title: The hypercoagulable state in Cushing's disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy.
abstract: BACKGROUND
  Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD.
  
  
  OBJECTIVE
  The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis.
  
  
  METHODS
  During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands.
  
  
  METHODS
  Seventeen patients with de novo, residual, or recurrent CD were included.
  
  
  METHODS
  We measured urinary free cortisol and parameters of coagulation and fibrinolysis.
  
  
  RESULTS
  Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly.
  
  
  CONCLUSIONS
  The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Centre, Room Ee 569, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. r.vanderpas@erasmusmc.nl
authors.forename: R
authors.initials: R
authors.lastname: van der Pas
authors.forename: C
authors.initials: C
authors.lastname: de Bruin
authors.forename: F W G
authors.initials: FW
authors.lastname: Leebeek
authors.forename: M P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: D C
authors.initials: DC
authors.lastname: Rijken
authors.forename: A M
authors.initials: AM
authors.lastname: Pereira
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
authors.forename: R T
authors.initials: RT
authors.lastname: Netea-Maier
authors.forename: A R
authors.initials: AR
authors.lastname: Hermus
authors.forename: P M J
authors.initials: PM
authors.lastname: Zelissen
authors.forename: F H
authors.initials: FH
authors.lastname: de Jong
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Lely
authors.forename: W W
authors.initials: WW
authors.lastname: de Herder
authors.forename: S W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: R A
authors.initials: RA
authors.lastname: Feelders
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000032:analysis*; D000077465:Cabergoline; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D016903:Drug Monitoring; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004873:Ergolines / Q000008:administration & dosage / Q000627:therapeutic use; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007654:Ketoconazole / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology* / Q000652:urine; D010908:Pituitary Hormones, Anterior / Q000037:antagonists & inhibitors*; D012074:Remission Induction; D013004:Somatostatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D019851:Thrombophilia / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control; D055815:Young Adult
chemical_list: D001779:Blood Coagulation Factors; D018491:Dopamine Agonists; D004873:Ergolines; D010908:Pituitary Hormones, Anterior; D013004:Somatostatin; C517782:pasireotide; D000077465:Cabergoline; D007654:Ketoconazole; D006854:Hydrocortisone