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


We conducted an institutional review board–approved, retrospective, longitudinal study among 208 patients with CS seen at Oregon Health & Science University Pituitary Center (July 2006 to August 2018), with a waiver of informed consent. We included patients undergoing all types of treatment—surgery (pituitary, unilateral, and BLA)—as well as patients on medical treatment. Exclusion criteria included pediatric patients, incomplete data, and patients with severe illness. A single entry was removed as an extreme data outlier. Two patients with ectopic Cushing syndrome (ECS) were excluded because their primary neuroendocrine tumor was very advanced with significant tumor burden and they died before follow-up in clinic. Two other patients were excluded from the time to TE analysis because of unknown TE dates. The following TEs were recorded at any point up until their last follow-up: myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke.

Diagnosis of CS was based on elevated 24-hour urinary free cortisol (UFC), elevated midnight salivary cortisol levels, and cortisol concentrations greater than 1.8 μg/dL after a 1 mg dexamethasone suppression test or a 2-day low-dose (2 mg/d) dexamethasone suppression test. Cortisol cutoff used for dexamethasone–corticotropin-releasing hormone (CRH) test was greater than 2.4 μg/dL.

CD was diagnosed by the presence of a pituitary adenoma and/or positive central-to-peripheral gradient on inferior petrosal sinus sampling (IPSS). Adrenal Cushing syndrome (ACS) was diagnosed in the presence of suppressed adrenocorticotropic hormone (ACTH) levels, or lack of response of ACTH to the dexamethasone–corticotropin-releasing hormone stimulation test and imaging confirming the presence of an adrenal mass. ECS was diagnosed based on elevated ACTH levels and gradient-negative inferior petrosal sinus sampling (suggestive of a nonpituitary ACTH production origin).

A mean of 3 × 24-hour UFC in patients who had BLA was calculated from the last 3 UFC obtained within the 6 months prior to BLA. Samples were sometimes analyzed in different laboratories; furthermore, because of the long duration of the study, methods changed, including immunoassay and liquid chromatography–mass spectrometry. Thus, we standardized the UFC levels by calculating the ratio of the absolute UFC level to the upper limit of normal range (ULN).

We evaluated all patients who received anticoagulation in the immediate postoperative period and up to 3 months postsurgery. Doses and complications for anticoagulation were assessed and recorded for each patient.

Statistical Analysis

Statistical analysis was performed using SAS 9.4 and included descriptive statistics, analysis of variance, and Kruskal-Wallis, chi-square, and t tests, and simple linear regression analysis. Descriptive data are presented as ± SD. Significance was considered as P < .05.