sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20210603sibmed-695Research ArticleОБЗОРЫREVIEWSОсобенности состояния эндотелия при Ph-негативных миелопролиферативных новообразованияхEndothelium state in Ph-negative myeloproliferative neoplasmshttps://orcid.org/0000-0003-1762-6862КорсаковаН. Е.KorsakovaN. E.

Наталья Евгеньевна Корсакова

191024, г. Санкт-Петербург, ул. 2-я Советская, 16

Natalya E. Korsakova 

191024, Saint Petersburg, 2nd Sovetskaya str., 16

natalya_kors@mail.ruРоссийский НИИ гематологии и трансфузиологии ФМБА РоссииРоссияRussian Research Institute of Hematology and Transfusiology of FMBA of RussiaRussian Federation2021251220214163044Copyright © Корсакова Н.Е., 20212021Корсакова Н.Е.Korsakova N.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/695

Тромботические осложнения вносят существенный вклад в тяжесть течения заболевания и смертность при Phнегативных миелопролиферативных новообразованиях (МПН), включая истинную полицитемию, эссенциальную тромбоцитемию и первичный миелофиброз. Сосудистый эндотелий является неотъемлемым компонентом системы гемостаза, нарушение функциональности которого играет важную роль в развитии протромботических состояний. В обзоре приведен анализ имеющихся данных литературы по оценке особенностей эндотелия при Ph-негативных МПН и их выявлению при помощи различных методов. Поиск литературных источников проводили с использованием баз данных PubMed и eLibrary. Анализ результатов исследований с применением различных методов оценки свидетельствует, что для пациентов с Ph-негативными МПН характерны активация, повреждение и, следовательно, дисфункция эндотелия. Ассоциированные с миелопролиферацией нарушения эндотелия отражаются на реализации всех его функций. Эндотелиальная дисфункция является важным патогенетическим звеном развития тромботических осложнений при Ph-негативных МПН.

Thrombotic complications contribute significantly in morbidity and mortality of patients with Ph-negative myeloproliferative neoplasms (MPN) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Vascular endothelium is essential component of hemostatic system, and its functionality failure plays important role in prothrombotic states development. This review comprises analysis of available data on assessment of endothelium state characteristics in Ph-negative MPN and their detection with different methods. The search of literature sources was carried out using PubMed and eLibrary databases. The analysis of research results obtained with the use of different estimation techniques indicates that patients with Ph-negative MPN are characterized by endothelium activation, damage, and, consequently, dysfunction. Endothelium abnormalities associated with myeloproliferation have an effect on all endothelial functions fulfillment. Endothelial dysfunction represents important component of thrombosis pathogenesis in Ph-negative MPN.

Ph-негативные миелопролиферативные новообразованиятромбозгемостазэндотелийэндотелиальная дисфункцияPh-negative myeloproliferative neoplasmsthrombosishemostasisendotheliumendothelial dysfunctionReferencesАбдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Миелопролиферативные новообразования. М.: Литтерра, 2016. 304 с. Abdulkadyrov K.M., Shuvaev V.A., Martynkevich I.S. Myeloproliferative neoplasms. Moscow: Litterra, 2016. 304 p. [In Russian].Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Миелопролиферативные новообразования. М.: Литтерра, 2016. 304 с. Abdulkadyrov K.M., Shuvaev V.A., Martynkevich I.S. Myeloproliferative neoplasms. Moscow: Litterra, 2016. 304 p. [In Russian].Finazzi G., Rambaldi A., Guerini V., Carobbo A., Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2V617F mutation status. Haematologica. 2007;92:135–136. doi: 10.3324/haematol.10634Finazzi G., Rambaldi A., Guerini V., Carobbo A., Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2V617F mutation status. Haematologica. 2007;92:135–136. doi: 10.3324/haematol.10634Landolfi R., di Gennaro L. Pathophysiology of thrombosis in myeloproliferative neoplasms. Haematologica. 2011;96(2):183–186. doi: 10.3324/haematol.2010.038299Landolfi R., di Gennaro L. Pathophysiology of thrombosis in myeloproliferative neoplasms. Haematologica. 