mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2018-6-785-796mimmun-1663Research ArticleОБЗОРЫREVIEWSТРОМБОЦИТЫ КАК АКТИВАТОРЫ И РЕГУЛЯТОРЫ ВОСПАЛИТЕЛЬНЫХ И ИММУННЫХ РЕАКЦИЙ. ЧАСТЬ 1. ОСНОВНЫЕ ХАРАКТЕРИСТИКИ ТРОМБОЦИТОВ КАК ВОСПАЛИТЕЛЬНЫХ КЛЕТОКBLOOD PLATELETS AS ACTIVATORS AND REGULATORS OF INFLAMMATORY AND IMMUNE REACTIONS. PART 1. BASIC CHARACTERISTICS OF PLATELETS AS INFLAMMATORY CELLSСеребрянаяН. Б.SerebryanayaN. B.

д.м.н., профессор, ведущий научный сотрудник отдела общей  патологии и патологической физиологии

197376, Россия, Санкт-Петербург, ул. АкадемикаПавлова, 9а.Тел.: 8 (812) 234-15-83.Факс: 8 (812) 234-94-93

PhD, MD (Medicine), Professor, Leading Research Associate, Department of General Pathology and Pathophysiology

197376, Russian Federation, St. Petersburg, Acad. Pavlov str., 9а.Phone: 7 (812) 234-15-83.Fax: 7 (812) 234-94-93.

nbvma@mail.ruШанинС. Н.ShaninS. N.

к.м.н., cтарший научный сотрудник отдела общей патологии и патологической физиологии

РhD (Medicine), Senior Research Associate, Department of General Pathology and Pathophysiology

ФомичеваЕ. Е.FomichevaE. E.

к.б.н., старший научный сотрудник отдела общей патологии и патологической физиологии

PhD (Biology), Senior Research Associate, Department of General Pathology and Pathophysiology

ЯкуцениП. П.YakutseniP. P.

д.б.н., главный научный сотрудник Центра перспективных исследований

PhD, MD (Biology), Chief Research Associate, Center for Advanced Studies

ФГБНУ «Институт экспериментальной медицины» ФГБОУ ВО «Санкт-Петербургский государственный университет» ФГБОУ ВО «Северо-Западный государственный медицинский университет имени И.И. Мечникова»РоссияInstitute of Experimental Medicine St. Petersburg State University I. Mechnikov North-Western State Medical UniversityRussian FederationФГБНУ «Институт экспериментальной медицины»РоссияInstitute of Experimental MedicineRussian FederationФГАОУ ВО «Санкт-Петербургский политехнический университет Петра Великого»РоссияPeter the Great St. Petersburg Polytechnic UniversityRussian Federation201812122018206785796Copyright © Серебряная Н.Б., Шанин С.Н., Фомичева Е.Е., Якуцени П.П., 20182018Серебряная Н.Б., Шанин С.Н., Фомичева Е.Е., Якуцени П.П.Serebryanaya N.B., Shanin S.N., Fomicheva E.E., Yakutseni P.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1663

Тромбоциты – самые мелкие клетки крови, которые суммарно имеют объем и площадь поверхности больше, чем все типы лейкоцитов вместе. Источником тромбоцитов являются мегакариоциты костного мозга, мегакариоциты в микрососудах легких. В легких производится приблизительно 50% всех тромбоцитов, что позволяет характеризовать их как основной сайт образования тромбоцитов. В малом круге кровообращения тромбоцитов примерно на 30% больше, чем в большом. Этот «избыток» тромбоцитов необходим для стабилизации эндотелиального барьера сосудов легких, регулятором которого является тромбоцитарный медиатор сфингозин-1-фосфат, поддерживающий плотные соединения эндотелиальных клеток. Удивительной особенностью тромбоцитов в циркуляции является способность «отпочковывать» новые про- и пре- тромбоциты, давая начало новым тромбоцитам. Удаление тромбоцитов из циркуляции осуществляется при их фагоцитозе макрофагами селезенки (в случае если тромбоциты покрыты IgG или связаны с иммунными комплексами) или Купферовскими клетками печени и гепатоцитами (если тромбоциты имеют неполные гликаны или десиалированные белки). В гомеостатических состояниях большая часть тромбоцитов удаляется в печени. При бактериальных инфекциях и сепсисе клиренс тромбоцитов ускорен из-за активности бактериальных сиалидаз. Распознавание десиалированных структур тромбоцитов осуществляется клетками печени через рецептор Asgr. Несмотря на отсутствие ДНК, тромбоциты способны синтезировать белки на матрицах мРНК, которые присутствуют в тромбоцитах в большом количестве. Активация тромбоцитов приводит к агрегации и экзоцитозу содержимого гранул, продукции иммуномодулирующих молекул. Однако активация тромбоцитов может быть неполной и приводить только к некоторым из перечисленных событий. При неклассической форме активации тромбоциты могут выпускать микрочастицы, которые содержат около 600 различных белков. В крови здоровых доноров около 75% микрочастиц – производные тромбоцитов. Подобно клеткам иммунной системы, тромбоциты активируются многочисленными эндогенными лигандами (аларминами), в числе которых АДФ и АТФ, которые связываются с пуринэргическими рецепторами P2Y1, P2Y12 и P2X1. Тромбоциты накапливают и сохраняют 99% серотонина, имеющегося в организме. Индукции воспаления тромбоциты способствуют путем высвобождения провоспалительных цитокинов, хемокинов и липидных медиаторов. Кроме того, тромбоциты являются источником ферментов и субстратов, дополняющих возможности нейтрофилов и эндотелия при производстве противовоспалительных липидных медиаторов, позволяющих перейти к процессам восстановления ткани после острой фазы воспаления.

