Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events

A Large, Single-Center, Retrospective Study

Maria Gabriela Suarez; Madeleine Stack; Jose Miguel Hinojosa-Amaya; Michael D. Mitchell; Elena V. Varlamov; Chris G. Yedinak; Justin S. Cetas; Brett Sheppard; Maria Fleseriu


J Endo Soc. 2020;4(2) 

In This Article

Abstract and Introduction


Background: The risk of Cushing syndrome (CS) patients experiencing a thrombotic event (TE) is significantly higher (odds ratio; OR 18%) than that of the general population. However, there are currently no anticoagulation guidelines.

Methods: A retrospective, single-center, longitudinal study of patients undergoing all types of treatment—surgical (pituitary, unilateral, and bilateral adrenalectomy) and medical treatment—was undertaken. TEs were recorded at any point up until last patient follow-up; myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke. Patients' doses and complications of anticoagulation were recorded.

Results: Included were 208 patients; a total of 165 (79.3%) were women, and mean age at presentation was 44 ± 14.7 years. Thirty-nine (18.2%) patients had a TE; extremity DVT (38%), cerebrovascular accident (27%), MI (21%), and PE (14%). Of 56 TEs, 27 (48%) were arterial and 29 (52%) were venous. Patients who underwent bilateral adrenalectomy (BLA) had an odds ratio of 3.74 (95% CI 1.69–8.27) of developing a TE. Of patients with TEs, 40.5% experienced the event within the first 60 days after surgery. Baseline 24-hour urinary free cortisol levels did not differ in patients with or without TE after BLA. Of 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery, with 2% having bleeding complications.

Conclusions: The risk of TEs in patients with CS was approximately 20%. Many patients had more than 1 event, with higher risk 30 to 60 days postoperatively. The optimal prophylactic anticoagulation duration is unknown, but most likely needs to continue up to 60 days postoperatively, particularly after BLA.


Cushing syndrome (CS) is associated with a 2- to 4-fold higher mortality rate compared to the general population when not appropriately treated.[1–4] largely because of an increase in cardiovascular disease and infection.[1,5–7] Hypercoagulability has been described both in patients with CS and in patients on glucocorticoid (GC) treatment;[8] however, an underlying mechanism has yet to be determined. Coagulation factors VIII, IX, and XI, and von Willebrand factor were shown to be increased indirectly in some studies that compared healthy controls to endogenous hypercortisolemic patients, representing activation of the coagulation pathway.[9–13] Patients with CS also have a significant increase in fast-activating plasminogen activator inhibitor 1, impairing the fibrinolytic system and thereby increasing coagulation risk.[10,14] The presence of inflammation in patients with CS, enhanced oxidative stress, and platelet activation may also have a pathogenic role.[15,16] Increased inflammatory and procoagulant activity, and decreased fibrinolytic factors, lead to an elevated risk both of venous and arterial thromboembolism in patients with CS.

The risk of a thrombotic event (TE) in patients with CS has been reported to be up to 10 times higher than that of the general population.[17,18] A systematic review found TE risk to be 1.9% to 2.5% in the absence of surgical intervention, corresponding to an incidence of 2.5 to 3.1 per 1000 person-years.[18] In a recent meta-analysis, we reported that the calculated odds ratio (OR) of venous thromboembolism events (VTEs) in patients with CS was 17.82 compared to that of the general population.[19] Furthermore, a multicenter cohort study reported that the risk of postoperative VTE was significantly higher in patients with Cushing disease (CD) compared to patients undergoing pituitary surgery for a nonfunctioning pituitary adenoma, suggesting that the high risk for postoperative VTE in patients with CS is cortisol mediated,[17] with similarly reported results in smaller series.[18,20–22]

A thromboprophylaxis protocol is well established for orthopedic surgeries, which are considered high VTE risk (TE up to 40% to 60% of patients if not on prophylaxis,[23,24]), but there are currently no guidelines for hypercortisolemic patients undergoing transsphenoidal surgery (TSS), unilateral adrenalectomy (UA), or bilateral adrenalectomy (BLA).[25] Thus, the outcomes for patients with CS, with or without perioperative anticoagulation treatment, remain unclear. Here we evaluate the risk both of arterial TEs and VTEs and thromboembolic events in patients with CS and postoperative complications associated with prophylactic anticoagulation after TSS or BLA.