sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.15372/SSMJ20190118sibmed-110Research ArticleКЛИНИЧЕСКАЯ МЕДИЦИНАCLINICAL MEDICINEРОЛЬ ЭНДОТЕЛИАЛЬНОЙ ДИСФУНКЦИИ КАК ПРОЯВЛЕНИЯ СИСТЕМНОЙ ВОСПАЛИТЕЛЬНОЙ РЕАКЦИИ В ПАТОГЕНЕЗЕ АГРЕССИВНЫХ И ИНДОЛЕНТНЫХ ВАРИАНТОВ НЕХОДЖКИНСКИХ ЗЛОКАЧЕСТВЕННЫХ ЛИМФОМTHE ROLE OF ENDOTHELIAL DYSFUNCTION AS A PART OF SYSTEMIC INFLAMMATORY RESPONSE IN PATHOGENESIS OF AGGRESSIVE AND INDOLENT NON-HODGKIN’S LYMPHOMASСерегинаО. Б.SereginaO. B.

Ольга Борисовна СЕРЕГИНА –  ассистент кафедры терапии, гематологии и трансфузиологии ФПК и ППВ,

630091, г. Новосибирск, Красный просп., 52

Olga Borisovna SEREGINA – assistant professor of the department of therapy, hematology and transfusiology 

630091, Novosibirsk, Krasny av., 52

alepu@yandex.ruБабаеваТ. Н.BabaevaT. N.

Татьяна Николаевна БАБАЕВА – к.м.н., ассистент кафедры терапии, гематологии и трансфузиологии ФПК и ППВ 

630091, г. Новосибирск, Красный просп., 52

Tatyana Nikolaevna BABAEVA – candidate of medical sciences, assistant professor of the department of therapy, hematology and transfusiology 

630091, Novosibirsk, Krasny av., 52

babaeva_tatyana@inbox.ruПоспеловаТ. Н.PospelovaT. I.

Татьяна Ивановна ПОСПЕЛОВА – д.м.н., проф., зав. кафедрой терапии, гематологии и трансфузиологии ФПК и ППВ 

630091, г. Новосибирск, Красный просп., 52

Tatyana Ivanovna POSPELOVA – doctor of medical sciences, professor, vice rector on scientific work, head of the department of therapy, hematology and transfusiology 

630091, Novosibirsk, Krasny av., 52

post_gem@mail.ruНовосибирский государственный медицинский университет Минздрава РоссииРоссияNovosibirsk State Medical University of Minzdrav of RussiaRussian Federation201902032019391125135Copyright © Серегина О.Б., Бабаева Т.Н., Поспелова Т.Н., 20192019Серегина О.Б., Бабаева Т.Н., Поспелова Т.Н.Seregina O.B., Babaeva T.N., Pospelova T.I.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/110

Цель – исследовать проявления ангиогенной и гемостатической форм эндотелиальной дисфунции (ЭД) и системной воспалительной реакции (СВР) у больных неходжкинскими злокачественными лимфомами (НХЗЛ) в дебюте заболевания. 

Материал и методы

Материал и методы. Обследовано 99 пациентов, 55 из которых страдали агрессивными вариантами НХЗЛ и 44 – индолентными. Средний возраст больных составил 60,71 ± 10,63 года. В качестве маркера ангиогенной формы ЭД измерялся уровень фактора роста эндотелия сосудов (VEGF), гемостатической – содержание тромбомодулина, D-димеров, растворимых фибрин-мономерных комплексов (РФМК) и активность фактора Виллебранда в сыворотке крови. Для оценки степени выраженности СВР в сыворотке крови определяли концентрацию провоспалительных цитокинов (TNF-α, IL-1β, IL-6), С-реактивного белка (СРБ), фибриногена, для оценки антивоспалительной резистентности – противовоспалительного цитокина IL-4. 

Результаты и их обсуждение. Содержание провоспалительных цитокинов TNF-α, IL-1β и IL-6 у пациентов обеих исследуемых групп было больше, чем в группе контроля. Уровень противовоспалительного цитокина IL-4 не отличался от значений контрольной группы. Концентрация СРБ и фибриногена была повышена только в группе больных агрессивными вариантами НХЗЛ, у которых также наблюдалась статистически значимая корреляция между уровнем СРБ и провоспалительных цитокинов. Содержание VEGF, тромбомодулина, D-димеров, РФМК и активность фактора Виллебранда были увеличены в сыворотке крови больных как агрессивными, так и индолентными лимфомами в сравнении с группой контроля. У пациентов с агрессивными лимфомами концентрация тромбомодулина, D-димеров, РФМК и активность фактора фон Виллебранда были достоверно больше, чем у больных индолентными вариантами. 