Platelets are the smallest blood cells, and yet their total volume and surface area exceed those of all types of leukocytes combined. Platelets are produced by the bone marrow megakaryocytes and megakaryocytes in the lung microvessels. Approximately 50% of all platelets are produced in the lungs, which makes it possible to characterize them as the main site for the production of platelets. In small circuit of blood circulation, there are approximately 30% more platelets than in large circuit. This “excess” of platelets is necessary for the stabilization of the endothelial barrier of the lung vessels regulated by the platelet mediator sphingosine-1-phosphate, a regulator of tight junctions of endothelial cells. The circulating platelets have an amazing ability to “bud” new pro- and pre-platelets, giving rise to new platelets. The removal of platelets from circulation proceeds via their phagocytosis by spleen macrophages (if platelets are covered with IgG or are bound to immune complexes), or Kupffer liver cells and hepatocytes (if platelets have incomplete glycans or desialated proteins). In homeostatic conditions, most of the platelets are removed in liver. Platelet clearance in bacterial infections and sepsis is accelerated because of the activity of bacterial sialidases. Recognition of desialized platelet structures is carried out by the liver cells through the Asgr receptor. Despite DNA absence, the platelets are able to synthesize proteins at mRNAs that are present in majority of platelets. Activation of platelets leads to aggregation and exocytosis of the granule contents, and production of immunomodulating molecules. However, activation of platelets may be incomplete and has various consequences. In a non-classical activation model, platelets can release microparticles that contain about 600 different proteins. About 75% of microparticles in the blood of healthy donors are derived from platelets. Like as immune system cells, platelets are activated by numerous endogenous ligands (alarms), including ADP and ATP, which bind to purinergic receptors P2Y1, P2Y12 andP2X1. Platelets accumulate and retain 99% of the serotonin stored in the body. The platelets contribute to induction of inflammation by releasing proinflammatory cytokines, chemokines, and lipid mediators. In addition, platelets are the source of enzymes that accomplish the capacities of neutrophils and endothelium for production of anti-inflammatory lipid mediators that contribute to tissue repair following acute phase of inflammation.

