Abstract
Cushing's syndrome (CS) is associated with a hypercoagulable state resulting in an increased risk on venous thromboembolism (VTE). In patients with untreated active CS VTE incidence is up to 18-fold higher compared to the general population, whereas after pituitary and adrenal surgery a postoperative VTE risk between 2.6 and 5.6% has been reported. Interestingly, after surgery the VTE risk is not only increased in the first week but also during several months postoperatively. The hypercoagulable state in CS is thought to be caused, at least in part, by an imbalance between activity of pro- and anticoagulant pathways. However, changes in activated partial thromboplastin time and plasma concentrations of pro-and anticoagulant factors are not observed in every CS patient. Only retrospective studies have shown that thromboprophylaxis lowers VTE risk in CS. Future prospective studies should asses the optimal timing, duration and type of thromboprophylaxis in CS to improve VTE-related morbidity and mortality.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Cushing’s syndrome (CS) is a multisystem disorder that is accompanied by a high risk of cardiovascular morbidity and mortality [1]. Less well known is that CS, irrespective of the cause, is associated with a hypercoagulable state predisposing these patients to venous thromboembolism (VTE) that may contribute to the cardiovascular morbidity as well [2]. This hypercoagulable state may seem discrepant with the increased bruising of CS and might be considered as a ‘CS coagulation paradox’. However, the increased bruising of CS is caused by skin atrophy and capillary fragility, whereas the prothrombotic state is due to an imbalance between the activity of pro- and anticoagulant pathways. In this overview the incidence, pathophysiology and prophylaxis of VTE associated with CS will be discussed.
Incidence
Two phases are important with respect to the incidence of CS-associated VTE: the untreated active hypercortisolemic phase and the postoperative phase. In a systematic review, van Zaane and co-workers found an increased incidence rate of VTE in active CS (2.5–3.1 per 1000 person years) compared to the control population (0.27 per 1000 person years) [3]. In a systematic meta-analysis, VTE incidence in patients with CS was almost 18-fold higher compared to the general population [4], whereas a Swedish nation-wide study demonstrated a standardized incidence ratio for VTE of 13.8 (interquartile range 3.8–35.3) in the 3-year period before diagnosis of CS [5].
Postoperative VTE risk in the van Zaane study increased to 5.6%, comparable to the VTE risk after orthopedic surgery under routine thromboprophylaxis. Subsequently, a retrospective multicenter cohort study of 473 CS patients demonstrated an overall VTE incidence rate of 14.6 per 1000 person-years, which corresponds to more than a tenfold increased risk for VTE compared to the general population [6]. In this study the postoperative risk of VTE in patients with pituitary-dependent CS of 4.3% was increased compared to 0% incidence in patients operated for a nonfunctional pituitary adenoma [6]. Interestingly, no increased postoperative VTE risk was found in patients with ACTH-independent CS following adrenalectomy. In contrast, in a large retrospective study of 4217 patients who underwent adrenal surgery, Babic and co-workers found a VTE prevalence of 2.6% in patients (n = 310) with CS versus 0.9% in non-CS patients [7].
Interestingly, the postoperative VTE risk is not only increased in the first week after pituitary or adrenal surgery, but also up to 2–3 months or even years postoperatively, despite biochemical remission, which may indicate a delayed reversibility of the prothrombotic state [5,6,7].
Pathogenesis
The hypercoagulable state in CS is not fully understood, but is thought to be caused by an imbalance between activity of pro- and anticoagulant pathways [2]. Indeed, functional assays show a shortening of the activated partial thromboplastin time (aPTT) and an increased clot lysis time in a subset of CS patients [2, 4]. In addition, concentrations of the procoagulant factors (fibrinogen, von Willebrand factor (vWF) and factor VIII) and fibrinolysis inhibitors (plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI) and alpha-2-antiplasmin) [2, 4] are increased in active CS (Table 1.). Some studies show elevated levels of protein C, protein S and antithrombin III [4] which may be a compensatory mechanism for the hypercoagulable state. Glucocorticoids are thought to have direct stimulatory effects on the production of factors like fibrinogen, vWF, factor VIII, PAI-1 and TAFI [2], although no relation was found between severity of hypercortisolism and VTE risk in CS [4]. It should be emphasized, though, that reported coagulation profiles in CS patients are very heterogenous, presumably explained by individual patient characteristics and by differences in used assays that measure hemostatic parameters.
Several studies show sustained abnormalities in pro- and anticoagulant factors after curative surgery in a subset of patients, which may in part explain the earlier mentioned prolonged VTE risk despite control of cortisol production. For instance, hemostatic parameters did not normalize after short-term biochemical remission, i.e. three months, induced by medical therapy [8]. Similarly, not all procoagulant factors normalized after longer follow-up, i.e. one year after surgical cure [9]. Persistent abdominal obesity, which is known to be associated with elevated plasma levels of fibrinogen, vWF and PAI-1, may underlie this prolonged elevation [10].
In addition to changes in hemostasis mediated by cortisol excess, other mechanisms may contribute to the increased VTE risk. After successful pituitary or adrenal surgery, a sudden fall in cortisol levels may lead to an inflammatory response [11] that can activate the coagulation cascade [12]. Further, in patients with ectopic ACTH production and patients with a cortisol producing adrenal carcinoma, the underlying malignant disorder itself predisposes for VTE. Retrospective studies have identified other more common risk factors for VTE, such as age, body mass index, reduced mobility, acute infections, previous cardiovascular events, midnight plasma cortisol level and a shortened aPTT [13].