Заключение

Заключение. У больных НХЗЛ наблюдались признаки ангиогенной и гемостатической форм ЭД, сопровождаемых проявлениями СВР и снижением антивоспалительной резистентности с развитием цитокинового дисбаланса с преобладанием провоспалительных цитокинов. Признаки СВР, а также гемостатическая форма ЭД с сопутствующей ей тромбинемией были ярче выражены у больных агрессивными НХЗЛ.

Objective

Objective. To study of manifestation of angiogenic and hemostatic forms of endothelial dysfunction and systemic inflammatory response in patients with non-Hodgkin’s lymphomas at the onset of disease. 

Material and methods

Material and methods. A total of 99 patients were enrolled in this study, including 55 patients with aggressive variants and 44 patients with indolent variants. The average age was 60.71±10.63 years. The serum level of vascular endothelial growth factor (VEGF) was measured as a marker of angiogenic form of endothelial dysfunction, the serum levels of thrombomodulin, D-dimers, soluble fibrin-monomer complex (SFMC) and level of Willebrand factor activity were used for evaluation of hemostatic form of endothelial dysfunction. To assess the degree of systemic inflammation response the serum levels of proinflammatory cytokines – TNF-α, IL-1β, IL-6 were measured, as well as serum level of acute phase proteins – C-reactive protein (CRP), fibrinogen. The serum level of IL-4 was used to evaluate antinflammation resistance. 

Results and discussion

Results and discussion. Proinflammatory cytokine (TNF-α, IL-1β and IL-6) content was higher in both studied groups compare to the control group. Serum concentration of anti-inflammatory cytokine IL-4 in studied groups did not differ from the level in the controls group. CRP and fibrinogen serum content was increased only in group of patients with aggressive variants. There was a significant correlation between the level of CRP and proinflammatory cytokines in aggressive lymphoma group. Serum content of VEGF, thrombomodulin, D-dimers, SFMC and Willebrand factor activity were increased in both studied group in comparison with the control group. Concentration of thrombomodulin, D-dimers, SFMC and Willebrand factor activity was higher in patients with aggressive than in patients with indolent lymphomas. 

Conclusion

Conclusion. The signs of angiogenic and hemostatic forms of endothelial dysfunction in patients with aggressive and indolent variants of non-Hodgkin’s lymphoma were detected, as well as manifestation of systemic inflammatory response and attenuation of anti-inflammatory resistance with development of cytokines imbalance with proinflammatory cytokines predominance. The manifestations of systemic inflammatory response and hemostatic type of endothelial dysfunction with activation of coagulation were displayed more prominently in the aggressive lymphoma group.