тромбоцитымегакариоцитымикрочастицырецепторыАТФлипидные медиаторыplateletsmegakaryocytesmicroparticlesreceptorsATPlipid mediatorsReferencesАлейникова Т.Л. Биохимия: Учебник для вузов. Под ред. Е.С. Северина. М.: ГЭОТАР-Медиа, 2003. 779 с. [Aleynikova T.L. Biochemistry: Textbook for high schools. Ed. E.S. Severin]. Moscow: GEOTAR-Media, 2003. 779 p.Алейникова Т.Л. Биохимия: Учебник для вузов. Под ред. Е.С. Северина. М.: ГЭОТАР-Медиа, 2003. 779 с. [Aleynikova T.L. Biochemistry: Textbook for high schools. Ed. E.S. Severin]. Moscow: GEOTAR-Media, 2003. 779 p.Воробьева И.И. Современные методы оценки функции тромбоцитов и их клиническое значение у больных с острым коронарным синдромом // Креативная кардиология, 2012. № 1. С. 50-63. [Vorobyova I.I. Modern methods of evaluation of platelet function and their clinical significance in patients with acute coronary syndrome. Kreativnaya kardiologiya = Creative Cardiology, 2012, Vol. 6, no. 1, pp. 50-63. (In Russ.)]Воробьева И.И. Современные методы оценки функции тромбоцитов и их клиническое значение у больных с острым коронарным синдромом // Креативная кардиология, 2012. № 1. С. 50-63. [Vorobyova I.I. Modern methods of evaluation of platelet function and their clinical significance in patients with acute coronary syndrome. Kreativnaya kardiologiya = Creative Cardiology, 2012, Vol. 6, no. 1, pp. 50-63. (In Russ.)]Гринштейн Ю.И., Косинова А.А., Гринштейн И.Ю. Контроль антитромбоцитарной терапии: кризис доверия или поиск новых решений // Рациональная фармакотерапия в кардиологии, 2013. Т. 9, № 6. С. 682- 689. [Grinshtein Yu.I., Kosinova A.A., Grinshtein I.Yu. Antiplatelet therapy control: credibility gap or search for new decisions? Ratsionalnaya farmakoterapiya v kardiologii = Rational Pharmacotherapy in Cardiology, 2013, Vol. 9, no 6, pp. 682-689. (In Russ.)]Гринштейн Ю.И., Косинова А.А., Гринштейн И.Ю. Контроль антитромбоцитарной терапии: кризис доверия или поиск новых решений // Рациональная фармакотерапия в кардиологии, 2013. Т. 9, № 6. С. 682- 689. [Grinshtein Yu.I., Kosinova A.A., Grinshtein I.Yu. Antiplatelet therapy control: credibility gap or search for new decisions? Ratsionalnaya farmakoterapiya v kardiologii = Rational Pharmacotherapy in Cardiology, 2013, Vol. 9, no 6, pp. 682-689. (In Russ.)]Куликов В.А., Гребенников И.Н. Резольвины, протектины и марезины – новые медиаторы воспаления // Вестник ВГМУ, 2012. Т. 11, № 1. С. 25-30. [Kulikov V.A., Grebennikov I.N. Resolvins, protectins and maresins as new mediators of an inflammation. Vestnik Vitebskogo gosudarstvennogo meditsinskogo universiteta =Bulletin of Vitebsk State Medical University 2012, Vol. 11, no. 1, pp. 25-30. (In Russ.)]Куликов В.А., Гребенников И.Н. Резольвины, протектины и марезины – новые медиаторы воспаления // Вестник ВГМУ, 2012. Т. 11, № 1. С. 25-30. [Kulikov V.A., Grebennikov I.N. Resolvins, protectins and maresins as new mediators of an inflammation. Vestnik Vitebskogo gosudarstvennogo meditsinskogo universiteta =Bulletin of Vitebsk State Medical University 2012, Vol. 11, no. 1, pp. 25-30. (In Russ.)]Andrews R.K., Gardiner E.E., Shen Y., Whisstock J.C., Berndt M.C. Glycoprotein Ib-IX-V. Int. J. Biochem. Cell Biol., 2003, Vol. 35, pp. 1170-1174.Andrews R.K., Gardiner E.E., Shen Y., Whisstock J.C., Berndt M.C. Glycoprotein Ib-IX-V. Int. J. Biochem. Cell Biol., 2003, Vol. 35, pp. 1170-1174.Aupaix K., Hugel B., Martin T., Bischoff P., Lill H., Pasquali J.L., Freyssinet J.M. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV 1 infection. J. Clin. Hivest., 1997, Vol. 99, pp. 1546-1554.Aupaix K., Hugel B., Martin T., Bischoff P., Lill H., Pasquali J.L., Freyssinet J.M. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV 1 infection. J. Clin. Hivest., 1997, Vol. 99, pp. 1546-1554.Bertozzi C.C., Schmaier A.A., Mericko P., Hess P.R., Zou Z., Chen M., Chen C-Y., Xu B., Lu M-M., Zhou D., Sebzda E., Santore M.T., Merianos D.J., Stadtfeld M., Flake A.W., Graf T., Skoda R., Maltzman J.S., Koretzky G.A., Kahn M.L. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood, 2010, Vol. 116, pp. 661-670.Bertozzi C.C., Schmaier A.A., Mericko P., Hess P.R., Zou Z., Chen M., Chen C-Y., Xu B., Lu M-M., Zhou D., Sebzda E., Santore M.T., Merianos D.J., Stadtfeld M., Flake A.W., Graf T., Skoda R., Maltzman J.S., Koretzky G.A., Kahn M.L. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood, 2010, Vol. 116, pp. 661-670.Bizzozero G. Sur un nouvel élément morphologique du sang chez les mammifères et sur son importance dans la thrombose et dans la coagulation. Archives Italiennes de Biologie, 1882, Vol. 1, pp. 1-4.Bizzozero G. Sur un nouvel élément morphologique du sang chez les mammifères et sur son importance dans la thrombose et dans la coagulation. Archives Italiennes de Biologie, 1882, Vol. 1, pp. 1-4.Boilard E., Nigrovic P.A., Larabee K., Watts G.F., Coblyn J.S., Weinblatt M.E., Massarotti E.M., Remold-O’Donnell E., Farndale R.W., Ware J., Lee D.M. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science, 2010, Vol. 327, pp. 580-583.Boilard E., Nigrovic P.A., Larabee K., Watts G.F., Coblyn J.S., Weinblatt M.E., Massarotti E.M., Remold-O’Donnell E., Farndale R.W., Ware J., Lee D.M. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science, 2010, Vol. 327, pp. 580-583.Bozza F.A., Shah A.M., Weyrich A.S., Zimmerman G.A. Amicus or adversary: Platelets in lung biology, acute injury, and inflammation. Am. J. Respir. Cell Mol. Biol., 2009, Vol. 40, no. 2, pp. 123-134.Bozza F.A., Shah A.M., Weyrich A.S., Zimmerman G.A. Amicus or adversary: Platelets in lung biology, acute injury, and inflammation. Am. J. Respir. Cell Mol. Biol., 2009, Vol. 40, no. 2, pp. 123-134.Brown G.T., McIntyre T.M. Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles. J. Immunol., 2011, Vol. 186, pp. 5489-5496.Brown G.T., McIntyre T.M. Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles. J. Immunol., 2011, Vol. 186, pp. 5489-5496.Choi J.W., Herr D.R., Noguchi K., Yung Y.C., Lee C.W., Mutoh T., Lin M.E., Teo S.T., Park K.E., Mosley A.N., Chun J. LPA receptors: subtypes and biological actions. Ann. Rev. Pharmacol. Toxicol., 2010, Vol. 50, pp. 157-186.Choi J.W., Herr D.R., Noguchi K., Yung Y.C., Lee C.W., Mutoh T., Lin M.E., Teo S.T., Park K.E., Mosley A.N., Chun J. LPA receptors: subtypes and biological actions. Ann. Rev. Pharmacol. Toxicol., 2010, Vol. 50, pp. 157-186.Coller B.S., Seligsohn U., West S.M., Scudder L.E., Norton K.J. Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIA and alpha v beta 3 integrins in platelet protein trafficking. Blood, 1991, Vol. 78, pp. 2603-2610.Coller B.S., Seligsohn U., West S.M., Scudder L.E., Norton K.J. Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIA and alpha v beta 3 integrins in platelet protein trafficking. Blood, 1991, Vol. 78, pp. 2603-2610.Dahm F., Nocito A., Bielawska A., Lang K.S., Georgiev P., Asmis L.M., Bielawski J., Madon J., Hannun Y.A., Clavien P.A. Distribution and dynamic changes of sphingolipids in blood in response to platelet activation. J. Thromb. Haemost., 2006, Vol. 4, pp. 2704-2709.Dahm F., Nocito A., Bielawska A., Lang K.S., Georgiev P., Asmis L.M., Bielawski J., Madon J., Hannun Y.A., Clavien P.A. Distribution and dynamic changes of sphingolipids in blood in response to platelet activation. J. Thromb. Haemost., 2006, Vol. 4, pp. 2704-2709.Dean W.L., Lee M.J., Cummins T.D., Schultz D.J., Powell D. Proteomic and functional characterisation of platelet microparticle size classes. J. Thromb. Haemost., 2009, Vol. 102, no. 4, pp. 711-718.Dean W.L., Lee M.J., Cummins T.D., Schultz D.J., Powell D. Proteomic and functional characterisation of platelet microparticle size classes. J. Thromb. Haemost., 2009, Vol. 102, no. 4, pp. 711-718.English D., Welch Z., Kovala A.T., Harvey K., Volpert O.V., Brindley D.N., Garcia J.G. Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J., 2000, Vol. 14, pp. 2255-2265.English D., Welch Z., Kovala A.T., Harvey K., Volpert O.V., Brindley D.N., Garcia J.G. Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J., 2000, Vol. 14, pp. 2255-2265.Farooqui A.A., Ong W.Y., Horrocks L.A. Inhibitors of brain phospholipase A2 activity: theirFarooqui A.A., Ong W.Y., Horrocks L.A. Inhibitors of brain phospholipase A2 activity: theirneuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharm. Rev., 2006, Vol. 58, pp. 591-620.neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharm. Rev., 2006, Vol. 58, pp. 591-620.Forlow S.B., McEver R.P., Nollert M.U. Leukocyte leukocyte interactions mediated by platelet microparticles under flow. Blood, 2000, Vol. 95, pp. 1317-1323.Forlow S.B., McEver R.P., Nollert M.U. Leukocyte leukocyte interactions mediated by platelet microparticles under flow. Blood, 2000, Vol. 95, pp. 1317-1323.Garcia B.A., Smalley D.M. ,Cho H., Shabanowitz J., Ley K., Hunt D.F. The platelet microparticle proteome. J. Proteome Res., 2005, Vol. 4, no. 5, pp. 1516-1521.Garcia B.A., Smalley D.M. ,Cho H., Shabanowitz J., Ley K., Hunt D.F. The platelet microparticle proteome. J. Proteome Res., 2005, Vol. 4, no. 5, pp. 1516-1521.Gyulkhandanyan A.V., Mutlu A., Freedman J., Leytin V. Markers of platelet apoptosis: methodology and applications. J. Thromb. Thrombolysis, 2012, Vol. 33, no. 4, pp. 397-411.Gyulkhandanyan A.V., Mutlu A., Freedman J., Leytin V. Markers of platelet apoptosis: methodology and applications. J. Thromb. Thrombolysis, 2012, Vol. 33, no. 4, pp. 397-411.Haaland H.D., Holmsen H. Potentiation by adrenaline of agonist-induced responses in normal human platelets in vitro. Platelets, 2011, Vol. 22, no. 5, pp. 328-337.Haaland H.D., Holmsen H. Potentiation by adrenaline of agonist-induced responses in normal human platelets in vitro. Platelets, 2011, Vol. 22, no. 5, pp. 328-337.Hartwig J., Italiano J. The birth of the platelet. J. Thromb. Haemost., 2003, no. 1, pp. 1580-1610.Hartwig J., Italiano J. The birth of the platelet. J. Thromb. Haemost., 2003, no. 1, pp. 1580-1610.Hastings J.W., Sailer M., Johnson K., Roy K.L., Vederas J.C., Stiles M.E. Characterization of leucocin A-UAL 187 and cloning of the bacteriocin gene from Leuconostoc gelidum. J. Bacteriol., 1991, Vol. 173, pp. 7491-7500.Hastings J.W., Sailer M., Johnson K., Roy K.L., Vederas J.C., Stiles M.E. Characterization of leucocin A-UAL 187 and cloning of the bacteriocin gene from Leuconostoc gelidum. J. Bacteriol., 1991, Vol. 173, pp. 7491-7500.Hechler B., Gachet C. Purinergic receptors in thrombosis and inflammation. arterioscler. Thromb. Vasc. Biol., 2015, Vol. 35, no. 11, pp. 2307-2315.Hechler B., Gachet C. Purinergic receptors in thrombosis and inflammation. arterioscler. Thromb. Vasc. Biol., 2015, Vol. 35, no. 11, pp. 2307-2315.Israels S.J., McMillan-Ward E.M. CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. J. Thromb. Haemost., 2005, no. 3, pp. 311-318.Israels S.J., McMillan-Ward E.M. CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. J. Thromb. Haemost., 2005, no. 3, pp. 311-318.Italiano J.E., Battinelli E.M. Selective sorting of alpha-granule proteins. J. Thromb. Haemost., 2009, Vol. 7, no. 1, pp. 173-176.Italiano J.E., Battinelli E.M. Selective sorting of alpha-granule proteins. J. Thromb. Haemost., 2009, Vol. 7, no. 1, pp. 173-176.Italiano J.E., Shivdasani R.A. Megakaryocytes and beyond: the birth of platelets. J. Thromb. Haemost., 2003, no. 1, pp. 1174-1182.Italiano J.E., Shivdasani R.A. Megakaryocytes and beyond: the birth of platelets. J. Thromb. Haemost., 2003, no. 1, pp. 1174-1182.James-Krack M.R., Sexe R.B., Shukla S.D. Picomolar platelet activating factor mobilizes Ca to change platelet shape without activating phospholipase C or protein kinase C: Simultaneous fluorometric measurements of intracellular free Ca concentration and aggregation. J. Pharm. Exper. Ther., 1994, Vol. 271, pp. 824-831.James-Krack M.R., Sexe R.B., Shukla S.D. Picomolar platelet activating factor mobilizes Ca to change platelet shape without activating phospholipase C or protein kinase C: Simultaneous fluorometric measurements of intracellular free Ca concentration and aggregation. J. Pharm. Exper. Ther., 1994, Vol. 271, pp. 824-831.Kahn M.L., Nakanishi-Matsui M., Shapiro M.J., Ishihara H., Coughlin S.R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest., 1999, Vol. 103, pp. 879-887.Kahn M.L., Nakanishi-Matsui M., Shapiro M.J., Ishihara H., Coughlin S.R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest., 1999, Vol. 103, pp. 