2011;96(2):183–186. doi: 10.3324/haematol.2010.038299Falanga A., Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology. Am. Soc. Hematol. Educ. Program. 2012;2012:571–581. doi: 10.1182/asheducation-2012.1.571Falanga A., Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology. Am. Soc. Hematol. Educ. Program. 2012;2012:571–581. doi: 10.1182/asheducation-2012.1.571Barbui T., Finazzi G., Falanga A. Myeloproliferative neoplasms and thrombosis. Blood. 2013;122(13): 2176–2184. doi: 10.1182/blood-2013-03-460154Barbui T., Finazzi G., Falanga A. Myeloproliferative neoplasms and thrombosis. Blood. 2013;122(13): 2176–2184. doi: 10.1182/blood-2013-03-460154Иванов А.Н., Гречихин А.А., Норкин И.А., Пучиньян Д.М. Методы диагностики эндотелиальной дисфункции. Регионар. кровообращ. и микроциркуляция. 2014;13(4-52):4–11. Ivanov A.N., Grechikhin A.A., Norkin I.A., Puchin’yan D.M. Methods of endothelial dysfunction diagnostics. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation. 2014;13(4-52):4–11. [In Russian].Иванов А.Н., Гречихин А.А., Норкин И.А., Пучиньян Д.М. Методы диагностики эндотелиальной дисфункции. Регионар. кровообращ. и микроциркуляция. 2014;13(4-52):4–11. Ivanov A.N., Grechikhin A.A., Norkin I.A., Puchin’yan D.M. Methods of endothelial dysfunction diagnostics. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation. 2014;13(4-52):4–11. [In Russian].Vianello F., Battisti A., Cella G., Marchetti M., Falanga A. Defining the thrombotic risk in patients with myeloproliferative neoplasms. Scientific World Journal. 2011;11:1131–1137. doi: 10.1100/tsw.2011.108Vianello F., Battisti A., Cella G., Marchetti M., Falanga A. Defining the thrombotic risk in patients with myeloproliferative neoplasms. Scientific World Journal. 2011;11:1131–1137. doi: 10.1100/tsw.2011.108Петрищев Н.Н., Васина Л.В., Власов Т.Д., Гавришева Н.А., Меншутина М.А. Типовые формы дисфункции эндотелия. Клин.-лаб. консилиум. 2007;18:31–35. Petrishchev N.N., Vasina L.V., Vlasov T.D., Gavrisheva N.A., Menshutina M.A. Typical forms of endothelium dysfunction. Kliniko-laboratornyy konsilium = Clinical and Laboratory Concilium. 2007;18:31–35. [In Russian].Петрищев Н.Н., Васина Л.В., Власов Т.Д., Гавришева Н.А., Меншутина М.А. Типовые формы дисфункции эндотелия. Клин.-лаб. консилиум. 2007;18:31–35. Petrishchev N.N., Vasina L.V., Vlasov T.D., Gavrisheva N.A., Menshutina M.A. Typical forms of endothelium dysfunction. Kliniko-laboratornyy konsilium = Clinical and Laboratory Concilium. 2007;18:31–35. [In Russian].Папаян Л.П., Капустин С.И., Шмелева В.М., Кобилянская В.А. Общие представления о системе гемостаза. Гемофилии. ДВС. Тромбофилии. В кн.: Гематология: национальное руководство. Ред. О.А. Рукавицын. М.: ГЭОТАР-Медиа, 2017;90–133. Papayan L.P., Kapustin S.I., Shmeleva V.M., Kobilyanskaya V.A. General overview of the hemostatic system. Hemophilia. DIC. Thrombophilia. In: Hematology: National Guidelines. Ed. O.A. Rukavitsyn. Moscow: GEOTAR-Media, 2017;90–133. [In Russian].Папаян Л.П., Капустин С.И., Шмелева В.М., Кобилянская В.А. Общие представления о системе гемостаза. Гемофилии. ДВС. Тромбофилии. В кн.: Гематология: национальное руководство. Ред. О.А. Рукавицын. М.: ГЭОТАР-Медиа, 2017;90–133. Papayan L.P., Kapustin S.I., Shmeleva V.M., Kobilyanskaya V.A. General overview of the hemostatic system. Hemophilia. DIC. Thrombophilia. In: Hematology: National Guidelines. Ed. O.A. Rukavitsyn. Moscow: GEOTAR-Media, 2017;90–133. [In Russian].Neunteufl T., Heher S., Stefenelli T., Pabinger I., Gisslinger H. Endothelial dysfunction in patients with polycythaemia vera. Br. J. Haematol. 2001;115(2):354– 359. doi: 10.1046/j.1365-2141.2001.03092.xNeunteufl T., Heher S., Stefenelli T., Pabinger I., Gisslinger H. Endothelial dysfunction in patients with polycythaemia vera. Br. J. Haematol. 2001;115(2):354– 359. doi: 10.1046/j.1365-2141.2001.03092.xReeves B.N., Beckman J.D. Novel pathophysiological mechanisms of thrombosis in myeloproliferative neoplasms. Curr. Hematol. Malig. Rep. 2021;16(3):304–313. doi: 10.1007/s11899-021-00630-8Reeves B.N., Beckman J.D. Novel pathophysiological mechanisms of thrombosis in myeloproliferative neoplasms. Curr. Hematol. Malig. Rep. 2021;16(3):304–313. doi: 10.1007/s11899-021-00630-8Farina M., Russo D., Hoffman R. The possible role of mutated endothelial cells in myeloproliferative neoplasms. Haematologica. 