типовые формы эндотелиальной дисфункциисистемная воспалительная реакциянеходжкинские злокачественные лимфомыцитокиновый дисбалансантивоспалительная резистентностьtypes of endothelial dysfunctionsystemic inflammatory responsenon-Hodgkin’s lymphomascytokines imbalanceanti-inflammatory resistanceReferencesАбросимов В.Н., Аристархов В.Г., Бяловский Ю.Ю., Вейс И.Е. Клиническая патофизиология. СПб.: СпецЛит, 2012. 432 с.Abrosimov V.N., Aristarkhov V.G., Byalovsky Yu.Yu., Weiss I.E. Clinical pathophysiology. Saint-Petersburg: SpetsLit, 2012. 432 p. [In Russian].Баркаган З.С., Момот А.П. Диагностика и контролируемая терапия нарушений гемостаза. М.: Ньюдиамед, 2008.Alves B.E., Montalvao S.A.L., Aranha F.J.P., Lorand-Metze I., De Souza C.A., Annichino-Bizzacchi J.M., De Paula E.V. Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study. J. Transl. Med. 2011. 9. (1). 23.Гусев Е.Ю., Черешнев В.А. Системное воспаление: теоретические и методологические подходы к описанию модели общепатологического процесса. Ч. 1. Общая характеристика процесса // Патол. физиология и эксперим. терапия. 2012. (4). 3–14.Arazi H.C., Doiny D.G., Torcivia R.S., Grancelli H., Waldman S.V., Nojek C., Fornari M.C., Badimon J.J. Impaired anti-platelet effect of aspirin, inflammation and platelet turnover in cardiac surgery. Interact. Cardiovasc. Thorac. Surg. 2010. 10. (6). 863-867.Демьянов А.В., Котов А.Ю., Симбирцев А.С. Диагностическая ценность исследования уровней цитокинов в клинической практике // Цитокины и воспаление. 2003. 2. (3). 20–35.Barkagan Z.S., Momot A.P. Diagnostics and controlled therapy of hemostatic disorders. Moscow: Newdiamed, 2008. [In Russian].Долгов В.В., Свирин П.В. Лабораторная диагностика нарушений гемостаза. Тверь: Триада, 2005. 227 с.Boehme M.W., Deng Y., Raeth U., Bierhaus A., Ziegler R., Stremmel W., Nawroth P.P. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology. 1996. 87. (1). 134-140.Папаян Л.П., Князева Е.С. D-димер в клинической практике: Пособие для врачей. М.: Инсайт полиграфика, 2002. 20 с.Boneu B., Abbal M., Plante J., Bierme R. Factor-VIII complex and endothelial damage. Lancet. 1975. 305. (7922). 1430.Петрищев Н.Н., Васина Л.В., Власов Т.Д. Типовые формы дисфункции эндотелия // Клин.-лаб. консилиум. 2007. (18). 31–36.Boneu B., Bes G., Pelzer H., Sie P., Boccalon H. D-Dimers, thrombin antithrombin III complexes and prothrombin fragments 1+2: diagnostic value in clinically suspected deep vein thrombosis. Thromb. Haemost. 1991. 65. (1). 28-31.Петрищев Н.Н., Власов Т.Д. Физиология и патофизиология эндотелия // Дисфункция эндотелия. Причины, механизмы, фармакологическая коррекция / ред. Н.Н. Петрищев. СПб., 2003. 184 с.Brown Z., Gerritsen M.E., Carley W.W., Strieter R.M., Kunkel S.L., Westwick J. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-gamma. Am. J. Pathol. 1994. 145. (4). 913-921.Чернеховская Н.Е., Шишло В.К., Чомаева А.А., Кодина Т.В. Эндотелий кровеносных и лимфатических сосудов. М.: ВНИИ животноводства, 2010. 182 с.Cedervall J., Dimberg A., Olsson A.K. tumor-induced local and systemic impact on blood vessel function. Mediators Inflamm. 2015. 2015. 1-8.Alves B.E., Montalvao S.A.L., Aranha F.J.P., Lorand-Metze I., de Souza C.A., Annichino-Bizzac¬chi J.M., de Paula E.V. Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study // J. Transl. Med. 2011. 9. (1). 23.Chernekhovskaya N.E., Shishlo V.K., Chomaeva A.A., Kodina T.V. Endothelium of blood and lymphatic vessels. Moscow: VNII zhivotnovodstva, 2010. 182 p. [In Russian].Arazi H.C., Doiny D.G., Torcivia R.S., Gran¬celli H., Waldman S.V., Nojek C., Fornari M.C., Badimon J.J. Impaired anti-platelet effect of aspirin, inflammation and platelet turnover in cardiac surgery // Interact. Cardiovasc. Thorac. Surg. 2010. 10. (6). 863–867.Cines D.B., Pollak E.S., Buck C.A., Loscalzo J., Zimmerman G.A., McEver R.P., Pober J.S., Wick T.M., Konkle B.A., Schwartz B.S., Barnathan E.S., McCrae K.R., Hug B.A., Schmidt A.M., Stern D.M. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998. 