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Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors

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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.

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Acknowledgments

This work was supported by an AIRC (Associazione Italiana Ricerca Cancro, Milan) grant to G.M. (IG-15507) and by Ricerca Funds by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. The authors wish to thank Dr. Paolo Bucciarelli for statistical advice.

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Authors and Affiliations

  1. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy

    Armando Tripodi, Lidia Padovan, Veena Chantarangkul & Flora Peyvandi

  2. Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy

    Armando Tripodi, Elena Malchiodi, Elisa Verrua, Emanuele Ferrante, Lidia Padovan, Veena Chantarangkul & Giovanna Mantovani

  3. Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy

    Concetta T. Ammollo, Fabrizio Semeraro & Mario Colucci

  4. Unit of Endocrinology and Diabetology, Milano, Italy

    Elena Malchiodi, Elisa Verrua, Emanuele Ferrante & Giovanna Mantovani

  5. Clinica di Endocrinologia e Malattie del Metabolismo, Ospedali Riuniti di Ancona, Ancona, Italy

    Giorgio Arnaldi & Laura Trementino

  6. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy

    Flora Peyvandi

  7. IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy

    Armando Tripodi, Elena Malchiodi, Elisa Verrua, Emanuele Ferrante, Lidia Padovan, Veena Chantarangkul, Flora Peyvandi & Giovanna Mantovani

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  1. Armando Tripodi
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  2. Concetta T. Ammollo
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Correspondence to Armando Tripodi.

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Tripodi, A., Ammollo, C.T., Semeraro, F. et al. Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors. Endocrine 56, 298–307 (2017). https://doi.org/10.1007/s12020-016-1027-1

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