title: Observational retrospective study of vascular modulator changes during treatment in essential thrombocythemia.
abstract: Essential thrombocythemia (ET) patients are at risk of developing thrombotic events. Qualitative platelet (PLT) abnormalities and activation of endothelial cells (ECs) and PLTs are thought to be involved. Microparticles (MPs) can originate from PLTs (PMPs), ECs (EMPs), or red cells (RMPs). Previous studies have indicated that MPs contribute to ET pathophysiology. Endothelial modulators (eg, nitric oxide [NO], adrenomedullin [ADM], and endothelin-1 [ET-1]) are also involved in the pathophysiology of this condition. We hypothesized that treatments for reducing PLT count might also indirectly affect MP generation and endothelial activity by altering endothelial modulator production. The rationale of this study was that hydroxyurea (HU), a cytostatic drug largely used in ET, induces the production of a potent vasoactive agent NO in ECs. An observational retrospective study was designed to investigate the relationship between MPs, NO, ADM, and ET-1 in ET patients on treatment with HU, anagrelide (ANA), aspirin (ASA), and a group of patients before treatment. A total of 63 patients with ET diagnosis: 18 on HU + ASA, 15 on ANA + ASA, 19 on ASA only, and 11 untreated patients, and 18 healthy controls were included in this study. Blood samples were analyzed for MP (absolute total values) and functional markers (percentage values) by flow cytometry. PLT-derived MPs were studied using CD61, CD62P, CD36, and CD63, whereas endothelial-derived MPs were studied using CD105, CD62E, and CD144. Endothelial modulator markers (NO, ADM, and ET-1) were measured by ELISA. Total MP count was higher in the group treated with ANA + ASA (P < 0.01). MP markers modified in ET patients returned to levels of healthy controls following treatment, in particular, in patients on ANA treatment. NO and ADM values were higher in the HU group (P < 0.001). HU and ANA treatment also affected MP production in a cell origin-specific manner. HU and ANA, although acting via different pathways, have similar final effects. For instance, HU causes vasodilatation by increasing NO and ADM levels, whereas ANA impairs vasoconstriction by reducing ET-1. In conclusion, therapy with HU cytostatic drugs and ANA can reduce PLT count in ET, and also affect endothelial modulatory agents, with HU sustaining vasodilation and prothrombotic MP concentration, whereas ANA decreases vasoconstriction.
authors.affiliation: Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria; Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy; Irish Blood Transfusion Service, Dublin, Ireland; IMREST Interdisciplinary Medical Research Center South Tyrol, Italy. Electronic address: apiccin@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Piccin
authors.affiliation: Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Steurer
authors.affiliation: Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Feistritzer
authors.affiliation: Irish Blood Transfusion Service, Dublin, Ireland.
authors.forename: Ciaran
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Irish Blood Transfusion Service, Dublin, Ireland.
authors.forename: Elva
authors.initials: E
authors.lastname: Eakins
authors.affiliation: Haematology and Clinical Chemistry Laboratory, OLVG, Amsterdam, The Netherlands.
authors.forename: Muriel
authors.initials: M
authors.lastname: Van Schilfgaarde
authors.affiliation: Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy; IMREST Interdisciplinary Medical Research Center South Tyrol, Italy.
authors.forename: Daisy
authors.initials: D
authors.lastname: Corvetta
authors.affiliation: IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Central Laboratory, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Di Pierro
authors.affiliation: IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Central Laboratory, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Pusceddu
authors.affiliation: Department of Diagnostic, Medicine University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marcheselli
authors.affiliation: Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambato
authors.affiliation: Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Martin
authors.initials: M
authors.lastname: Langes
authors.affiliation: Department of Haematology, University of Medicine, Verona, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Veneri
authors.affiliation: Department of Haematology, University of Medicine, Verona, Italy.
authors.forename: Omar
authors.initials: O
authors.lastname: Perbellini
authors.affiliation: Department of Haematology, Cà Foncello Hospital, Treviso, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Pacquola
authors.affiliation: Department of Haematology, Cà Foncello Hospital, Treviso, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Gottardi
authors.affiliation: Department of Haematology, Cà Foncello Hospital, Treviso, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Gherlinzoni
authors.affiliation: IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Department of Gastroenterology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mega
authors.affiliation: Department of Pathology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Tauber
authors.affiliation: Department of Pathology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Mazzoleni
authors.affiliation: Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Piva
authors.affiliation: Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
authors.affiliation: Department of Haematology, University of Medicine, Verona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Krampera
authors.affiliation: Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Gastl
mesh_terms: D053607:Adrenomedullin / Q000097:blood / Q000378:metabolism; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000473:pathology; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D011799:Quinazolines / Q000627:therapeutic use; D012189:Retrospective Studies; D013920:Thrombocythemia, Essential / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D019332:Endothelin-1; D011799:Quinazolines; D053607:Adrenomedullin; D009569:Nitric Oxide; C021139:anagrelide; D001241:Aspirin; D006918:Hydroxyurea