2021. doi: 10.3324/haematol.2021.278499 [Epub ahead of print]Farina M., Russo D., Hoffman R. The possible role of mutated endothelial cells in myeloproliferative neoplasms. Haematologica. 2021. doi: 10.3324/haematol.2021.278499 [Epub ahead of print]Flammer A.J., Anderson T., Celermajer D.S., Creager M.A., Deanfield J., Ganz P., Hamburg N.M., Lüscher T.F., Shechter M., Taddei S., Vita J.A., Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126(6):753–767. doi: 10.1161/CIRCULATIONAHA.112.093245Flammer A.J., Anderson T., Celermajer D.S., Creager M.A., Deanfield J., Ganz P., Hamburg N.M., Lüscher T.F., Shechter M., Taddei S., Vita J.A., Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126(6):753–767. doi: 10.1161/CIRCULATIONAHA.112.093245Lessiani G., Dragani A., Falco A., Fioritoni F., Santilli F., Davı` G. Soluble CD40 ligand and endothelial dysfunction in aspirin-treated polycythaemia vera patients. Br. J. Haematol. 2009;145(4):538–540. doi: 10.1111/j.1365-2141.2009.07636.xLessiani G., Dragani A., Falco A., Fioritoni F., Santilli F., Davı` G. Soluble CD40 ligand and endothelial dysfunction in aspirin-treated polycythaemia vera patients. Br. J. Haematol. 2009;145(4):538–540. doi: 10.1111/j.1365-2141.2009.07636.xYildiz A., Güryildirim M., Pepeler M.S., Yazol M., Oktar S.O., Acar K. Assessment of endothelial dysfunction with flow-mediated dilatation in myeloproliferative disorders. Clin. Appl. Thromb. Hemost. 2018;24(7):1102–1108. doi: 10.1177/1076029618766260Yildiz A., Güryildirim M., Pepeler M.S., Yazol M., Oktar S.O., Acar K. Assessment of endothelial dysfunction with flow-mediated dilatation in myeloproliferative disorders. Clin. Appl. Thromb. Hemost. 2018;24(7):1102–1108. doi: 10.1177/1076029618766260Cella G., Marchetti M., Vianello F., Panova-Noeva M., Vignoli A., Russo L., Barbui T., Falanga A. Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb. Haemost. 2010;104(1):151–156. doi: 10.1160/TH09-09-0663Cella G., Marchetti M., Vianello F., Panova-Noeva M., Vignoli A., Russo L., Barbui T., Falanga A. Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb. Haemost. 2010;104(1):151–156. doi: 10.1160/TH09-09-0663Piccin A., Steurer M., Feistritzer C., Murphy C., Eakins E., van Schilfgaarde M., Corvetta D., di Pierro A.M., Pusceddu I., Marcheselli L., Gambato R., Langes M., Veneri D., Perbellini O., Pacquola E., Gottardi M., Gherlinzoni F., Mega A., Tauber M., Mazzoleni G., Piva E., Plebani M., Krampera M., Gastl G. Observational retrospective study of vascular modulator changes during treatment in essential thrombocythemia. Transl. Res. 2017;184:21–34. doi: 10.1016/j.trsl.2017.02.001Piccin A., Steurer M., Feistritzer C., Murphy C., Eakins E., van Schilfgaarde M., Corvetta D., di Pierro A.M., Pusceddu I., Marcheselli L., Gambato R., Langes M., Veneri D., Perbellini O., Pacquola E., Gottardi M., Gherlinzoni F., Mega A., Tauber M., Mazzoleni G., Piva E., Plebani M., Krampera M., Gastl G. Observational retrospective study of vascular modulator changes during treatment in essential thrombocythemia. Transl. Res. 2017;184:21–34. doi: 10.1016/j.trsl.2017.02.001Cokic V.P., Beleslin-Cokic B.B., Tomic M., Stojilkovic S.S., Noguchi C.T., Schechter A.N. Hydroxyurea induces the eNOScGMP pathway in endothelial cells. Blood. 2006;108(1):184–191. doi: 10.1182/blood-2005-11-4454Cokic V.P., Beleslin-Cokic B.B., Tomic M., Stojilkovic S.S., Noguchi C.T., Schechter A.N. Hydroxyurea induces the eNOScGMP pathway in endothelial cells. Blood. 2006;108(1):184–191. doi: 10.1182/blood-2005-11-4454Friedenberg W.R., Roberts R.C., David D.E. Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders. Am. J. Hematol. 1992;40(4):283–289. doi: 10.1002/ajh.2830400408Friedenberg W.R., Roberts R.C., David D.E. Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders. Am. J. Hematol. 1992;40(4):283–289. doi: 10.1002/ajh.2830400408Bellucci S., Ignatova E., Jaillet N., Boffa M.C. Platelet hyperactivation in patients with essential thrombocythemia is not associated with vascular endothelial cell damage as judged by the level of plasma thrombomodulin, protein S, PAI-1, tPA and vWF. Thromb. Haemost. 