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.

Keywords: Cushing disease; Cushing syndrome; anticoagulation; hypercoagulability; venous thromboembolism.

Figure 1

Flow chart of the search strategy and selection.

Figure 2

Increase odds of VTE in CS. Total OR 17.82 (95% CI 15.24–20.85) of VTE in CS compared to general population when unadjusting for VTE within 30 days of an operation. However, the interpretability of this analysis is limited by the degree of heterogeneity of odds ratios between studies included, as indicated by the I² statistic of 91.0%.

Figure 3

Bias and overestimation of risk impact interpretation of risk of VTE in CS from literature. Funnel plot visually representing the heterogeneity among trials reporting odds of VTE in CS. As shown, included studies are asymmetrically distributed relative to the point estimate. This suggests that pooled results are influenced both by bias and overestimate of risk in the CS population.

Figure 4

Odds of VTE in CS without anticoagulation significantly less than hip fracture surgery without anticoagulation. Total OR 0.26 (95% CI 0.19–0.36) of postop (within 30 days of surgery) VTE in CS without anticoagulation compared to odds of postoperative VTE in cases of hip fracture repair without anticoagulation. This suggests the odds of VTE in CS patients in the perioperative period for those undergoing adrenalectomy or TSS are 84% less than that of patients undergoing surgery for hip fracture.

Figure 5

Odds of VTE in CS on anticoagulation significantly less than hip fracture surgery with anticoagulation. Total OR 0.34 (95% CI 0.20–0.61) of postop (within 30 days of surgery) VTE in CS with anticoagulation compared to odds of postoperative VTE in cases of hip fracture repair with anticoagulation. This suggests the odds of VTE in CS patients in the perioperative period for those undergoing adrenalectomy or TSS are 66% less than that of patients undergoing surgery for hip fracture.