Hypercoagulability in ACTH-Dependent Cushing Syndrome

Abstract

Introduction: ACTH-dependent Cushing syndrome (CS) is associated with hypercoagulability; however, the incidence and timing of thrombosis during evaluation and management of CS is unclear.Objective: To evaluate the incidence and timing of thrombotic events in patients with ACTH-dependent CS following diagnosis and management.Methods: We performed a retrospective, longitudinal study of patients with ACTH-dependent CS seen at Stanford University Health Care from 1998 to 2020. Thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral vascular accident (CVA), and myocardial infarction (MI) — were recorded between diagnosis and 12 months following therapeutic intervention.Results: Of 108 patients with ACTH-dependent CS, 97 (89.8%) were women, and the mean age at diagnosis was 43.0 years (± 15.7 years). Sixty-eight (63%) patients had hypertension, 38 (35.2%) had diabetes mellitus, and 11 (10.2%) were active smokers. Of the 108 subjects, 97 (89.8%) had Cushing Disease (CD) and 11 (10.2%) had ectopic CS. Of the 97 patients with CD, 38 (39.2%) underwent inferior petrosal sinus sampling (IPSS), 59 (60.8%) underwent transsphenoidal surgery (TSS), 19 required repeat TSS (19.6%), and 15 underwent TSS and bilateral adrenalectomy (BAL) (15.4%). Of the 11 patients with ectopic CS, 3 (27.2%) underwent IPSS, 6 (54.5%) underwent BAL, and 1 (9.1%) underwent TSS and BAL.There were 10 thrombotic events among 7 (7.2%) CD patients, but no thrombotic events among ectopic CS patients. Of the thrombotic events, there were 7 (70%) DVT/PE, 2 (20%) CVA, and 1 (10%) cortical vein thrombosis. Six (60%) occurred within 30 days after TSS (range 3-25 days), 2 (20%) between 31 days and 1 year after TSS (range 59-165 days), 1 (10%) 26 days after IPSS but prior to TSS, and 1 (10%) in a patient who did not undergo IPSS or surgery. No thrombotic events were noted after BAL. Of the 8 postoperative thrombotic events, 5 (62.5%) occurred while patients received supraphysiologic glucocorticoid replacement (defined as >25mg hydrocortisone or equivalent daily) after curative surgery, 1 (12.5%) occurred after a patient was tapered to physiologic glucocorticoid replacement, and 2 (25%) occurred in patients who had persistent disease despite surgery. The degree of hypercortisolism at baseline was not associated with risk of thrombotic events.Conclusions: In this retrospective study, 6.5% of ACTH-dependent CS patients had a thrombotic event, all in patients with CD. The majority had venous thromboembolism with DVT/PE, and the highest incidence occurred up to 30 days after surgery. The degree of hypercortisolism at baseline did not correlate with subsequent thrombotic events. Therefore, it is important to monitor all patients with ACTH-dependent CS following surgical intervention for venous thromboembolism.