1993;70(5):736–742.Bellucci S., Ignatova E., Jaillet N., Boffa M.C. Platelet hyperactivation in patients with essential thrombocythemia is not associated with vascular endothelial cell damage as judged by the level of plasma thrombomodulin, protein S, PAI-1, tPA and vWF. Thromb. Haemost. 1993;70(5):736–742.Falanga A., Marchetti M., Evangelista V., Vignoli A., Licini M., Balicco M., Manarini S., Finazzi G., Cerletti C., Barbui T. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96(13):4261–4266.Falanga A., Marchetti M., Evangelista V., Vignoli A., Licini M., Balicco M., Manarini S., Finazzi G., Cerletti C., Barbui T. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96(13):4261–4266.Arellano-Rodrigo E., Alvarez-Larraґn A., Reverter J.-C., Colomer D., Villamor N., Bellosillo B., Cervantes F. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: Relationship with thrombosis occurrence and JAK2 V617F allele burden. Am. J. Hematol. 2009;84(2):102–108. doi: 10.1002/ajh.21338Arellano-Rodrigo E., Alvarez-Larraґn A., Reverter J.-C., Colomer D., Villamor N., Bellosillo B., Cervantes F. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: Relationship with thrombosis occurrence and JAK2 V617F allele burden. Am. J. Hematol. 2009;84(2):102–108. doi: 10.1002/ajh.21338Etheridge S.L., Roh M.E., Cosgrove M.E., Sangkhae V., Fox N.E., Chen J., López J.A., Kaushansky K., Hitchcock I.S. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA. 2014;111(6):2295–2300. doi: 10.1073/pnas.1312148111Etheridge S.L., Roh M.E., Cosgrove M.E., Sangkhae V., Fox N.E., Chen J., López J.A., Kaushansky K., Hitchcock I.S. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. Proc. Natl. Acad. Sci. USA. 2014;111(6):2295–2300. doi: 10.1073/pnas.1312148111Guadall A., Lesteven E., Letort G., Toor S.A., Delord M., Pognant D., Brusson M., Verger E., Maslah N., Giraudier S., Larghero J., Vanneaux V., Chomienne C., El Nemer W., Cassinat B., Kiladjian J.-J. Endothelial cells harbouring the JAK2V617F mutation display pro-adherent and pro-thrombotic features. Thromb. Haemost. 2018;118(9):1586–1599. doi: 10.1055/s-0038-1667015Guadall A., Lesteven E., Letort G., Toor S.A., Delord M., Pognant D., Brusson M., Verger E., Maslah N., Giraudier S., Larghero J., Vanneaux V., Chomienne C., El Nemer W., Cassinat B., Kiladjian J.-J. Endothelial cells harbouring the JAK2V617F mutation display pro-adherent and pro-thrombotic features. Thromb. Haemost. 2018;118(9):1586–1599. doi: 10.1055/s-0038-1667015Guy A., Gourdou-Latyszenok V., Le Lay N., Peghaire C., Kilani B., Dias J.V., Duplaa C., Renault M.-A., Denis C., Villeval J.L., Boulaftali Y., Jandrot-Perrus M., Couffinhal T., James C. Vascular endothelial cell expression of JAK2V617F is sufficient to promote a prothrombotic state due to increased P-selectin expression. Haematologica. 2019;104(1):70–81. doi: 10.3324/haematol.2018.195321Guy A., Gourdou-Latyszenok V., Le Lay N., Peghaire C., Kilani B., Dias J.V., Duplaa C., Renault M.-A., Denis C., Villeval J.L., Boulaftali Y., Jandrot-Perrus M., Couffinhal T., James C. Vascular endothelial cell expression of JAK2V617F is sufficient to promote a prothrombotic state due to increased P-selectin expression. Haematologica. 2019;104(1):70–81. doi: 10.3324/haematol.2018.195321Mital A., Prejzner W., Bieniaszewska M., Hellmann A. Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients. Pol. Arch. Med. Wewn. 2015;125(12):914–920. doi: 10.20452/pamw.3211Mital A., Prejzner W., Bieniaszewska M., Hellmann A. Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients. Pol. Arch. Med. Wewn. 2015;125(12):914–920. doi: 10.20452/pamw.3211Mital A., Prejzner W., Hellmann A. Acquired von Willebrand syndrome during the course of myelofibrosis: Analysis of 32 cases. Adv. Clin. Exp. Med. 2015;24(6):1001–1006. doi: 10.17219/acem/52361Mital A., Prejzner W., Hellmann A. Acquired von Willebrand syndrome during the course of myelofibrosis: Analysis of 32 cases. Adv. Clin. Exp. Med. 2015;24(6):1001–1006. doi: 10.17219/acem/52361Mital A., Prejzner W., Swiatkowska-Stodulska R., Hellmann A. Factors predisposing to acquired von Willebrand syndrome during the course of polycythemia vera – retrospective analysis of 142 consecutive cases. Thromb. Res. 2015;136(4):754–757. doi: 