title: Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors.
abstract: Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy. armando.tripodi@unimi.it.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy. armando.tripodi@unimi.it.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy. armando.tripodi@unimi.it.
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
authors.forename: Concetta T
authors.initials: CT
authors.lastname: Ammollo
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Semeraro
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Colucci
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|Unit of Endocrinology and Diabetology, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Malchiodi
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|Unit of Endocrinology and Diabetology, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Verrua
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|Unit of Endocrinology and Diabetology, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ferrante
authors.affiliation: Clinica di Endocrinologia e Malattie del Metabolismo, Ospedali Riuniti di Ancona, Ancona, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Arnaldi
authors.affiliation: Clinica di Endocrinologia e Malattie del Metabolismo, Ospedali Riuniti di Ancona, Ancona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Trementino
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Padovan
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Veena
authors.initials: V
authors.lastname: Chantarangkul
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.|Unit of Endocrinology and Diabetology, Milano, Italy.|IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood*; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D065206:Extracellular Traps / Q000378:metabolism*; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D006801:Humans; D009504:Neutrophils / Q000378:metabolism*; D047748:Pituitary ACTH Hypersecretion / Q000097:blood*; D011486:Protein C / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*
chemical_list: D011486:Protein C; C078147:F8 protein, human; D005169:Factor VIII; D000324:Adrenocorticotropic Hormone; D013917:Thrombin
keywords: Activated partial thromboplastin time; Antithrombin; Factor VIII; Myeloperoxidase; Plasma DNA; Protein C; Thrombomodulin; Thrombosis