879-887.Kappos L., Antel J., Comi G., Montalban X., O’Connor P., Polman C.H., Haas T., Korn A.A., Karlsson G., Radue E.W. Oral fingolimod (FTY720) for relapsing multiple sclerosis [with editorial, p1088-91]. New Engl. J. Med., 2006, Vol. 355, pp. 1124-1140.Kappos L., Antel J., Comi G., Montalban X., O’Connor P., Polman C.H., Haas T., Korn A.A., Karlsson G., Radue E.W. Oral fingolimod (FTY720) for relapsing multiple sclerosis [with editorial, p1088-91]. New Engl. J. Med., 2006, Vol. 355, pp. 1124-1140.Kenney D.M., Linck R.W. The cystoskeleton of unstimulated blood platelets: structure and composition of the isolated marginal microtubular band. J. Cell Sci., 1985, Vol. 78, pp. 1-22.Kenney D.M., Linck R.W. The cystoskeleton of unstimulated blood platelets: structure and composition of the isolated marginal microtubular band. J. Cell Sci., 1985, Vol. 78, pp. 1-22.Kubera M., Maes M., Kenis G., Kim Y.K., Lasoń W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor and interleukin-6. Psychiatry Res., 2005, Vol. 134, pp. 251- 258.Kubera M., Maes M., Kenis G., Kim Y.K., Lasoń W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor and interleukin-6. Psychiatry Res., 2005, Vol. 134, pp. 251- 258.Lam F.W., Vijayan K.V., Rumbaut R.E. Platelets and their interactions with other immune cells. Compr. Physiol., 2015, Vol. 15, no. 3, pp. 1265-1280.Lam F.W., Vijayan K.V., Rumbaut R.E. Platelets and their interactions with other immune cells. Compr. Physiol., 2015, Vol. 15, no. 3, pp. 1265-1280.Lannan K.L., Sahler J., Kim N., Spinelli S.L., Maggirwar S.B., Garraud O., Cognasse F., Blumberg N., Phipps R.P. Breaking the mold: transcription factors in the anucleate pplatelet and platelet-derived microparticles. Front Immunol., 2015, no. 6, pp. 48-60.Lannan K.L., Sahler J., Kim N., Spinelli S.L., Maggirwar S.B., Garraud O., Cognasse F., Blumberg N., Phipps R.P. Breaking the mold: transcription factors in the anucleate pplatelet and platelet-derived microparticles. Front Immunol., 2015, no. 6, pp. 48-60.Lefrançais E., Ortiz- Muñoz G., Caudrillier A., Mallavia B., Liu F., Sayah D.M., Thornton E.E., Headley M.B., David T., Coughlin S.R., Krummel M.F., Leavitt A.D., Passegué E., Looney M.R. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 2017, Vol. 544, no. 7648, pp. 105-109.Lefrançais E., Ortiz- Muñoz G., Caudrillier A., Mallavia B., Liu F., Sayah D.M., Thornton E.E., Headley M.B., David T., Coughlin S.R., Krummel M.F., Leavitt A.D., Passegué E., Looney M.R. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 2017, Vol. 544, no. 7648, pp. 105-109.Lin C.I., Chen C.N., Lee H. Lysophospholipids increase IL-8 and MCP-1 expression in human umbilical cord vein endothelial cells through as IL-1-dependent mechanisms. J. Cell Biochem., 2006, Vol. 99, pp. 1216-1232.Lin C.I., Chen C.N., Lee H. Lysophospholipids increase IL-8 and MCP-1 expression in human umbilical cord vein endothelial cells through as IL-1-dependent mechanisms. J. Cell Biochem., 2006, Vol. 99, pp. 1216-1232.Loria F., Petrosino S., Mestre L., Spagnolo A., Correa F., Hernangomez M., Guaza C., DiMarzo V., Docagne F. Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoyl ethanolamine. Eur. J. Neurosci., 2008, Vol. 28, pp. 633-542.Loria F., Petrosino S., Mestre L., Spagnolo A., Correa F., Hernangomez M., Guaza C., DiMarzo V., Docagne F. Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoyl ethanolamine. Eur. J. Neurosci., 2008, Vol. 28, pp. 633-542.Maynard D.M., Heijnen H.F., Horne M.K., White J.G., Gahl W.A. Proteomic analysis of platelet alphagranules using mass spectrometry. J. Thromb. Haemost., 2007, Vol. 5, no. 9, pp. 1945-1955.Maynard D.M., Heijnen H.F., Horne M.K., White J.G., Gahl W.A. Proteomic analysis of platelet alphagranules using mass spectrometry. J. Thromb. Haemost., 2007, Vol. 5, no. 9, pp. 1945-1955.O’Flaherty J.T., Wykle R.L., Miller C.H., Lewis J.C., Waite M., Bass D.A., McCall C.E., DeChatelet L.R. 1-O -alkyl-sn-glyceryl-3- phosphorylcholines. A novel class of neutrophil stimulants. Am. J. Pathol., 1981, Vol. 103, pp. 70-79.O’Flaherty J.T., Wykle R.L., Miller C.H., Lewis J.C., Waite M., Bass D.A., McCall