Hypercoagulability and Risk of Venous Thromboembolic Events in Endogenous Cushing's Syndrome: A Systematic Meta-Analysis

Abstract

Background: Hypercortisolism has been implicated in the development of venous thromboembolic events (VTE). We aimed to characterize VTE risk in endogenous Cushing's syndrome (CS) patients, compare that risk to other pathologies, and determine if there are any associated coagulation factor changes.Methods: Medline and Scopus search for “hypercortisolism” and “thromboembolic disease” from January 1980 to April 2017 to include studies that reported VTE rates and/or coagulation profile of CS patients. A systematic review and meta-analysis were performed.Results: Forty-eight studies met inclusion criteria. There were 7,142 CS patients, average age was 42 years and 77.7% female. Odds ratio of spontaneous VTE in CS is 17.82 (95%CI 15.24–20.85, p < 0.00001) when comparing to a healthy population. For CS patients undergoing surgery, the odds ratio (both with / without anticoagulation) of spontaneous VTE is 0.26 (95%CI 0.07–0.11, p < 0.00001)/0.34 (0.19–0.36, p < 0.00001) when compared to patients undergoing hip fracture surgery who were not treated with anticoagulants. Coagulation profiles in patients with CS showed statistically significant differences compared to controls, as reflected by increases in von Willebrand factor (180.11 vs. 112.53 IU/dL, p < 0.01), as well as decreases in activated partial thromboplastin time (aPTT; 26.91 vs. 30.65, p < 0.001) and increases in factor VIII (169 vs. 137 IU/dL, p < 0.05).Conclusion: CS is associated with significantly increased VTE odds vs. general population, but lower than in patients undergoing major orthopedic surgery. Although exact timing, type, and dose of anticoagulation medication remains to be established, clinicians might consider monitoring vWF, PTT, and factor VIII when evaluating CS patients and balance advantages of thromboprophylaxis with risk of bleeding.

A challenging case of Cushing’s disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report

“…Thromboembolic complications are four-fold higher among patients with CS [ 11 ]. This is due to increased synthesis of fibrinogen and von Willebrand factor stimulated by cortisol, as well as increased synthesis of plasminogen activator inhibitor type 1 [ 12 , 13 ]. Venous thrombo-embolism is the most commonly reported thrombotic phenomenon in these patients while acute mesenteric ischemia as seen in this patient is only rarely reported [ 14 ].…”

“…The Endocrine Society Clinical Practice guidelines suggest considering anticoagulation treatment peri-operatively specially as the risk of thrombo-embolism is highest in the first 4 weeks after surgery, due to worsening of the clotting profile [ 16 , 17 ]. The sudden reduction of cortisol level with its anti-inflammatory activity, leading to increased risk of inflammation and thrombotic state also contributes to the post-surgical worsening of the thrombotic risk [ 12 ]. This could have been a contributory factor for these complications in our patient, as she had normal post-operative cortisol level.…”

Pulmonary embolism as the presenting symptom and a confounder in ACTH-secreting bronchial carcinoid

“…Her presentation with spontaneous pulmonary embolism is atypical, but hypercoagulability is a known complication of hypercortisolism. Untreated CS can be associated with increased venous thromboembolism risk due to both activation of the coagulation cascade and an impaired fibrinolysis (5). Increased levels of Factor VIII, vWF antigen and vWF ristocetin activity and reduced fibrinogen levels were present in our patient.…”

Hypercortisolemia Recurrence in Cushing's Disease; a Diagnostic Challenge

“…Endogenous Cushing's syndrome (CS) is caused in ~80% of cases by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (Cushing's disease; CD), in other cases by a cortisol-producing adrenal source (adrenal adenoma, hyperplasia, or carcinoma) and in less frequent cases an ectopic ACTH-secreting neuroendocrine tumor (1–4).…”

“…Hypercortisolemia is associated with changes in body composition and metabolic comorbidities such as dyslipidemia, insulin resistance, diabetes mellitus, hypercoagulability, and hypertension (1–4). Untreated CS, especially in severe cases, has a poor prognosis and high mortality, with patient survival rates of only 50% after 5 years (5) while treated disease has a much better prognosis (3).…”