Venous thromboembolism in Cushing syndrome: current evidence and a practical thromboprophylaxis algorithm

Cushing syndrome (CS) is a rare endocrine disorder associated with a markedly increased risk of venous thromboembolism (VTE). Chronic hypercortisolism induces a prothrombotic state through activation of coagulation pathways, impaired fibrinolysis, and endothelial dysfunction. VTE represents a major source of morbidity and mortality in this population, yet optimal strategies for prevention and treatment remain insufficiently standardized. To summarize current evidence on the epidemiology, pathophysiology, risk factors, prevention, and treatment of VTE in patients with endogenous CS and to propose a practical thromboprophylaxis approach. A narrative review of the literature was conducted using MEDLINE/PubMed, Scopus, and Embase databases. Observational studies, registry data, systematic reviews, and expert consensus statements addressing VTE in CS were analyzed, with particular attention to peri-operative risk and persistence of hypercoagulability after remission. Patients with CS have a 10–20-fold higher risk of VTE compared with the general population. The peri-operative period, especially after TSS or adrenalectomy, represents the highest-risk phase, although increased thrombotic risk may persist for 3–6 months after biochemical remission. Key mechanisms include elevated factor VIII, von Willebrand factor, plasminogen activator inhibitor-1, increased thrombin generation, and endothelial dysfunction. Recent evidence from the ERCUSYN registry and the 2025 Delphi consensus supports early and extended thromboprophylaxis. Current expert consensus supports low-molecular-weight heparin as the preferred peri-operative pharmacological agent, whereas direct oral anticoagulants may be considered in selected patients during long-term management. CS should be regarded as a persistent prothrombotic condition in which early and, when appropriate, extended thromboprophylaxis should be considered following individualized assessment of thrombotic and bleeding risk. Prospective studies are needed to develop evidence-based, individualized prevention strategies.