10.1016/j.thromres.2015.07.029Mital A., Prejzner W., Swiatkowska-Stodulska R., Hellmann A. Factors predisposing to acquired von Willebrand syndrome during the course of polycythemia vera – retrospective analysis of 142 consecutive cases. Thromb. Res. 2015;136(4):754–757. doi: 10.1016/j.thromres.2015.07.029Rottenstreich A., Kleinstern G., Krichevsky S., Varon D., Lavie D., Kalish Y. Factors related to the development of acquired von Willebrand syndrome in patients with essential thrombocythemia and polycythemia vera. Eur. J. Intern. Med. 2017;41:49–54. doi: 10.1016/j.ejim.2016.11.011Rottenstreich A., Kleinstern G., Krichevsky S., Varon D., Lavie D., Kalish Y. Factors related to the development of acquired von Willebrand syndrome in patients with essential thrombocythemia and polycythemia vera. Eur. J. Intern. Med. 2017;41:49–54. doi: 10.1016/j.ejim.2016.11.011Alvarez-Larra´n A., Arellano-Rodrigo E., Reverter J.C., Domingo A., Villamor N., Colomer D., Cervantes F. Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis. Ann. Hematol. 2008;87(4):269–276. doi: 10.1007/s00277-007-0386-3Alvarez-Larra´n A., Arellano-Rodrigo E., Reverter J.C., Domingo A., Villamor N., Colomer D., Cervantes F. Increased platelet, leukocyte, and coagulation activation in primary myelofibrosis. Ann. Hematol. 2008;87(4):269–276. doi: 10.1007/s00277-007-0386-3Musolino C., Alonci A., Bellomo G., Tringali O., Spatari G., Quartarone C., Rizzo V., Calabrò L., Bagnato G., Frisina N. Myeloproliferative disease: Markers of endothelial and platelet status in patients with essential thrombocythemia and polycythemia vera. Hematology. 2000;4(5):397–402. doi: 10.1080/10245332.1999.11746464Musolino C., Alonci A., Bellomo G., Tringali O., Spatari G., Quartarone C., Rizzo V., Calabrò L., Bagnato G., Frisina N. Myeloproliferative disease: Markers of endothelial and platelet status in patients with essential thrombocythemia and polycythemia vera. Hematology. 2000;4(5):397–402. doi: 10.1080/10245332.1999.11746464Jensen M.K., de Nully Brown P., Thorsen S., Hasselbalch H.C. Frequent occurrence of anticardiolipin antibodies, Factor V Leiden mutation, and perturbed endothelial function in chronic myeloproliferative disorders. Am. J. Hematol. 2002;69(3):185–191. doi: 10.1002/ajh.10054Jensen M.K., de Nully Brown P., Thorsen S., Hasselbalch H.C. Frequent occurrence of anticardiolipin antibodies, Factor V Leiden mutation, and perturbed endothelial function in chronic myeloproliferative disorders. Am. J. Hematol. 2002;69(3):185–191. doi: 10.1002/ajh.10054Musolino C., Alonci A., Allegra A., Spatari G., Bellomo G., Tringali O., Quartarone C., Squadrito G., Quartarone M. Increased levels of the soluble adhesion molecule E-selectin in patients with chronic myeloproliferative disorders and thromboembolic complications. Am. J. Hematol. 1998;57(2):109–112. doi: 10.1002/(sici)1096-8652(199802)57:2<109::aidajh3>3.0.co;2-#Musolino C., Alonci A., Allegra A., Spatari G., Bellomo G., Tringali O., Quartarone C., Squadrito G., Quartarone M. Increased levels of the soluble adhesion molecule E-selectin in patients with chronic myeloproliferative disorders and thromboembolic complications. Am. J. Hematol. 1998;57(2):109–112. doi: 10.1002/(sici)1096-8652(199802)57:2<109::aidajh3>3.0.co;2-#Belotti A., Elli E., Speranza T., Lanzi E., Pioltelli P., Pogliani E. Circulating endothelial cells and endothelial activation in essential thrombocythemia: Results from CD146+ immunomagnetic enrichment – Flow cytometry and soluble E-selectin detection. Am. J. Hematol. 2012;87(3):319–320. doi: 10.1002/ajh.22264Belotti A., Elli E., Speranza T., Lanzi E., Pioltelli P., Pogliani E. Circulating endothelial cells and endothelial activation in essential thrombocythemia: Results from CD146+ immunomagnetic enrichment – Flow cytometry and soluble E-selectin detection. Am. J. Hematol. 2012;87(3):319–320. doi: 10.1002/ajh.22264Robertson B., Urquhart C., Ford I., Townend J., Watson H.G., Vickers M.A., Greaves M. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J. Thromb. Haemost. 2007;5(8):1679–1685. doi: 10.1111/j.1538-7836.2007.02626.xRobertson B., Urquhart C., Ford I., Townend J., Watson H.G., Vickers M.A., Greaves M. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J. Thromb. Haemost. 