Molekulyarnaya Meditsina (Molecular medicine)Molekulyarnaya Meditsina (Molecular medicine)Молекулярная медицина1728-29182499-9490Russkiy Vrach Publishing House11331310.29296/24999490-2020-05-01ArticlesСтатьиResearch ArticleBlood system under COVID-19 infection: pathogenic mechanisms of disorders and perspectives of therapyСистема крови при инфицировании COVID-19: патогенетические механизмы нарушений и перспективы терапииMartusevichA. KМартусевичА. К

доктор биологических наук

cryst-mart@yandex.ruPrivozhsky Research Medical UniversityФГБОУ ВО «ПИМУ» Минздрава России15052020185VOL 18, NO5 (2020)ТОМ 18, №5 (2020)31018112022Copyright ©; 2020, Russkiy Vrach Publishing HouseCopyright ©; 2020, ИД "Русский врач"2020Russkiy Vrach Publishing HouseИД "Русский врач"https://journals.eco-vector.com/1728-2918/article/view/113313

The purpose of this review is a systematic analysis of data from clinical observations, international experience, and reviews related to the pathogenetic aspects of the impact of a new coronavirus infection on the blood system. Information was searched in MedLine, PubMed, and RSCI databases. A brief description of the etiological agent with a detailed analysis of the structure of this virus is given. The features and mechanisms of immunological shifts induced by SARS-CoV-2 infection are analyzed. Hematological and metabolic changes in the blood of COVID-19 patients are presented and described. The reaction of erythron to the development of a new coronavirus infection was evaluated from pathogenetic and clinical positions. In whole, the agent of a new coronavirus infection was shown in patients to have a multifaceted negative effect on the blood system, which is reflected in the dysfunction of the immune system (predominantly cellular) with the formation of a special syndrome termed as «cytokine storm», a hypercoagulable state until the development of disseminated intravascular coagulation, as well as reducing the absolute number of all formed elements of blood. Understanding the mechanisms of development of these shifts creates opportunities for delivering new technologies for targeted therapy.

Целью данного обзора является системный анализ данных клинических наблюдений, международного опыта и обзоров, касающихся патогенетических аспектов влияния новой коронавирусной инфекции (КВИ) на систему крови. Поиск информации осуществлялся по базам MedLine, PubMed, РИНЦ. Приведена краткая характеристика этиологического агента с подробным анализом структуры данного вируса. Проанализированы особенности и механизмы иммунологических сдвигов, индуцированных SARS-CoV-2-инфицированием. Приведены и описаны гематологические и метаболические сдвиги в крови пациентов с COVID-19. С патогенетических и клинических позиций оценена реакция эритрона на развитие новой КВИ. Показано, что возбудитель новой КВИ оказывает многогранное негативное действие на систему крови пациентов, которое выражается в дисфункции иммунитета (преимущественно - клеточного) с формированием особого синдрома - «цитокинового шторма», гиперкоагуляции вплоть до развития синдрома диссеминированного внутрисосудистого свертывания, а также снижения абсолютного количества всех форменных элементов крови. Понимание механизмов развития данных сдвигов создает возможности для создания новых технологий таргентой терапии.

