Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery

Abstract

Objectives: To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). Design: Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. Patients and methods: Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. Results: CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P!0.0001, a 2 antiplasmin, PZ0.0004, thrombin-antithrombin complex (TAT), PZ0.01, factor IX (F9), PZ0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P!0.0001), PAI-1 (PZ0.004), TAT (PZ0.0001), ATIII (PZ0.0002) and a 2 antiplasmin (or SERPINF2; PZ0.006)), whereas aPTT levels (PZ0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (PZ0.04). Conclusions: Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

D-dimer as a significant marker of deep vein thrombosis in patients with subclinical or overt Cushing’s syndrome

“…The D-dimer levels were found to be elevated [6] or unchanged [32] relative to those in healthy control subjects. No changes in the D-dimer levels in patients with soCS were observed at 28 and 77 days after medical treatment [28].…”

“…Regarding the mechanistic insight, patients with CS have been reported to present with elevated plasma levels of clotting factors, including VWF and factor VIII, which increases the plasma D-dimer levels [6,28,29]. On the other hand, the levels of PAI-1, the primary inhibitor of the fibrinolytic system, were found to be elevated in patients with CS [6,30,31].…”

“…On the other hand, the levels of PAI-1, the primary inhibitor of the fibrinolytic system, were found to be elevated in patients with CS [6,30,31]. PAI-1 attenuates D-dimer elevation by inducing a coagulation cascade, suggesting that the elevated PAI-1 levels in CS might reduce the D-dimer levels.…”

“…In a hypercortisol state, an impaired hemostatic system was found to associate significantly with several biomarkers such as elevated levels of von Willebrand factor (VWF), factor VIII, factor IX, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) [4][5][6]. Recently, VWF gene promoter polymorphisms have been reported to increase the risk of VTE via elevated levels of VWF in CS patients [7].…”

Cushing`s disease: Fibrinogen and D-dimer levels fail to normalize despite early postoperative remission — a prospective, controlled study

“…The hypercoagulable state can lead to increased incidence of thromboembolic episodes in the postoperative period or during diagnostic procedures such as inferior petrosal sinus sampling [9][10][11][12][13][14]. Boscaro et al demonstrated significantly higher thromboembolic mortality and morbidity in a group of Cushing's syndrome patients receiving no anti-thromboembolic prevention in comparison with those in a group receiving prophylactic treatment with the use of warfarin or heparin [14].…”