2007;5(8):1679–1685. doi: 10.1111/j.1538-7836.2007.02626.xKarakantza M., Giannakoulas N.C., Zikos P., Sakellaropoulos G., Kouraklis A., Aktypi A., Metallinos I.C., Theodori E., Zoumbos N.C., Maniatis A. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera. Int. J. Hematol. 2004;79(3):253–259. doi: 10.1532/IJH97.E0316Karakantza M., Giannakoulas N.C., Zikos P., Sakellaropoulos G., Kouraklis A., Aktypi A., Metallinos I.C., Theodori E., Zoumbos N.C., Maniatis A. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera. Int. J. Hematol. 2004;79(3):253–259. doi: 10.1532/IJH97.E0316Bilgir F., Bilgir O., Calan M., Sari F. The levels of adhesion molecules in essential thrombocythemia. Panminerva Med. 2013;55(4):385–390.Bilgir F., Bilgir O., Calan M., Sari F. The levels of adhesion molecules in essential thrombocythemia. Panminerva Med. 2013;55(4):385–390.Musolino C., Calabro’ L., Bellomo G., Martello F., Loteta B., Pezzano C., Rizzo V., Alonci A. Soluble angiogenic factors: implications for chronic myeloproliferative disorders. Am. J. Hematol. 2002;69(3):159–163. doi: 10.1002/ajh.10020Musolino C., Calabro’ L., Bellomo G., Martello F., Loteta B., Pezzano C., Rizzo V., Alonci A. Soluble angiogenic factors: implications for chronic myeloproliferative disorders. Am. J. Hematol. 2002;69(3):159–163. doi: 10.1002/ajh.10020Murphy P., Ahmed N., Hassan H.T. Increased serum levels of vascular endothelial growth factor correlate with splenomegaly in polycythemia vera. Leuk. Res. 2002;26(11):1007–1010. doi: 10.1016/s0145-2126(02)00053-xMurphy P., Ahmed N., Hassan H.T. Increased serum levels of vascular endothelial growth factor correlate with splenomegaly in polycythemia vera. Leuk. Res. 2002;26(11):1007–1010. doi: 10.1016/s0145-2126(02)00053-xMedinger M., Passweg J. Angiogenesis in myeloproliferative neoplasms, new markers and future directions. Memo. 2014;7:206–210. doi: 10.1007/s12254-014-0142-zMedinger M., Passweg J. Angiogenesis in myeloproliferative neoplasms, new markers and future directions. Memo. 2014;7:206–210. doi: 10.1007/s12254-014-0142-zAlonci A., Allegra A., Bellomo G., Penna G., D’Angelo A., Quartarone E., Musolino C. Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases. Hematol. Oncol. 2008;26(4):235–239. doi: 10.1002/hon.865Alonci A., Allegra A., Bellomo G., Penna G., D’Angelo A., Quartarone E., Musolino C. Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases. Hematol. Oncol. 2008;26(4):235–239. doi: 10.1002/hon.865Panteli K., Bai M., Hatzimichael E., Zagorianakou N., Agnantis N.J., Bourantas K. Serum levels, and bone marrow immunohistochemical expression of vascular endothelial growth factor in patients with chronic myeloproliferative diseases. Hematology. 2007;12(6):481–486. doi: 10.1080/10245330701554664Panteli K., Bai M., Hatzimichael E., Zagorianakou N., Agnantis N.J., Bourantas K. Serum levels, and bone marrow immunohistochemical expression of vascular endothelial growth factor in patients with chronic myeloproliferative diseases. Hematology. 2007;12(6):481–486. doi: 10.1080/10245330701554664Trelin´ski J., Wierzbowska A., Krawczyn´ska A., Sakowicz A., Pietrucha T., Smolewski P., Robak T., Chojnowski K. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int. J. Hematol. 2010;91:792–798. doi: 10.1007/s12185-010-0596-7Trelin´ski J., Wierzbowska A., Krawczyn´ska A., Sakowicz A., Pietrucha T., Smolewski P., Robak T., Chojnowski K. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int. J. Hematol. 2010;91:792–798. doi: 10.1007/s12185-010-0596-7Treliński J., Wierzbowska A., Krawczyńska A., Sakowicz A., Pietrucha T., Smolewski P., Robak T., Chojnowski K. Plasma levels of angiogenic factors and circulating endothelial cells in essential thrombocythemia: correlation with cytoreductive therapy and JAK2-V617F mutational status. Leuk. Lymphoma. 2010;51(9):1727– 1733. doi: 10.3109/10428194.2010.500435Treliński J., Wierzbowska A., Krawczyńska A., Sakowicz A., Pietrucha T., Smolewski P., Robak T., Chojnowski K. Plasma levels of angiogenic factors and circulating endothelial cells in essential thrombocythemia: correlation with cytoreductive therapy and JAK2-V617F mutational status. Leuk. Lymphoma. 