91. (10). 3527-3561.Boehme M.W., Deng Y., Raeth U., Bierhaus A., Ziegler R., Stremmel W., Nawroth P.P. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies // Immunology. 1996. 87. (1). 134–140.Cohen T., Nahari D., Cerem L.W., Neufeld G., Levi B.-Z. Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor. J. Biol. Chem. 1996. 271. (2). 736-741.Boneu B., Abbal M., Plante J., Bierme R. Factor-VIII complex and endothelial damage // Lancet. 1975. 305. (7922). 1430.Demyanov A.V., Kotov A.Yu., Simbirtsev A.S. The diagnostic value of cytokine level study in clinical practice. Tsitokiny i vospalenie = Cytokines and Inflammation. 2003. 2. (3). 20–35.Boneu B., Bes G., Pelzer H., Sie P., Boccalon H. D-Dimers, thrombin antithrombin III complexes and prothrombin fragments 1+2: diagnostic value in clini¬cally suspected deep vein thrombosis // Thromb. Haemost. 1991. 65. (1). 28–31.Dharmasaroja P., Dharmasaroja P.A., Sobhon P. Increased plasma soluble thrombomodulin levels in cardioembolic stroke. Clin. Appl. Thromb. Hemost. 2012. 18. (3). 289-293.Brown Z., Gerritsen M.E., Carley W.W., Strieter R.M., Kunkel S.L., Westwick J. Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-gamma // Am. J. Pathol. 1994. 145. (4). 913–921.Dirkx A.E.M., oude Egbrink M.G.A., Wagstaff J., Griffioen A.W. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J. Leukocyte Biol. 2006. 80. (6). 1183-1196.Cedervall J., Dimberg A., Olsson A.K. Tumor-induced local and systemic impact on blood vessel function // Mediators Inflamm. 2015. 2015. 1–8.Dolgov V.V., Svirin P.V. Laboratory diagnosis of hemostasis disorders. Tver: Triadа, 2005. 227 p. [In Russian].Cines D.B., Pollak E.S., Buck C.A., Loscal¬zo J., Zimmerman G.A., McEver R.P., Pober J.S., Wick T.M., Konkle B.A., Schwartz B.S., Barnathan E.S., McCrae K.R., Hug B.A., Schmidt A.M., Stern D.M. Endothelial cells in physiology and in the pathophy¬siology of vascular disorders // Blood. 1998. 91. (10). 3527–3561.Dormond O., Bezzi M., Mariotti A., Ruegg C. Prostaglandin E2 promotes integrin Vβ3-dependent endothelial cell adhesion, Rac-activation, and spreading through cAMP/PKA-dependent signaling. J. Biol. Chem. 2002. 277. (48). 45838-45846.Cohen T., Nahari D., Cerem L.W., Neufeld G., Levi B.-Z. Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor // J. Biol. Chem. 1996. 271. (2). 736–741.Duvoix A., Dickens J., Haq I., Mannino D., Miller B., Tal-Singer R., Lomas D.A. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax. 2013. 68. (7). 670-676.Dharmasaroja P., Dharmasaroja P.A., Sob¬hon P. Increased plasma soluble thrombomodulin le¬vels in cardioembolic stroke // Clin. Appl. Thromb. Hemost. 2012. 18. (3). 289–293.Emilie D., Wijdenes J., Gisselbrecht C., Jarrousse B., Billaud E., Blay J.Y., Gabarre J., Gaillard J.P., Brochier J., Raphael M. Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood. 1994. 84. (8). 2472-2479.Dirkx A.E.M., oude Egbrink M.G.A., Wag¬staff J., Griffioen A.W. Monocyte/macrophage infiltra¬tion in tumors: modulators of angiogenesis // J. Leukocyte Biol. 2006. 80. (6). 1183–1196.Erdman L.K., Dhabangi A., Musoke C., Conroy A.L., Hawkes M., Higgins S., Rajwans N., Wolofsky K.T., Streiner D.L., Liles W.C., Cserti-Gazdewich C.M., Kain K.C. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case-control study. PLoS ONE. 2011. 6. (2). e17440.Dormond O., Bezzi M., Mariotti A., Ruegg C. Prostaglandin E2 promotes integrin αVβ3-dependent endothelial cell adhesion, Rac-activation, and spreading through cAMP/PKA-dependent signaling // J. Biol. Chem. 2002. 277. (48). 45838–45846.Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Semin. Oncol. 2002. 29. (6). 10-14.Duvoix A., Dickens J., Haq I., Mannino D., Miller B., Tal-Singer R., Lomas D.A. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease // Thorax. 2013. 68. (7). 670–676.Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocri. Rev. 1997. 18. (1). 4-25.Emilie D., Wijdenes J., Gisselbrecht C., Jarrousse B., Billaud E., Blay J.Y., Gabarre J., Gaillard J.P., Brochier J., Raphael M. Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms // Blood. 1994. 84. (8). 2472–2479.Ferrara N., Keyt B. Vascular endothelial growth factor: Basic biology and clinical implications. EXS. 1997. 79. 209-232.Erdman L.K., Dhabangi A., Musoke C., Conroy A.L., Hawkes M., Higgins S., Rajwans N., Wolofsky K.T., Streiner D.L., Liles W.C., Cserti-Gazdewich C.M., Kain K.C. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case-control study // PLoS One. 2011. 6. (2). e17440.Fischer C., Jonckx B., Mazzone M., Zacchigna S., Loges S., Pattarini L., Chorianopoulos E., Liesenborghs L., Koch M., De Mol M., Autiero M., Wyns S., Plaisance S., Moons L., van Rooijen N., Giacca M., Stassen J.-M., Dewerchin M., Collen D., Carmeliet P. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007. 131. (3). 463-475.Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications // Semin. Oncol. 2002. 29. (6). 10–14.Folkman J. Angiogenesis. Annu. Rev. Med. 2006. 57. (1). 1-18.Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor // Endocr. Rev. 1997. 18. (1). 4–25.Foss H.-d., Araujo I., Demel G., Klotzbach H., Hummel M., Stein H. Expression of vascular endothelial growth factor in lymphomas and Castleman's disease. J. Pathol. 1997. 183. (1). 44-50.Ferrara N., Keyt B. Vascular endothelial growth factor: Basic biology and clinical implications // EXS. 1997. 79. 209–232.Gabay C., Kushner I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med. 1999. 340. (6). 448-454.Fischer C., Jonckx B., Mazzone M., Zac¬chigna S., Loges S., Pattarini L., Chorianopoulos E., Liesenborghs L., Koch M., de Mol M., Autiero M., Wyns S., Plaisance S., Moons L., van Rooijen N., Giacca M., Stassen J.-M., Dewerchin M., Collen D., Carmeliet P. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels // Cell. 2007. 131. (3). 463–475.Gerber H.-P., Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J. Mol. Med. (Berl). 2002. 81. (1). 20-31.Folkman J. Angiogenesis // Annu. Rev. Med. 2006. 57. (1). 1–18.Gusev E.Yu., Chereshnev V.A. Systemic inflammation: theoretical and methodological approaches to the description of the general pathological process model. Part 1. General characteristics of the process. Patologicheskaya fiziologiya i eksperimental'naya terapiya = Pathological physiology and experimental therapy. 2012. (4). 3-14. [In Russian].Foss H.-d., Araujo I., Demel G., Klotzbach H., Hummel M., Stein H. Expression of vascular endothelial growth factor in lymphomas and Castleman’s disease // J. Pathol. 1997. 183. (1). 44–50.Hwa C., Aird W.C. The history of the capillary wall: doctors, discoveries, and debates. Am. J. Physiol. Heart Circ. Physiol. 2007. 293. (5). H2667-H2679.Gabay C., Kushner I. Acute-phase proteins and other systemic responses to inflammation // N. Engl. J. Med. 1999. 340. (6). 448–454.Kadowaki I., Ichinohasama R., Harigae H., Ishizawa K., Okitsu Y., Kameoka J., Sasaki T. Accelerated lymphangiogenesis in malignant lymphoma: possible role of VEGF-A and VEGF-C. Br. J. Haematol. 2005. 130. (6). 869-877.Gerber H.-P., Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis // J. Mol. Med. (Berl). 2002. 81. (1). 20–31.Kato H., Kinoshita T., Suzuki S., Nagasaka T., Hatano S., Murate T., Saito H., Hotta T. Production and effects of interleukin-6 and other cytokines in patients with non-Hodgkin's lymphoma. Leuk. Lymphoma. 1998. 29. (1-2). 71-79.Hwa C., Aird W.C. The history of the capillary wall: doctors, discoveries, and debates // Am. J. Physiol. Heart Circ. Physiol. 2007. 293. (5). H2667–H2679.Klein B., Wijdenes J., Zhang X.G., Jourdan M., Boiron J.M., Brochier J., Liautard J., Merlin M., Clement C., Morel-Fournier B. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia // Blood. 1991. 78. (5). 1198-1204.Kadowaki I., Ichinohasama R., Harigae H., Ishizawa K., Okitsu Y., Kameoka J., Sasaki T. Accele¬rated lymphangiogenesis in malignant lymphoma: possible role of VEGF-A and VEGF-C // Br. J. Haematol. 2005. 130. (6). 869–877.Kokame K., Zheng X., Sadler J.E. Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomodulin and is inhibited competitively by protein C. J. Biol. Chem. 1998. 273. (20). 12135-12139.Kato H., Kinoshita T., Suzuki S., Nagasaka T., Hatano S., Murate T., Saito H., Hotta T. Production and effects of interleukin-6 and other cytokines in patients with non-Hodgkin’s lymphoma // Leuk. Lymphoma. 1998. 29. (1-2). 71–79.Krishnaswamy G., Kelley J., Yerra L., Smith J.K., Chi D.S. Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. J. Interferon Cytokine Res. 1999. 19. (2). 91-104.Klein B., Wijdenes J., Zhang X.G., Jourdan M., Boiron J.M., Brochier J., Liautard J., Merlin M., Clement C., Morel-Fournier B. Murine anti-inter¬leukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia // Blood. 1991. 78. (5). 1198–1204.Kuby J. Role of cytokines in the inflammatory response. Immunology, 2nd edition. Ed. J. Kuby. N.Y.: W.H. Freeman and Company. 313–315.Kokame K., Zheng X., Sadler J.E. Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomo¬dulin and is inhibited competitively by protein C // J. Biol. Chem. 1998. 273. (20). 12135–12139.Lin S.-M., Wang Y.-M., Lin H.-C., Lee K.-Y., Huang C.-D., Liu C.-Y., Wang C.-H., Kuo H.-P. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit. Care Med. 2008. 36. (3). 683-689.Krishnaswamy G., Kelley J., Yerra L., Smith J.K., Chi D.S. Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease // J. Interferon Cytokine Res. 1999. 19. (2). 91–104.Liu Z.H., Wei R., Wu Y.P., Lisman T., Wang Z.X., Han J.J., Ren D.L., Chen B., Xia Z.L., Zhu Z., Zhang Y., Cui X., Hu H.T., de Groot P.G., Xu W.B. Elevated plasma tissue-type plasminogen activator (t-PA) and soluble thrombomodulin in patients suffering from severe acute respiratory syndrome (SARS) as a possible index for prognosis and treatment strategy. Biomed Environ Sci. 2005. 18. (4). 260-264.Kuby J. Role of cytokines in the inflammatory response. Immunology, 2nd edition / Ed. J. Kuby. N.Y.: W.H. Freeman and Company, 1994. 313–315.Maroeska te Loo D., Bosma N., van Hinsbergh V., Span P., de Waal R., Clarijs R., Sweep C., Monnens L., van den Heuvel L. Elevated levels of vascular endothelial growth factor in serum of patients with D+ HUS. Pediatr. Nephrol. 2004. 19. (7). 754-760.Lin S.-M., Wang Y.-M., Lin H.-C., Lee K.-Y., Huang C.-D., Liu C.-Y., Wang C.-H., Kuo H.-P. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis // Crit. Care Med. 2008. 36. (3). 683–689.Martin F.A., Murphy R.P., Cummins P.M. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol. 2013. 304. (12). H1585-H1597.Liu Z.H., Wei R., Wu Y.P., Lisman T., Wang Z.X., Han J.J., Ren D.L., Chen B., Xia Z.L., Zhu Z., Zhang Y., Cui X., Hu H.T., de Groot P.G., Xu W.B. Elevated plasma tissue-type plasminogen activator (t-PA) and soluble thrombomodulin in patients suffering from severe acute respiratory syndrome (SARS) as a possible index for prognosis and treatment strategy // Biomed. Environ. Sci. 2005. 18. (4). 260–264.Mok C.C., Poon W.L., Lai J.P.S., Wong C.K., Chiu S.M., Lun S.W.M., Ko G.T.C., Lam C.W.K., Lam C.S. Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus. Scand. J. Rheumatol. 2010. 39. (1). 42-49.Maroeska te Loo D., Bosma N., van Hinsbergh V., Span P., de Waal R., Clarijs R., Sweep C., Monnens L., van den Heuvel L. Elevated levels of vascular endothe¬lial growth factor in serum of patients with D+ HUS // Pediatr. Nephrol. 2004. 19. (7). 754–760.Niitsu N., Okamoto M., Nakamine H., Yoshino T., Tamaru J.-i., Nakamura S., Higashihara M., Hirano M. Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin's lymphoma. Eur. J. Haematol. 2002. 68. (2). 91-100.Martin F.A., Murphy R.P., Cummins P.M. Thrombomodulin and the vascular endothelium: in¬sights into functional, regulatory, and therapeutic aspects // Am. J. Physiol. Heart Circ. Physiol. 2013. 304. (12). H1585–H1597.Nilsen E.M., Johansen F.E., Jahnsen F.L., Lundin K.E.A., Scholz T., Brandtzaeg P., Haraldsen G. Cytokine profiles of cultured microvascular endothelial cells from the human intestine. Gut. 1998. 42. (5). 