolism: A Casual or Causative Association. Semin Thromb Hemost 2016; 42 (01) 63-68
    PubMedGoogle Scholar
  • 40 Rizkallah J, Man SFP, Sin DD. Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest 2009; 135 (03) 786-793
    CrossrefPubMedGoogle Scholar
  • 41 Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spencer FA. Venous thromboembolism in patients with chronic obstructive pulmonary disease. Am J Med 2012; 125 (10) 1010-1018
    CrossrefPubMedGoogle Scholar
  • 42 Mejza F, Lamprecht B, Niżankowska-Mogilnicka E, Undas A. Arterial and venous thromboembolism in chronic obstructive pulmonary disease: from pathogenic mechanisms to prevention and treatment. Pneumonol Alergol Pol 2015; 83 (06) 485-494
    CrossrefPubMedGoogle Scholar
  • 43 Cao YQ, Dong LX, Cao J. Pulmonary embolism in patients with acute exacerbation of chronic obstructive pulmonary disease. Chin Med J (Engl) 2018; 131 (14) 1732-1737
    CrossrefPubMedGoogle Scholar
  • 44 Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375 (9715): 657-663
    CrossrefPubMedGoogle Scholar
  • 45 Nguyen GC, Bernstein CN, Bitton A. et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology 2014; 146 (03) 835-848.e6
    CrossrefPubMedGoogle Scholar
  • 46 Cheng K, Faye AS. Venous thromboembolism in inflammatory bowel disease. World J Gastroenterol 2020; 26 (12) 1231-1241
    CrossrefPubMedGoogle Scholar
  • 47 Choi HK, Rho Y-H, Zhu Y, Cea-Soriano L, Aviña-Zubieta JA, Zhang Y. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis 2013; 72 (07) 1182-1187
    CrossrefPubMedGoogle Scholar
  • 48 Ogdie A, Kay McGill N, Shin DB. et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J 2018; 39 (39) 3608-3614
    CrossrefPubMedGoogle Scholar
  • 49 Li L, Lu N, Avina-Galindo AM. et al. The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study. Rheumatology (Oxford) 2020; keaa262
    PubMedGoogle Scholar
  • 50 Johannesdottir SA, Schmidt M, Horváth-Puhó E, Sørensen HT. Autoimmune skin and connective tissue diseases and risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost 2012; 10 (05) 815-821
    CrossrefPubMedGoogle Scholar
  • 51 Zöller 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 (9812): 244-249
    CrossrefPubMedGoogle Scholar
  • 52 Tamaki H, Khasnis A. Venous thromboembolism in systemic autoimmune diseases: a narrative review with emphasis on primary systemic vasculitides. Vasc Med 2015; 20 (04) 369-376
    CrossrefPubMedGoogle Scholar
  • 53 Ungprasert P, Wijarnpreecha K, Thongprayoon C. Risk of venous thromboembolism in patients with bullous pemphigoid: a systematic review and meta-analysis. Indian J Dermatol Venereol Leprol 2018; 84 (01) 22-26
    CrossrefPubMedGoogle Scholar
  • 54 Cosgriff SW, Diefenbach AF, Vogt Jr W. Hypercoagulability of the blood associated with ACTH and cortisone therapy. Am J Med 1950; 9 (06) 752-756
    CrossrefPubMedGoogle Scholar
  • 55 Cosgriff SW. Thromboembolic complications associated with ACTH and cortisone therapy. J Am Med Assoc 1951; 147 (10) 924-926
    CrossrefPubMedGoogle Scholar
  • 56 Huerta C, Johansson S, Wallander M-A, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007; 167 (09) 935-943
    CrossrefPubMedGoogle Scholar
  • 57 Albucher JF, Vuillemin-Azaïs C, Manelfe C, Clanet M, Guiraud-Chaumeil B, Chollet F. Cerebral thrombophlebitis in three patients with probable multiple sclerosis. Role of lumbar puncture or intravenous corticosteroid treatment. Cerebrovasc Dis 1999; 9 (05) 298-303
    CrossrefPubMedGoogle Scholar
  • 58 Gazioglu S, Solmaz D, Boz C. Cerebral venous thrombosis after high dose steroid in multiple sclerosis: a case report. Hippokratia 2013; 17 (01) 88-90
    PubMedGoogle Scholar
  • 59 Kalanie H, Harandi AA, Alidaei S, Heidari D, Shahbeigi S, Ghorbani M. Venous thrombosis in multiple sclerosis patients after high-dose intravenous methylprednisolone: the preventive effect of enoxaparin. Thrombosis 2011; 2011: 785459
    CrossrefPubMedGoogle Scholar
  • 60 Al-Khalaf AH, Khatri IA. Cerebral venous sinus thrombosis in a patient with Cushings syndrome due to topical steroid. Neurosciences (Riyadh) 2016; 21 (01) 75-76
    CrossrefPubMedGoogle Scholar
  • 61 Sneeboer MMS, Hutten BA, Majoor CJ, Bel EHD, Kamphuisen PW. Oral and inhaled corticosteroid use and risk of recurrent pulmonary embolism. Thromb Res 2016; 140: 46-50
    CrossrefPubMedGoogle Scholar
  • 62 Pengo V, Lensing AWA, Prins MH. et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
    CrossrefPubMedGoogle Scholar
  • 63 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
    CrossrefPubMedGoogle Scholar
  • 64 Winter M-P, Schernthaner GH, Lang IM. Chronic complications of venous thromboembolism. J Thromb Haemost 2017; 15 (08) 1531-1540
    CrossrefPubMedGoogle Scholar
  • 65 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 66 Kahn SR, Comerota AJ, Cushman M. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014; 130 (18) 1636-1661
    CrossrefPubMedGoogle Scholar
  • 67 Kahn SR. The post-thrombotic syndrome. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 413-418
    CrossrefPubMedGoogle Scholar
  • 68 Kearon C, Kahn SR. Long-term treatment of venous thromboembolism. Blood 2020; 135 (05) 317-325
    CrossrefPubMedGoogle Scholar
  • 69 Shin J, Lee J-J, Kim K. et al; Korean Multiple Myeloma 151 Investigators. Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone. Int J Hematol 2019; 109 (01) 79-90
    CrossrefPubMedGoogle Scholar