C.E., DeChatelet L.R. 1-O -alkyl-sn-glyceryl-3- phosphorylcholines. A novel class of neutrophil stimulants. Am. J. Pathol., 1981, Vol. 103, pp. 70-79.Offermanns S. Activation of platelet function through G protein coupled receptors. Circ. Res., 2006, Vol. 99, pp. 1293-1304.Offermanns S. Activation of platelet function through G protein coupled receptors. Circ. Res., 2006, Vol. 99, pp. 1293-1304.Pacher P., Bátkai S., Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev., 2006, Vol. 58, no. 3, pp. 389-462.Pacher P., Bátkai S., Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev., 2006, Vol. 58, no. 3, pp. 389-462.Piotrowicz R.S., Orchekowski R.P., Nugent D.J., Yamada K.Y., Kunicki T.J. Glycoprotein Ic-IIa functions as an activation-independent fibronectin receptor on human platelets. J. Cell Biol., 1988, Vol. 106, pp. 1359-1364.Piotrowicz R.S., Orchekowski R.P., Nugent D.J., Yamada K.Y., Kunicki T.J. Glycoprotein Ic-IIa functions as an activation-independent fibronectin receptor on human platelets. J. Cell Biol., 1988, Vol. 106, pp. 1359-1364.Pytela R., Pierschbacher M.D., Ruoslahti E. A 125/115-kDa cell surface receptor specific for vitronectininteracts with the arginine-glycine-aspartic acid adhesion sequence derived from fibronectin. Proc. Natl. Acad. Sci. USA, 1985, Vol. 82, pp. 5766-5770.Pytela R., Pierschbacher M.D., Ruoslahti E. A 125/115-kDa cell surface receptor specific for vitronectininteracts with the arginine-glycine-aspartic acid adhesion sequence derived from fibronectin. Proc. Natl. Acad. Sci. USA, 1985, Vol. 82, pp. 5766-5770.Rendu F., Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets, 2001, Vol. 12, no. 5, pp. 261-273.Rendu F., Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets, 2001, Vol. 12, no. 5, pp. 261-273.Romo G.M., Dong J.F., Schade A.J., Gardiner E.E., Kansas G.S., Li C.Q., McIntire L.V., Berndt M.C., López J.A. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J. Experim. Med., 1999, Vol. 190, pp. 803-814.+Romo G.M., Dong J.F., Schade A.J., Gardiner E.E., Kansas G.S., Li C.Q., McIntire L.V., Berndt M.C., López J.A. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J. Experim. Med., 1999, Vol. 190, pp. 803-814.+Rumbaut R.E., Thiagarajan P. Platelet-vessel wall interactions in hemostasis and thrombosis. San Rafael (CA): Morgan & Claypool Life Sciences, 2010, pp. 1-75.Rumbaut R.E., Thiagarajan P. Platelet-vessel wall interactions in hemostasis and thrombosis. San Rafael (CA): Morgan & Claypool Life Sciences, 2010, pp. 1-75.Sanson E., Trautwein C. Hepatocytes clear platelets and are key regulators of disseminated intravascular coagulation during sepsis. J. Hepatology, 2009, Vol. 50, pp. 1060-1064.Sanson E., Trautwein C. Hepatocytes clear platelets and are key regulators of disseminated intravascular coagulation during sepsis. J. Hepatology, 2009, Vol. 50, pp. 1060-1064.Shinohara M., Mirakaj V., Serhan C.N. Functional metabolomics reveals novel active products in the DHA metabolome. Front. Immunol., 2012, no. 3, pp. 81-90.Shinohara M., Mirakaj V., Serhan C.N. Functional metabolomics reveals novel active products in the DHA metabolome. Front. Immunol., 2012, no. 3, pp. 81-90.Skop B.P., Brown T.M. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics, 1996, Vol. 37, pp. 12-16.Skop B.P., Brown T.M. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics, 1996, Vol. 37, pp. 12-16.Slichter S.J. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus. Med. Rev., 2004, Vol. 18, no. 3, pp. 153-167.Slichter S.J. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus. Med. Rev., 2004, Vol. 18, no. 3, pp. 153-167.Smyth S.S., Cheng H.Y., Miriyala S., Panchatcharam M., Morris A.J. Role of lysophosphatidic acid in cardiovascular pysiology and disease. Biochim. Biophys. Acta., 2008, Vol. 1781, pp. 563-570.Smyth S.S., Cheng H.Y., Miriyala S., Panchatcharam M., Morris A.J. Role of lysophosphatidic acid in cardiovascular pysiology and disease. Biochim. Biophys. Acta., 2008, Vol. 1781, pp. 563-570.Sonnenberg A., Modderman P.W., Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature, 1988, Vol. 336, pp. 487-489.Sonnenberg A., Modderman