Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children75610.24287/1726-1708-2024-23-2-198-207LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫStructural and functional properties of thrombomodulinСтруктурно-функциональные свойства тромбомодулинаBleskinD. A.БлескинД. А.
Russian Federation

Dmitry A. Bleskin, a junior researcher at the Laboratory of Biorheology and Biomechanics of the Center for Theoretical Problems of Physical and Chemical Pharmacology, Russian Academy of Sciences

30 Srednyaya Kalitnikovskaya St., Moscow 109029, Russia 

Блескин Дмитрий Алексеевич, младший научный сотрудник лаборатории биореологии и биомеханики Центра теоретических проблем физикохимической фармакологии РАН

109029, Москва, ул. Средняя Калитниковская, 30

 

dmitriybleskin@gmail.comhttps://orcid.org/0000-0003-0167-6726KoltsovaE. M.КольцоваЕ. М.
Russian Federation

Moscow

Москва

NechipurenkoD. Yu.НечипуренкоД. Ю.
Russian Federation

Moscow

Москва

Center for Theoretical Problems of Physical and Chemical Pharmacology, Russian Academy of SciencesФГБУН «Центр теоретических проблем физико-химической фармакологии» РАНN.M. Emanuel Institute of Biochemical Physics, Russian Academy of SciencesФГБУН «Институт биохимической физики им. Н.М. Эмануэля» РАНDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава РоссииM.V. Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»080720242321982073108202309112023Copyright ©; 2025, «D. Rogachev NMRCPHOI»Copyright ©; 2025, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2025«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/756

Thrombomodulin (TM) is an integral component of a multimolecular system, localized primarily in the vascular endothelium, and regulating a number of crucial physiological responses of an organism, including blood coagulation and inflammation. This review presents the currently known key functions of TM in the context of its structure. The first part of the review examines the domain structure of the TM molecule and describes the key molecular processes in which the corresponding domains participate. The second part of the review is devoted to a more detailed analysis of the TM molecule participation in the regulation of physiological processes in the human organism. Since the main function of TM is associated with the regulation of the hemostatic response to vascular wall injury, special attention is paid to the role of this molecule in the activation of protein C and thrombin-activated fibrinolysis inhibitor, which is responsible for stopping fibrinolysis. In addition, the review briefly describes some data on the role of TM in the mitogenesis of various cell types and in angiogenesis processes. One section of the review is devoted to the current knowledge of TM participation in the regulation of inflammatory reactions of the body. This section describes the key mechanisms through which TM is able to limit the level of pro-inflammatory signals, as well as regulate the processes of complement system activation.

Тромбомодулин (ТМ) является неотъемлемым компонентом мультимолекулярной системы, локализованной главным образом в эндотелии сосудов и регулирующей ряд важнейших физиологических ответов организма, включая свертывание крови и воспаление. В данном обзоре приведены известные на сегодняшний день ключевые функции ТМ в контексте его структуры. В первой части обзора рассмотрена доменная структура молекулы ТМ и описаны ключевые молекулярные процессы, в которых участвуют соответствующие домены. Вторая часть обзора посвящена более детальному анализу участия молекулы ТМ в регуляции физиологических процессов в организме человека. Так как центральная функция ТМ связана с регуляцией гемостатического ответа на повреждение сосудистой стенки, отдельное внимание уделяется роли данной молекулы в активации протеина С и тромбин-активируемого ингибитора фибринолиза, ответственного за остановку процесса фибринолиза. В работе также кратко описаны некоторые данные о роли ТМ в митогенезе различных типов клеток и процессах ангиогенеза. Отдельный раздел обзора посвящен современным представлениям об участии ТМ в регуляции воспалительных реакций организма. В данном разделе описаны ключевые механизмы, за счет которых ТМ способен ограничивать уровень провоспалительных сигналов, а также регулировать процессы активации системы комплемента.