2010;51(9):1727– 1733. doi: 10.3109/10428194.2010.500435di Raimondo F., Azzaro M.P., Palumbo G.A., Bagnato S., Stagno F., Giustolisi G.M., Cacciola E., Sortino G., Guglielmo P., Giustolisi R. Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis. Leukemia. 2001;15(6):976– 980. doi: 10.1038/sj.leu.2402124di Raimondo F., Azzaro M.P., Palumbo G.A., Bagnato S., Stagno F., Giustolisi G.M., Cacciola E., Sortino G., Guglielmo P., Giustolisi R. Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis. Leukemia. 2001;15(6):976– 980. doi: 10.1038/sj.leu.2402124di Raimondo F., Palumbo G.A., Molica S., Giustolisi R. Angiogenesis in chronic myeloproliferative diseases. Acta Haematol. 2001;106(4):177–183. doi: 10.1159/000046614di Raimondo F., Palumbo G.A., Molica S., Giustolisi R. Angiogenesis in chronic myeloproliferative diseases. Acta Haematol. 2001;106(4):177–183. doi: 10.1159/000046614Gadomska G., Bartoszewska-Kubiak A., Boinska J., Matiakowska K., Ziołkowska K., Haus O., Ros´c´ D. Selected parameters of angiogenesis and the JAK2, CALR, and MPL mutations in patients with essential thrombocythemia. Clin. Appl. Thromb. Hemost. 2018;24(7): 1056–1060. doi: 10.1177/1076029617740222Gadomska G., Bartoszewska-Kubiak A., Boinska J., Matiakowska K., Ziołkowska K., Haus O., Ros´c´ D. Selected parameters of angiogenesis and the JAK2, CALR, and MPL mutations in patients with essential thrombocythemia. Clin. Appl. Thromb. Hemost. 2018;24(7): 1056–1060. doi: 10.1177/1076029617740222Weltermann A., Wolzt M., Petersmann K., Czerni C., Graselli U., Lechner K., Kyrle P.A. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler. Thromb. Vasc. Biol. 1999;19(7):1757–1760. doi: 10.1161/01.atv.19.7.1757Weltermann A., Wolzt M., Petersmann K., Czerni C., Graselli U., Lechner K., Kyrle P.A. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler. Thromb. Vasc. Biol. 1999;19(7):1757–1760. doi: 10.1161/01.atv.19.7.1757Cacciola R.R., di Francesco E., Giustolisi R., Cacciola E. Elevated serum vascular endothelial growth factor levels in patients with polycythemia vera and thrombotic complications Haematologica. 2002;87(7):774–775.Cacciola R.R., di Francesco E., Giustolisi R., Cacciola E. Elevated serum vascular endothelial growth factor levels in patients with polycythemia vera and thrombotic complications Haematologica. 2002;87(7):774–775.Fadini G.P., Avogaro A. Cell-based methods for ex vivo evaluation of human endothelial biology. Cardiovasc. Res. 2010;87(1):12–21. doi: 10.1093/cvr/cvq119Fadini G.P., Avogaro A. Cell-based methods for ex vivo evaluation of human endothelial biology. Cardiovasc. Res. 2010;87(1):12–21. doi: 10.1093/cvr/cvq119Goon P.K., Boos C.J., Lip G.Y. Circulating endothelial cells: markers of vascular dysfunction. Clin. Lab. 2005;51(9-10):531–538.Goon P.K., Boos C.J., Lip G.Y. Circulating endothelial cells: markers of vascular dysfunction. Clin. Lab. 2005;51(9-10):531–538.Torres C., Fonseca A.M., Leander M., Matos R., Morais S., Campos M., Lima M. Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. PLoS One. 2013;8(12):e81574. doi:10.1371/journal.pone.0081574Torres C., Fonseca A.M., Leander M., Matos R., Morais S., Campos M., Lima M. Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. PLoS One. 2013;8(12):e81574. doi:10.1371/journal.pone.0081574Wu H., Chen H., Hu P.C. Circulating endothelial cells and endothelial progenitors as surrogate biomarkers in vascular dysfunction. Clin. Lab. 2007;53(5–6):285–295.Wu H., Chen H., Hu P.C. Circulating endothelial cells and endothelial progenitors as surrogate biomarkers in vascular dysfunction. Clin. Lab. 2007;53(5–6):285–295.Carobbio A., Finazzi G., Guerini V., Spinelli O., Delaini F., Marchioli R., Borrelli G., Rambaldi A., Barbui T. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood. 2007;109(6):2310–2313. doi: 10.1182/blood-2006-09-046342Carobbio A., Finazzi G., Guerini V., Spinelli O., Delaini F., Marchioli R., Borrelli G., Rambaldi A., Barbui T. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood. 2007;109(6):2310–2313. doi: 10.1182/blood-2006-09-046342Landolfi R., di Gennaro L., Barbui T., de Stefano V., Finazzi G., Marfisi R., Tognoni G., Marchioli R. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446– 2452. doi: 10.1182/blood-2006-08-042515Landolfi R., di Gennaro L., Barbui T., de Stefano V., Finazzi G., Marfisi R., Tognoni G., Marchioli R. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446– 2452. doi: 10.1182/blood-2006-08-042515Lowe G.D.O. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J. Thromb. Haemost. 2005;3(8):1618–1627. doi: 10.1111/j.1538-7836.2005.01416.xLowe G.D.O. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J. Thromb. Haemost. 2005;3(8):1618–1627. doi: 10.1111/j.1538-7836.2005.01416.xZwicker J.I., Liebman H.A., Neuberg D., Lacroix R., Bauer K.A., Furie B.C., Furie B. Tumorderived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin. Cancer Res. 2009;15(22):6830–6840. doi: 10.1158/1078-0432.CCR-09-0371Zwicker J.I., Liebman H.A., Neuberg D., Lacroix R., Bauer K.A., Furie B.C., Furie B. Tumorderived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin. Cancer Res. 2009;15(22):6830–6840. doi: 10.1158/1078-0432.CCR-09-0371Trappenburg M.C., van Schilfgaarde M., Marchetti M., Spronk H.M., ten Cate H., Leyte A., Terpstra W.E., Falanga A. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94(7):911– 918. doi: 10.3324/haematol.13774Trappenburg M.C., van Schilfgaarde M., Marchetti M., Spronk H.M., ten Cate H., Leyte A., Terpstra W.E., Falanga A. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94(7):911– 918. doi: 10.3324/haematol.13774Bar-Natan M., Hoffman R. New insights into the causes of thrombotic events in patients with myeloproliferative neoplasms raise the possibility of novel therapeutic approaches. Haematologica. 2019;104(1):3–6. doi:10.3324/haematol.2018.205989Bar-Natan M., Hoffman R. New insights into the causes of thrombotic events in patients with myeloproliferative neoplasms raise the possibility of novel therapeutic approaches. Haematologica. 2019;104(1):3–6. doi:10.3324/haematol.2018.205989Sozer S., Fiel M.I., Schiano T., Xu M., Mascarenhas J., Hoffman R. The presence of JAK2 V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood. 2009;113(21):5246– 5249. doi: 10.1182/blood-2008-11-191544Sozer S., Fiel M.I., Schiano T., Xu M., Mascarenhas J., Hoffman R. The presence of JAK2 V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood. 2009;113(21):5246– 5249. doi: 10.1182/blood-2008-11-191544Rosti V., Villani L., Riboni R., Poletto V., Bonetti E., Tozzi L., Bergamaschi G., Catarsi P., Dallera E., Novara F., Massa M., Campanelli R., Fois G., Peruzzi B., Lucioni M., Guglielmelli P., Pancrazzi A., Fiandrino G., Zuffardi O., Magrini U., Paulli M., Vannucchi A.M., Barosi G., Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) investigators. Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation. Blood. 2013;121(2):360–368. doi: 10.1182/blood-2012-01-404889Rosti V., Villani L., Riboni R., Poletto V., Bonetti E., Tozzi L., Bergamaschi G., Catarsi P., Dallera E., Novara F., Massa M., Campanelli R., Fois G., Peruzzi B., Lucioni M., Guglielmelli P., Pancrazzi A., Fiandrino G., Zuffardi O., Magrini U., Paulli M., Vannucchi A.M., Barosi G., Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) investigators. Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F mutation. Blood. 2013;121(2):360–368. doi: 10.1182/blood-2012-01-404889Teofili L., Martini M., Iachininoto M.G., Capodimonti S., Nuzzolo E.R., Torti L., Cenci T., Larocca L.M., Leone G. Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood. 2011;117(9):2700–2707. doi 10.1182/blood-2010-07-297598Teofili L., Martini M., Iachininoto M.G., Capodimonti S., Nuzzolo E.R., Torti L., Cenci T., Larocca L.M., Leone G. Endothelial progenitor cells are clonal and exhibit the JAK2V617F mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood. 2011;117(9):2700–2707. doi 10.1182/blood-2010-07-297598Castiglione M., Jiang Y.-P., Mazzeo C., Lee S., Chen J.-S., Kaushansky K., Yin W., Lin R.Z., Zheng H., Zhan H. Endothelial JAK2 V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm. J. Thromb. Haemost. 2020;18(12):3359–3370. doi: 10.1111/jth.15095Castiglione M., Jiang Y.-P., Mazzeo C., Lee S., Chen J.-S., Kaushansky K., Yin W., Lin R.Z., Zheng H., Zhan H. Endothelial JAK2 V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm. J. Thromb. Haemost. 2020;18(12):3359–3370. doi: 10.1111/jth.15095

The authors declare that there are no conflicts of interest present.