P.W., Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature, 1988, Vol. 336, pp. 487-489.Staatz W.D., Rajpara S.M., Wayner E.A., Carter W.G., Santoro S.A. The membrane glycoprotein Ia-IIa (VLA- 2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J. Cell Biol., 1989, Vol. 108, pp. 1917-1924.Staatz W.D., Rajpara S.M., Wayner E.A., Carter W.G., Santoro S.A. The membrane glycoprotein Ia-IIa (VLA- 2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J. Cell Biol., 1989, Vol. 108, pp. 1917-1924.Stimler N.P., Bloor C.M., Hugli T.E., Wykle R.L., McCall C.E., O’Flaherty J.T. Anaphylactic action of platelet activating factor. Am. J. Pathol., 1981, Vol. 105, pp. 64-69.Stimler N.P., Bloor C.M., Hugli T.E., Wykle R.L., McCall C.E., O’Flaherty J.T. Anaphylactic action of platelet activating factor. Am. J. Pathol., 1981, Vol. 105, pp. 64-69.von Hundelshausen Ph., Weber Ch. Platelets as immune cells. Bridging inflammation and cardiovascular disease. Circul. Res., 2007, Vol. 100, pp. 27-40.von Hundelshausen Ph., Weber Ch. Platelets as immune cells. Bridging inflammation and cardiovascular disease. Circul. Res., 2007, Vol. 100, pp. 27-40.Wardlaw A.J., Moqbel R., Cromwell O., Kay A.B. Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils. J. Clin. Invest., 1986, Vol. 78, pp. 1701-1706.Wardlaw A.J., Moqbel R., Cromwell O., Kay A.B. Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils. J. Clin. Invest., 1986, Vol. 78, pp. 1701-1706.Warkentin T.E., Aird W.C., Rand J.H. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology Am. Soc. Hematol. Educ. Program., 2003, pp. 497-519.Warkentin T.E., Aird W.C., Rand J.H. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology Am. Soc. Hematol. Educ. Program., 2003, pp. 497-519.Warshaw A.L., Laster L., Shulman N.R. Protein synthesis by human platelets. J. Biol. Chem., 1967, Vol. 242, no. 9, pp. 2094-2097.Warshaw A.L., Laster L., Shulman N.R. Protein synthesis by human platelets. J. Biol. Chem., 1967, Vol. 242, no. 9, pp. 2094-2097.Weerheim A.M., Kolb A.M., Sturk A., Nieuwland R. Phospholipid com position of cell derived microparticles determined by one dimensional high per formance thin layer chromatography. Anal. Biochem., 2002, Vol. 302, pp. 191-198.Weerheim A.M., Kolb A.M., Sturk A., Nieuwland R. Phospholipid com position of cell derived microparticles determined by one dimensional high per formance thin layer chromatography. Anal. Biochem., 2002, Vol. 302, pp. 191-198.Weylandt K.H. Docosapentaenoic acid derived metabolites and mediators – the new world of lipid mediator medicine in a nutshell. Eur. J. Pharmacol., 2016, Vol. 785, no. 15, pp. 108-115.Weylandt K.H. Docosapentaenoic acid derived metabolites and mediators – the new world of lipid mediator medicine in a nutshell. Eur. J. Pharmacol., 2016, Vol. 785, no. 15, pp. 108-115.Weyrich A.S., Zimmerman G.A. Platelets in lung biology. Annu. Rev. Physiol., 2013, Vol. 75, pp. 569-591.Weyrich A.S., Zimmerman G.A. Platelets in lung biology. Annu. Rev. Physiol., 2013, Vol. 75, pp. 569-591.Weyrich A.S., Schwertz H., Kraiss L.W., Zimmerman G.A. Protein synthesis by platelets: historical and new perspectives. J. Thromb. Haemost., 2009, Vol. 7, no. 2, pp. 241-246.Weyrich A.S., Schwertz H., Kraiss L.W., Zimmerman G.A. Protein synthesis by platelets: historical and new perspectives. J. Thromb. Haemost., 2009, Vol. 7, no. 2, pp. 241-246.White J.G. Platelet structure. In: Michelson A.D., editor. Platelets. Academic Press, 2007, pp. 45-73.White J.G. Platelet structure. In: Michelson A.D., editor. Platelets. Academic Press, 2007, pp. 45-73.Yatomi Y. Plasma sphingosine 1-phosphate metabolism and analysis. Biochim. Biophys. Acta, 2008, Vol. 1780, pp. 606-611.Yatomi Y. Plasma sphingosine 1-phosphate metabolism and analysis. Biochim. Biophys. Acta, 2008, Vol. 1780, pp. 606-611.Yung Y.C., Stoddard N.C., Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J. Lipid Res., 2014, Vol. 55, no. 7, pp. 1192-2014.Yung Y.C., Stoddard N.C., Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J. Lipid Res., 2014, Vol. 55, no. 7, pp. 1192-2014.

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