thrombomodulinendothelial protein C receptorprotein C pathwaythrombinhemostatic systemтромбомодулин, эндотелиальный рецептор к протеину С, путь протеина С, тромбин, система гемостазаРабота выполнена при поддержке гранта Российского научного фонда №22-24-01028.Hemker H.C., Kessels H. Feedback mechanisms in coagulation. Pathophysiol Haemost Thromb 1991; 21 (4): 189–96.Атауллаханов Ф.И., Зарницына В.И., Кондратович А.Ю., Лобанова Е.С., Сарбаш В.И. Особый класс автоволн – автоволны с остановкой – определяет пространственную динамику свертывания крови. Успехи физических наук 2002; 172 (6): 671–90. DOI: 10.1070/PU2002v045n06ABEH001090 [Ataullakhanov F.I., Zarnitsyna V.I., Kondratovich A.Yu., Lobanova E.S., Sarbash V.I. A new class of stopping self-sustained waves: a factor determining the spatial dynamics of blood coagulation. Phys. Usp. 2002; 172 (6): 671–90. (In Russ.)].Атауллаханов Ф.И., Зарницына В.И., Кондратович А.Ю., Лобанова Е.С., Сарбаш В.И. Особый класс автоволн – автоволны с остановкой – определяет пространственную динамику свертывания крови. Успехи физических наук 2002; 172 (6): 671–90. DOI: 10.1070/PU2002v045n06ABEH001090Пантелеев М.А., Котова Я.Н., Токарев А.А., Атауллаханов Ф.И. Механизмы регуляции свертывания крови. Терапевтический архив 2008; 80 (7): 88–91. [Panteleev M.A., Kotova I.N., Tokarev A.A., Ataullakhanov F.I. Blood coagulation: mechanisms of regulation. Therapeutic Archive 2008; 80 (7): 88–91. (In Russ.)].Panteleev M.A., Ovanesov M.V., Kireev D.A., Shibeko A.M., Sinauridze E.I., Ananyeva N.M., et al. Spatial propagation and localization of blood coagulation are regulated by intrinsic and protein C pathways, respectively. Biophys J 2006; 90 (5): 1489–500.Пантелеев М.А., Атауллаханов Ф.И. Свертывание крови: биохимические основы. Клиническая онкогематология 2008; 1 (1): 50–62. [Panteleev M.A., Ataullakhanov F.I. Blood coagulation: basical biochemistry. Clinical Oncohematology 2008; 1 (1): 50–62. (In Russ.)].Amiral J., Seghatchian J. Revisiting the activated protein C-protein S-thrombomodulin ternary pathway: Impact of new understanding on its laboratory investigation. Transfus Apher Sci 2019; 58 (4): 538–44.Marar T.T., Matzko C.N., Wu J., Esmon C.T., Sinno T., Brass L.F., et al. Thrombin spatial distribution determines protein C activation during hemostasis and thrombosis. Blood 2022; 139 (12): 1892–902.Loghmani H., Conway E.M. Exploring traditional and nontraditional roles for thrombomodulin. Blood 2018; 132 (2): 148–58.Khan K.A., McMurray J.L., Mohammed F., Bicknell R. C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation. FEBS J 2019; 286 (17): 3299–332.Hermann D.M., Kleinschnitz C. Thrombomodulin, a Master Switch Controlling Poststroke Microvascular Remodeling and Angiogenesis. Arterioscler Thromb Vasc Biol 2020; 40 (12): 2818–20.Alonso F., Dong Y., Génot E. Thrombomodulin, an Unexpected New Player in Endothelial Cell Invasion During Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1672–4.Jackman R.W., Beeler D.L., Fritze L., Soff G., Rosenberg R.D. Human thrombomodulin gene is intron depleted: Nucleic acid sequences of the cDNA and gene predict protein structure and suggest site of regulatory control. Proc Natl Acad Sci U S A 1987; 84 (18): 6425–9.Ishii H., Majerus P.W. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76 (6): 2178–81.Maruyama I., Elliott Bell C., Majerus P.W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta. J Cell Biol 1985; 101 (2): 363–71.Suzuki K., Nishioka J., Hayashi T., Kosaka Y. Functionally active thrombomodulin is present in human platelets. J Biochem 1988; 104 (4): 628–32.Maruyama I., Majerus P.W. The turnover of thrombinthrombomodulin complex in cultured human umbilical vein endothelial cells and A549 lung cancer cells. Endocytosis and degradation of thrombin. J Biol Chem 1985; 260 (29): 15432–8.Xu J., Esmon N.L., Esmon C.T. Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation. J Biol Chem 1999; 274 (10): 6704–10.Campbell J.E., BrummelZiedins K.E., Butenas S., Mann K.G. Cellular regulation of blood coagulation: A model for venous stasis. Blood 2010; 116 (26): 6082–91.Senet P., Peyri N., Berard M., Dubertret L., Boffa M.C. Thrombomodulin, a functional surface protein on human keratinocytes, is regulated by retinoic acid. Arch Dermatol Res 1997; 289 (3): 151–7.Maillard C. Thrombomodulin is synthesized by osteoblasts, stimulated by 1,25-(OH)2D3 and activates protein C at their cell membrane. Endocrinology 1993; 133 (2): 668–74.Pruna A., Peyri N., Berard M., Boffa M.C. Thrombomodulin is synthesized by human mesangial cells. Kidney Int 1997; 51 (3): 687– 93.Conway E., Nowakowski B., SteinerMosonyi M. Human neutrophils synthesize thrombomodulin that does not promote thrombindependent protein C activation. Blood 1992; 80 (5): 1254–63.McCachren S.S., Diggs J., Weinberg J.B., Dittman W.A. Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood 1991; 78 (12): 3128–32.Suzuki K. Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C. Nihon Ketsueki Gakkai Zasshi 1988; 51 (8): 1655–64.Bohlson S., Greenlee M., Sullivan S. CD93 and Related Family Members: Their Role in Innate Immunity. Curr Drug Targets 2008; 9 (2): 130–8.Huang H.C., Shi G.Y., Jiang S.J., Shi C.S., Wu C.M., Yang H.Y., et al. Thrombomodulin-mediated cell adhesion: Involvement of its lectinlike domain. J Biol Chem 2003; 278 (47): 46750–9.Glaser C.B., Morser J., Clarke J.H., Blasko E., McLean K., Kuhn I., et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity: A potential rapid mechanism for modulation of coagulation. J Clin Invest 1992; 90 (6): 2565–73.Ross C.C., MacLeod S.L., Plaxco J.R., Froude J.W., Fink L.M., Wang J., et al. Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium. Radiat Res 2008; 23 (1): 408–16.Fuentes-Prior P., Iwanaga Y., Huber R., Paglia R., Rumennik G., Seto M., et al. Structural basis for the anticoagulant activity of the thrombin thrombomodulin complex. Nature 2000; 404 (6777):Zushi M., Gomi K., Honda G., Kondo S., Yamamoto S., Hayashi T., et al. Aspartic acid 349 in the fourth epidermal growth factor-like structure of human thrombomodulin plays a role in its Ca2+-mediated binding to protein C. J Biol Chem 1991; 266 (30): 19886–9.Edano T., Kumai N., Mizoguchi T., Ohkuchi M. The glycosylation sites and structural characteristics of oligosaccharides on recombinant human thrombomodulin. Int J Biochem Cell Biol 1998; 30 (1): 77–88.Koyama T., Parkinson J.F., Sie P., Bang N.U., Muller-Berghaus G., Preissner K.T. Different glycoforms of human thrombomodulin. Their glycosaminoglycan-dependent modulatory effects on thrombin inactivation by heparin cofactor II and antithrombin III. Eur J Biochem 1991; 198 (3): 563–70.Elisen. Erratum: Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin induced activation of protein in human plasma. Blood 1998; 91 (8): 3091.Hsu Y., Shi G., Kuo C., Liu S., Wu C., Ma C., et al. Thrombomodulin is an ezrin‐interacting protein that controls epithelial morphology and promotes collective cell migration. FASEB J 2012; 26 (8): 3440–52.Jackson D.E., Tetaz T.J., Salem H.H., MitchELL C.A. Purification and characterization of two forms of soluble thrombomodulin from human urine. Eur J Biochem 1994; 221 (3): 1079– 87.Boron M., Hauzer-Martin T., Keil J., Sun X.-L. Circulating Thrombomodulin: Release Mechanisms, Measurements, and Levels in Diseases and Medical Procedures. TH Open 2022; 6 (3): e194–212.Wang L., Bastarache J.A., Wickersham N., Fang X., Matthay M.A., Ware L.B. Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. Am J Respir Cell Mol Biol 2007; 36 (4): 497–503.Lohi O., Urban S., Freeman M. Diverse Substrate Recognition Mechanisms for Rhomboids: Thrombomodulin Is Cleaved by Mammalian Rhomboids. Curr Biol 2004; 14 (3): 236–41.Matsumoto H., Yamakawa K., Ogura H., Koh T., Matsumoto N., Shimazu T. Enhanced expression of cell-specific surface antigens on endothelial microparticles in sepsisinduced disseminated intravascular coagulation. Shock 2015; 43 (5):443–9.Ye J., Liu L.W., Esmon C.T., Johnson A.E. The fifth and sixth growth factor-like domains of thrombomodulin bind to the anionbinding exosite of thrombin and alter its specificity. J Biol Chem 1992; 267 (16): 11023–8.Mathews I.I., Padmanabhan K.P., Tulinsky A., Sadler J.E. Structure of a Nonadecapeptide of the Fifth EGF Domain of Thrombomodulin Complexed with Thrombin. Biochemistry 1994; 33 (46): 13547– 52.Hall S.W., Nagashima M., Zhao L., Morser J., Leung L.L.K. Thrombin interacts with thrombomodulin, protein C, and thrombin – activatable fibrinolysis inhibitor via specific and distinct domains. J Biol Chem 1999; 274 (36): 25510–6.Chen K., Stafford A.R., Wu C., Yeh C.H., Kim P.Y., Fredenburgh J.C., et al. Exosite 2-Directed Ligands Attenuate Protein C Activation by the Thrombin-Thrombomodulin Complex. Biochemistry 2017; 56 (24): 3119–28.Lane D.A., Philippou H., Huntington J.A. Directing thrombin. Blood 2005; 106 (8): 2605–12.Pozzi N., Barranco-Medina S., Chen Z., Di Cera E. Exposure of R169 controls protein C activation and autoactivation. Blood 2012; 120 (3): 664–70.Stearns-Kurosawa D.J., Kurosawa S., Mollica J.S., Ferrell G.L., Esmon C.T. The endothelial cell protein C receptor augments protein C activation by the thrombinthrombomodulin complex. Proc Natl Acad Sci U S A 1996; 93 (19): 10212–6.Wu C., Kim P.Y., Swystun L.L., Liaw P.C., Weitz J.I. Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells. J Thromb Haemost 2016; 14 (2): 366–74.Slungaard A., Key N.S. Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis. J Biol Chem 1994; 269 (41): 25549–56.Preston R.J.S., Tran S., Johnson J.A., Áinle F.N., Harmon S., White B., et al. Platelet factor 4 impairs the anticoagulant activity of activated protein C. J Biol Chem 2009; 284 (9): 5869–75.Suleiman L., Négrier C., Boukerche H. Protein S: A multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Crit Rev Oncol Hematol 2013; 88 (3): 637–54.Gierula M., Ahnström J. Anticoagulant protein S – New insights on interactions and functions. J Thromb Haemost 2020; 18 (11): 2801–11.Rezaie A.R., Mather T., Sussman F., Esmon C.T. Mutation of Glu-80 → Lys results in a protein C mutant that no longer requires Ca2+ for rapid activation by the thrombinthrombomodulin complex. J Biol Chem 1994; 269 (5): 3151–4.Light D.R., Glaser C.B., Betts M., Blasko E., Campbell E., Clarke J.H., et al. The interaction of thrombomodulin with Ca2+. Eur J Biochem 1999; 262 (2): 522–33.Hayashi T., Zushi M., Yamamoto S., Suzuki K. Further localization of binding sites for thrombin and protein C in human thrombomodulin. J Biol Chem 1990; 265 (33): 20156–9.Mann K.G., Whelihan M.F., Butenas S., Orfeo T. Citrate anticoagulation and the dynamics of thrombin generation. J Thromb Haemost 2007; 5(10): 2055–61.Mcnicol A., Israels S.J. Platelet Dense Granules : Structure, Function and Implications for Haemostasis. Thromb Res 1999; 95 (1): 1–18.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): 12135–9.Wang W., Nagashima M., Schneider M., Morser J., Nesheim M. Elements of the primary structure of thrombomodulin required for efficient thrombin-activable fibrinolysis inhibitor activation. J Biol Chem 2000; 275 (30): 22942–7.Wu H.L., Lin C.I., Huang Y.L., Chen P.S., Kuo C.H., Chen M.S., et al. Lysophosphatidic acid stimulates thrombomodulin lectin-like domain shedding in human endothelial cells. Biochem Biophys Res Commun 2008; 367 (1): 162–8.Kuo C.-H., Sung M.-C., Chen P.-K., Chang B.-I., Lee F.-T., Cho C.