635-642.Mok C.C., Poon W.L., Lai J.P.S., Wong C.K., Chiu S.M., Lun S.W.M., Ko G.T.C., Lam C.W.K., Lam C.S. Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus // Scand. J. Rheumatol. 2010. 39. (1). 42–49.Page A.V., Liles W.C. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence. 2013. 4. (6). 507-516.Niitsu N., Okamoto M., Nakamine H., Yoshino T., Tamaru J.-I., Nakamura S., Higashihara M., Hirano M. Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin’s lymphoma // Eur. J. Haematol. 2002. 68. (2). 91–100.Papayan L.P., Knyazeva E.S. D-dimer in clinical practice: A handbook for physicians. Moscow: Insayt poligrafika, 2002. 20 p. [In Russian].Nilsen E.M., Johansen F.E., Jahnsen F.L., Lundin K.E.A., Scholz T., Brandtzaeg P., Haraldsen G. Cytokine profiles of cultured microvascular endothelial cells from the human intestine // Gut. 1998. 42. (5). 635–642.Pawlak K., Mysliwiec M., Pawlak D. Hepatitis C virus seropositivity and TNF superfamily receptors: sCD40, sFas - the new putative determinants of endothelial dysfunction in haemodialysis patients. Thromb. Res. 2010. 126. (5). 393-398.Page A.V., Liles W.C. Biomarkers of endothelial activation/dysfunction in infectious diseases // Viru¬lence. 2013. 4. (6). 507–516.Pedersen L.M., Jurgensen G.W., Johnsen H.E. Serum levels of inflammatory cytokines at diagnosis correlate to the bcl-6 and CD10 defined germinal centre (GC) phenotype and bcl-2 expression in patients with diffuse large B-cell lymphoma. Br. J. Haematol. 2005. 128. (6). 813-819.Pawlak K., Mysliwiec M., Pawlak D. Hepatitis C virus seropositivity and TNF superfamily receptors: sCD40, sFas – the new putative determinants of endothelial dysfunction in haemodialysis patients // Thromb. Res. 2010. 126. (5). 393–398.Perez-Atayde A.R., Sallan S.E., Tedrow U., Connors S., Allred E., Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol. 1997. 150. (3). 815-821.Pedersen L.M., Jurgensen G.W., Johnsen H.E. Serum levels of inflammatory cytokines at diagnosis correlate to the bcl-6 and CD10 defined germinal centre (GC) phenotype and bcl-2 expression in patients with diffuse large B-cell lymphoma // Br. J. Haematol. 2005. 128. (6). 813–819.Petrishchev N.N., Vasina L.V., Vlasov T.D. Typical forms of endothelium dysfunction. Kliniko-laboratornyy konsilium = Clinical and laboratory consultation. 2007. (18). 31-36. [In Russian].Perez-Atayde A.R., Sallan S.E., Tedrow U., Connors S., Allred E., Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia // Am. J. Pathol. 1997. 150. (3). 815–821.Petrishchev N.N., Vlasov Т.D. Physiology and pathophysiology of the endothelium. Endothelial dysfunction. Causes, mechanisms, pharmacological correction. Ed. N.N. Petrishchev. Saint-Petersburg, 2003. 184 p. [In Russian].Righini M., Perrier A., de Moerloose P., Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later // J. Thromb. Haemost. 2008. 6. (7). 1059–1071.Righini M., Perrier A., De Moerloose P., Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J. Thromb. Haemost. 2008. 6. (7). 1059-1071.Riihijarvi S., Nurmi H., Holte H., Bjorkholm M., Fluge O., Pedersen L.M., Rydstrom K., Jerkeman M., Eriksson M., Leppa S. High serum vascular endothelial growth factor level is an adverse prognostic factor for high-risk diffuse large B-cell lymphoma patients treated with dose-dense chemoimmunotherapy // Eur. J. Haematol. 2012. 89. (5). 395–402.Riihijarvi S., Nurmi H., Holte H., Bjorkholm M., Fluge O., Pedersen L.M., Rydstrom K., Jerkeman M., Eriksson M., Leppa S. High serum vascular endothelial growth factor level is an adverse prognostic factor for high-risk diffuse large B-cell lymphoma patients treated with dose-dense chemoimmunotherapy. Eur. J. Haematol. 2012. 89. (5). 395-402.Robinson C.J., Stringer S.E. The splice variants of vascular endothelial growth factor (VEGF) and their receptors // J. Cell Sci. 2001. 114. (Pt. 5). 853–865.Robinson C.J., Stringer S.E. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J. Cell Sci. 2001. 114. (Pt. 5). 