Thromboprophylaxis
To date, no prospective studies or guidelines have been published on efficacy, duration and type of thromboprophylaxis in active CS and in the postoperative period. However, retrospective studies have shown that the incidence of VTE was lower in patients who received thromboprophylaxis compared to those who did not [14, 15]. Apart from thromboprophylaxis, preoperative cortisol-lowering therapy may reduce VTE risk, although this was only shown in one retrospective study [6], whereas another retrospective study found no benefit [16]. A recent survey assessing current clinical practice of thromboprophylaxis in reference centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN) demonstrated considerable heterogeneity with respect to timing, duration and type of thromboprophylaxis [17]. Most centers started thrombophylaxis from diagnosis onwards, usually with low molecular weight heparin, but treatment duration was highly variable and often a thromboprophylaxis protocol was unavailable.
Currently the best approach may be to give thromboprophylaxis in a tailor-made manner in CS patients, both in the active phase and postoperatively, considering additional risk factors for thrombosis like history of VTE, age, obesity, current use of oestrogen or oral contraceptives and mobility, but also considering the risk of bleeding complications [18]. Further, it can be considered to temporarily stop oestrogen therapy in female patients before surgery. Thromboprophylaxis should be discontinued before transsphenoidal adenomectomy to minimize the risk of intraoperative bleeding [18]. In the postoperative setting, extended thromboprophylaxis, i.e. four to eight weeks, is recommended, especially for high-risk patients [2]. In addition, early postoperative ambulation and use of compression stockings are useful supportive measures to prevent VTE [18].
Conclusion
CS is associated with an increased VTE risk. Currently there is no standard protocol for preoperative or postoperative thromboprophylaxis in patients with CS. Future studies should focus on the pathogenesis of the hypercoagulable state in CS and delineate which subgroups of CS are at greater risk for VTE based on clinical features and perhaps also based on profiles of coagulation parameters. This should be assessed for both the untreated active phase and the (extended) postoperative phase. Finally, there is a clear need for prospective studies that generate data that can guide the timing, duration and type of thromboprophylaxis in CS. The risk(s) for and the optimal prevention of life-threatening thrombotic events deserve more targeted investigation to improve morbidity and mortality.
References
Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015) Cushing’s syndrome. Lancet 386(9996):913–927
van der Pas R, Leebeek FW, Hofland LJ, de Herder WW, Feelders RA (2013) Hypercoagulability in Cushing’s syndrome: prevalence, pathogenesis and treatment. Clin Endocrinol (Oxf) 78(4):481–488
Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E et al (2009) Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 94(8):2743–2750
Wagner J, Langlois F, Lim DST, McCartney S, Fleseriu M (2018) Hypercoagulability and risk of venous thromboembolic events in endogenous Cushing’s syndrome: a systematic meta-analysis. Front Endocrinol (Lausanne) 9:805
Papakokkinou E, Olsson DS, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T et al (2020) Excess morbidity persists in patients with Cushing’s disease during long-term remission: a swedish nationwide study. J Clin Endocrinol Metab 105(8):2616–2624
Stuijver DJ, van Zaane B, Feelders RA, Debeij J, Cannegieter SC, Hermus AR et al (2011) Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab 96(11):3525–3532
Babic B, De Roulet A, Volpe A, Nilubol N (2019) Is VTE prophylaxis necessary on discharge for patients undergoing adrenalectomy for Cushing syndrome? J Endocr Soc 3(2):304–313
van der Pas R, de Bruin C, Leebeek FW, de Maat MP, Rijken DC, Pereira AM et al (2012) 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 97(4):1303–1310
Manetti L, Bogazzi F, Giovannetti C, Raffaelli V, Genovesi M, Pellegrini G et al (2010) 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 163(5):783–791
Targher G, Zoppini G, Moghetti P, Day CP (2010) Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin Thromb Hemost 36(1):41–48
Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP (1996) Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J Clin Endocrinol Metab 81(6):2303–2306
Levi M (2010) The coagulant response in sepsis and inflammation. Hamostaseologie 30(1):10-2-14–6
Zilio M, Mazzai L, Sartori MT, Barbot M, Ceccato F, Daidone V et al (2016) A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine 52(2):322–332
Boscaro M, Sonino N, Scarda A, Barzon L, Fallo F, Sartori MT et al (2002) Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing’s syndrome. J Clin Endocrinol Metab 87(8):3662–3666
Barbot M, Daidone V, Zilio M, Albiger N, Mazzai L, Sartori MT et al (2015) Perioperative thromboprophylaxis in Cushing’s disease: What we did and what we are doing? Pituitary 18(4):487–493
Valassi E, Franz H, Brue T, Feelders RA, Netea-Maier R, Tsagarakis S et al (2018) Preoperative medical treatment in Cushing’s syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. Eur J Endocrinol 178(4):399–409
van Haalen FM, Kaya M, Pelsma ICM, Dekkers OM, Biermasz NR, Cannegieter SC et al (2022) Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference network on rare endocrine conditions (Endo-ERN). Orphanet J Rare Dis 17(1):178
Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 9(12):847–875
Acknowledgements
This work was created in part through the support of the NIDDK intramural program of the National Institutes of Health
Funding
No funding.
Author information
Authors and Affiliations
Contributions
RAF and LKN Both authors equally contributed to the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Conflict of interest
Nothing to declare.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Feelders, R.A., Nieman, L.K. Hypercoagulability in Cushing’s syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols. Pituitary 25, 746–749 (2022). https://doi.org/10.1007/s11102-022-01261-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11102-022-01261-9