-F., et al. FGFR1 mediates recombinant thrombomodulin domain-induced angiogenesis. Cardiovasc Res 2015; 105 (1): 107–17.Cheng T.L., Chen P.K., Huang W.K., Kuo C.H., Cho C.F., Wang K.C., et al. Plasminogen/thrombomodulin signaling enhances VEGF expression to promote cutaneous wound healing. J Mol Med 2018; 96 (12): 1333–44.Chen C.H., Lai C.H., Hong Y.K., Lu J.M., Lin S.Y., Lee T.C., et al. Thrombomodulin Functional Domains Support Osteoblast Differentiation and Bone Healing in Diabetes in Mice. J Bone Miner Res 2020; 35 (9): 1812–23.Burnier L., Mosnier L.O. Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of proteaseactivated receptor 3. Blood 2013; 122 (5): 807–16.Roy R.V., Ardeshirylajimi A., Dinarvand P., Yang L., Rezaie A.R. Occupancy of human EPCR by protein C induces b-arrestin-2 biased PAR1 signaling by both APC and thrombin. Blood 2016; 128 (14): 1884–93.Soh U.J.K., Trejo J.A. Activated protein C promotes proteaseactivated receptor-1 cytoprotective signaling through b-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci U S A 2011; 108 (50): E1372–80.Kuo C.H., Huang Y.H., Chen P.K., Lee G.H., Tang M.J., Conway E.M., et al. VEGF-Induced Endothelial Podosomes via ROCK2-Dependent Thrombomodulin Expression Initiate Sprouting Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1657–71.Conway E.M., Van De Wouwer M., Pollefeyt S., Jurk K., Van Aken H., De Vriese A., et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kB and mitogenactivated protein kinase pathways. J Exp Med 2002; 196 (5): 565–77.Geudens N., Van De Wouwer M., Vanaudenaerde B.M., Vos R., Van De Wauwer C., Verleden G.M., et al. The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury. Eur Respir J 2008; 32 (4): 862–70.Nishizawa S., Kikuta J., Seno S., Kajiki M., Tsujita R., Mizuno H., et al. Thrombomodulin induces antiinflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo. J Pharmacol Sci 2020; 143 (1): 17–22.Воробьева Н.В. Нейтрофильные внеклеточные ловушки: новые аспекты. Вестник Московского университета. Серия 16. Биология. 2020; 75 (4): 210–25. [Vorobjeva N.V. Neutrophil extracellular traps: new aspects. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya 2020; 75 (4): 210–25. (In Russ.)].Воробьева Н.В. Нейтрофильные внеклеточные ловушки: новые аспекты. Вестник Московского университета. Серия 16. Биология. 2020; 75 (4): 210–25.Martinod K., Wagner D.D. Thrombosis: Tangled up in NETs. Blood 2014; 123 (18): 2768–76.Watanabe-Kusunoki K., Nakazawa D., Ishizu A., Atsumi T. Thrombomodulin as a Physiological Modulator of Intravascular Injury. Front Immunol 2020; 11: 1–12.Ammollo C.T., Semeraro F., Xu J., Esmon N.L., Esmon C.T. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 2011; 9 (9): 1795–803.Lin W.L., Chen C.C., Shi G.Y., Ma C.Y., Chang C.F., Wu H.L. Monocytic thrombomodulin promotes cell adhesion through interacting with its ligand, Lewisy. Immunol Cell Biol 2017; 95 (4): 372–9.Shi C.S., Shi G.Y., Hsiao S.M., Kao Y.C., Kuo K.L., Chih-Yuan M., et al. Lectinlike domain of thrombomodulin binds to its specific ligand Lewis y antigen and neutralizes lipopolysaccharideinduced inflammatory response. Blood 2008; 112 (9): 3661–70.Kuo C.H., Chen P.K., Chang B.I., Sung M.C., Shi C.S., Lee J.S., et al. The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen. Blood 2012; 119 (5): 1302–13.Gardella S., Andrei C., Ferrera D., Lotti L.V., Torrisi M.R., Bianchi M.E., et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 2002; 3 (10): 995–1001.Tsujita R., Tsubota M., Sekiguchi F., Kawabata A. Role of high‐mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain. Br J Pharmacol 2021; 178 (4): 798–812.Abeyama K., Stern D.M., Ito Y., Kawahara K.I., Yoshimoto Y., Tanaka M., et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115 (5): 1267–74.Wang H., Vinnikov I., Shahzad K., Bock F., Ranjan S., Wolter J., et al. The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. Thromb Haemost 2012; 108 (6): 1141–53.Delvaeye M., Noris M., De Vriese A., Esmon C.T., Esmon N.L., Ferrell G., et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N Engl J Med 2009; 361 (4): 345–57.Heuberger D.M., Franchini A.G., Madon J., Schuepbach R.A. Thrombin cleaves and activates the proteaseactivated receptor 2 dependent on thrombomodulin co-receptor availability. Thromb Res 2019; 177: 91–101.Mahmood I., Hamdan F., Al-Tameemi W. Role of endothelial dysfunction in relation to prothrombogenesis in polycythemia vera. Iraqi J Hematol 2018; 7 (1): 8.Page A.V., Liles W.C. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence 2013; 4 (6): 507–16.Salomaa V., Matei C., Aleksic N., Sansores-Garcia L., Folsom A.R., Juneja H., et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: A case-cohort study. Lancet 1999; 353 (9166): 1729–34.Kampoli A.M., Tousoulis D., Antoniades C., Siasos G., Stefanadis C. Biomarkers of premature atherosclerosis. Trends Mol Med 2009; 15 (7): 323–32.Wada H., Mori Y., Shimura M., Hiyoyama K., Ioka M., Nakasaki T., et al. Poor outcome in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with severe vascular endothelial cell injuries. Am J Hematol 1998; 58 (3): 189–94.Lin S.M., Wang Y.M., Lin H.C., Lee K.Y., Da H.C., Liu C.Y., et al. 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): 683–9.Mori Y., Wada H., Okugawa Y., Tamaki S., Nakasaki T., Watanabe R., et al. Increased Plasma Thrombomodulin as a Vascular Endothelial Cell Marker in Patients With Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome. Clin Appl Thromb 2001; 7 (1): 5–9.Shimizu M., Kuroda M., Inoue N., Konishi M., Igarashi N., Taneichi H., et al. Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine 2014; 66 (1): 1–6.Budzyń M., Iskra M., Turkiewicz W., Krasiński Z., Gryszczyńska B., Kasprzak M.P. Plasma concentration of selected biochemical markers of endothelial dysfunction in women with various severity of chronic venous insufficiency (CVI) – A pilot study. PLoS One 2018; 13 (1): 1–17.Mihajlovic D.M., Lendak D.F., Draskovic B.G., Mikic A.S.N., Mitic G.P., Cebovic T.N., et al. Thrombomodulin is a Strong Predictor of Multiorgan Dysfunction Syndrome in Patients with Sepsis. Clin Appl Thromb 2015; 21 (5): 469– 74.Faust S.N., Levin M., Harrison O.B., Goldin R.D., Lockhart M.S., Kondaveeti S., et al. Dysfunction of Endothelial Protein C Activation in Severe Meningococcal Sepsis. N Engl J Med 2001; 345 (6): 408–16.Wei X., Du X., Liu Y., Wu J., Zhang J. High plasma soluble thrombomodulin levels indicated poor prognosis of decompensated liver cirrhosis: A prospective cohort study. Eur J Gastroenterol Hepatol 2022; 34 (11): 1140–6.Tripodi A., Salerno F., Chantarangkul V., Clerici M., Cazzaniga M., Primignani M., et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (3): 553–8.Zanetto A., Campello E., Bulato C., Gavasso S., Saggiorato G., Shalaby S., et al. Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections. JHEP Rep 2022; 4 (7): 100493.Напалкова О.С., Эмануэль В.Л., Карпенко М.А., Вавилова Т.В., Березовская Г.А., Яковлев А.Н. и др. Тест генерации тромбина в оценке риска повторной операции реваскуляризации миокарда. Тромбоз, гемостаз и реология 2016; 1 (65): 65–71. [Napalkova O.S., Emanuel V.L., Karpenko M.A., Vavilova T.V., Berezovskaya G.A., Yakovlev A.N., et al. Thrombin generation test in risk assessment for reoperation of myocardium revascularization. Tromboz, gemostaz i reologia 2016; 1 (65): 65–71. (In Russ.)].Напалкова О.С., Эмануэль В.Л., Карпенко М.А., Вавилова Т.В., Березовская Г.А., Яковлев А.Н. и др. Тест генерации тромбина в оценке риска повторной операции реваскуляризации миокарда. Тромбоз, гемостаз и реология 2016; 1 (65): 65–71.Ito T., Thachil J., Asakura H., Levy J.H., Iba T. Thrombomodulin in disseminated intravascular coagulation and other critical conditions – A multi-faceted anticoagulant protein with therapeutic potential. Crit Care 2019; 23 (1): 280.