853-865.Rousseau A., Favier R., van Dreden P. Eleva¬ted circulating soluble thrombomodulin activity, tissue factor activity and circulating procoagulant phospholipids: New and useful markers for pre-eclampsia? // Eur. J. Obstet. Gynecol. Reprod. Biol. 2009. 146. (1). 46–49.Rousseau A., Favier R., Van Dreden P. Elevated circulating soluble thrombomodulin activity, tissue factor activity and circulating procoagulant phospholipids: New and useful markers for pre-eclampsia?. Eur. J. Obstet. Gynecol. Reprod. Biol. 2009. 146. (1). 46-49.Roy L.D., Ghosh S., Pathangey L.B., Tinder T.L., Gruber H.E., Mukherjee P. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer // BMC Cancer. 2011. 11. (1).Roy L.D., Ghosh S., Pathangey L.B., Tinder T.L., Gruber H.E., Mukherjee P. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer. BMC Cancer. 2011. 11. (1).Sathupan P., Khongphattanayothin A., Srisai J., Srikaew K., Poovorawan Y. The role of vascular endothelial growth factor leading to vascular leakage in children with dengue virus infection // Ann. Trop. Paediatr. 2007. 27. (3). 179–184.Sathupan P., Khongphattanayothin A., Srisai J., Srikaew K., Poovorawan Y. The role of vascular endothelial growth factor leading to vascular leakage in children with dengue virus infection. Ann. Trop. Paediatr. 2007. 27. (3). 179-184.Shapiro N.I., Yano K., Okada H., Fischer C., Howell M., Spokes K.C., Ngo L., Angus D.C., Aird W.C. A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis // Shock. 2008. 29. (4). 452–457.Shapiro N.I., Yano K., Okada H., Fischer C., Howell M., Spokes K.C., Ngo L., Angus D.C., Aird W.C. A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock. 2008. 29. (4). 452-457.Taylan A., Sari I., Kozaci D.L., Yildiz Y., Bilge S., Coker I., Maltas S., Gunay N., Akkoc N. Evaluation of various endothelial biomarkers in ankylosing spondylitis // Clin. Rheumatol. 2011. 31. (1). 23–28.Taylan A., Sari I., Kozaci D.L., Yildiz Y., Bilge S., Coker I., Maltas S., Gunay N., Akkoc N. Evaluation of various endothelial biomarkers in ankylosing spondylitis. Clin. Rheumatol. 2011. 31. (1). 23-28.Triggle C.R., Ding H. A review of endothelial dysfunction in diabetes: a focus on the contribution of a dysfunctional eNOS // J. Am. Soc. Hypertens. 2010. 4. (3). 102–115.Triggle C.R., Ding H. A review of endothelial dysfunction in diabetes: a focus on the contribution of a dysfunctional eNOS. J. Am. Soc. Hypertens. 2010. 4. (3). 102-115.Urban M., Wojtkielewicz K., Glowinska B., Peczynska J. Soluble thrombomodulin – a molecular marker of endothelial cell injury in children and adolescents with obesity // Endokrynol. Diabetol. Chor. Przemiany Materii Wieku Rozw. 2005. 11. (2).73–77.Urban M., Wojtkielewicz K., Glowinska B., Peczynska J. Soluble thrombomodulin--a molecular marker of endothelial cell injury in children and adolescents with obesity. Endokrynologia, diabetologia i choroby przemiany materii wieku rozwojowego: organ Polskiego Towarzystwa Endokrynologow Dzieciecych = Endocrinology, diabetology and metabolic diseases of the developmental age: organ of the Polish Society of Endocrinologists. 2005. 11. (2).73-77. [In Polish].Walker T.S., Brown J.S., Hoover C.S., Mor¬gan D.A. Endothelial Prostaglandin Secretion: Effects of Typhus Rickettsiae // J. Infect. Dis. 1990. 162. (5). 1136–1136.Walker T.S., Brown J.S., Hoover C.S., Morgan D.A. Endothelial Prostaglandin Secretion: Effects of Typhus Rickettsiae. J. Infect. Dis. 1990. 162. (5). 1136-1136.Zhao W.-L., Mourah S., Mounier N., Le¬boeuf C., Daneshpouy M.E., Legres L., Meignin V., Oksenhendler E., Maignin C.L., Calvo F., Briere J., Gisselbrecht C., Janin A. Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression // Lab. Invest. 2004. 84. (11). 1512–1519.Zhao W.-L., Mourah S., Mounier N., Leboeuf C., Daneshpouy M.E., Legres L., Meignin V., Oksenhendler E., Maignin C.L., Calvo F., Briere J., Gisselbrecht C., Janin A. Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression. Lab. Invest. 2004. 84. (11). 1512-1519.

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