SARS-CoV-2COVID-19SARS-CoV-2COVID-19pathogenesispathogenic therapyreviewпатогенезпатогенетическая терапияобзорМартусевич А.К., Перетягин С.П. Новая коронавирусная инфекция (COVID-19) как глобальная угроза человечеству: некоторые вопросы эпидемиологии, патогенеза и диагностики. Биорадикалы и антиоксиданты. 2020; 7 (1): 42-71.Lu R., Zhao X., Li J., Niu R, Yang B., Wu H., Wang W., Song H., Huang B., Zhu N. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395: 565.McIntosh K. Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention. https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-epidemiology-virolo-gy-clinical-features-diagnosis-and-preventionPerlman S. Another Decade, Another Coronavirus. N. Engl. J. Med. 2020; 382: 760.World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020Chen G., Wu D., Guo W., Cao Y, Huang D., Wang H., Wang T. et al. Qin Ning Clinical and Immunological Features of Severe and Moderate Coronavirus Disease 2019. J. Clin. Invest. 2020; 130 (5): 2620-9. https://doi.org/10.1172/JCI137244.Frater J.L., Zini G., d'Onofrio G., Rogers H.J. COVID-19 and the Clinical Hematology Laboratory Int. J. Lab. Hematol. 2020. https://doi. org/10.1111/ijlh.13229. Online ahead of print.Wang F, Hou H., Luo Y, Tang G., Wu S., Huang M., Liu W., Zhu Y, Lin Q., Mao L., Fang M., Zhang H., Sun Z. The laboratory tests and host immunity of COVID-19 patients with different severity of illness. JCI Insight. 2020; 5 (10): e137799. https://doi.org/10.1172/jci.insight.137799.Горенков Д.В., Хантимирова Л.М., Шевцов В.А., Рукавишников А.В., Меркулов В.А., Олефир Ю.В. Вспышка нового инфекционного заболевания COVID-19: р-коронавирусы как угроза глобальному здравоохранению. БИОпрепараты. Профилактика, диагностика, лечение. 2020; 20 (1): 6-20. https://doi.org/10.30895/2221-996X-2020-20-1-6-20Львов Д.К., Альховский С.В., Колобухина Л.В., Бурцева Е.И. Этиология эпидемической вспышки COVID-19 в г. Ухань (провинция Хубэй, Китайская Народная Республика), ассоциированной с вирусом 2019-CoV (Nidovirales, Coronaviridae, Coronavirinae, Betacoronavirus, подрод Sarbecovirus): уроки эпидемии SARS-CoV. Вопросы вирусологии. 2020; 65 (1): 6-15. https://doi.org/10.36233/0507-4088-2020-65-1-6-15Никифоров В.В., Суранова Т.Г., Чернобровкина Т.Я., Янковская Я.Д., Бурова С.В. Новая коронавирусная инфекция (covid-19): клиникоэпидемиологические аспекты. Архивъ внутренней медицины. 2020; 10 (2): 87-93. https://doi.org/10.20514/2226-6704-2020-10-2-87-93Старшинова А.А., Кушнарева Е.А., Малкова А.М., Довгалюк И.Ф., Кумай Д.А. Новая коронавирусная инфекция: особенности клинического течения, возможности диагностики, лечения и профилактики инфекции у взрослых и детей. Вопросы современной педиатрии. 2020; 19(2): 123-131.Абатуров А.Е., Агафонова Е.А., Кривуша Е.Л., Никулина А.А. Патогенез COVID-19. Здоровье ребенка. 2020; 15 (2): 133-44. https://doi.org/10.22141/2224-0551.15.1.2020.200598Zhou P, Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W., Si H.-R., Zhu Y, Li B., Huang C.-L. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579: 270.Gorbalenya A.E., Baker S.C., Baric R.S., de Groot R.J., Drosten C., Gulyaeva A.A., Haagmans B.L., Lauber C., Leontovich A.M., Neuman B.W. et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses - a statement of the Coronavirus Study Group. bioRxiv 2020. https://www.biorxiv.org/content/10.1101/2020.02.07.937862v1Coleman C.M., Sisk J.M., Mingo R.M., Nelson E.A., White J.M., Frieman M.B. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J. Virol. 2016; 90 (19): 8924-33. https://doi.org/10.1128/JVI.01429-16.Zhu N., Zhang D., Wang W, Li X., Yang B., Song J., Zhao X., Huang B., Shi W, Lu R. et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020; 382: 727.Tang X., Wu C., Li X. et al. On the origin and continuing evolution of SARS-CoV-2. National Science Review 2020.Chaw S.-M., Tai J.-H., Chen S.-L., Hsieh C.-H., Chang S.-Y, Yeh S.-H., Yang W.-S., Chen P.-J., Wang H.-Y The origin and underlying driving forces of the SARS-CoV-2 outbreak. J. Biomed. Sci. 2020; 27: 73. https://doi.org/10.1186/s12929-020-00665-8Li G., Fa Y, Lai Y., Han T., Li Z., Zhou P., Pan P., Wang W., Hu D., Liu X., Zhang Q., Wu J. Coronavirus Infections and Immune Responses. J. Med. Virol. 2020; 92 (4): 424-32. https://doi.org/10.1002/jmv.25685.Zhu F-C., Li Y-H., Guan X.-H., Hou L.-H., Wang W.-J., Li J.-X., Wu S.-P, Wang B.-S., Wang Z., Wang L., Jia S.-Y et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)31208-3Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124 (4): 783-801.Kell A.M., Gale M. Jr. RIG-I in RNA virus recognition. Virology 2015; 479-480: 110-121.Yoneyama M., Fujita T RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 2009; 227 (1): 54-65.Davis B.K., Roberts R.A., Huang M.T., Willingham S.B., Conti B.J., Brickey W.J., Barker B.R., Kwan M., Taxman D.J., Accavitti-Loper M.-A., Duncan J.A., Ting J. P-Y Cutting edge: NLRC5-dependent activation of the inflammasome. J. Immunol. 2011; 186 (3): 1333-7.Hornung V, Ablasser A., Charrel-Dennis M., Bauernfeind F., Horvath G., Caffrey D.R., Latz E., Fitzgerald K.A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009; 458 (7237): 514-8.Inohara C., McDonald C., Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu. Rev Biochem. 2005; 74: 355-83.Zhu X., Wang Y, Zhang H., Liu X., Chen T., Yang R., Shi Y, Cao W., Li P, Ma Q., Zhai Y, He F, Zhou G., Cao C. Genetic variation of the human alpha-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection. PLOS One. 2011; 6 (8): e23730.Shanmugaraj B., Siriwattananon K., Wangkanont K., Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac. J. Allergy Immunol. 2020; 38: 10-8. https://doi. org/10.12932/AP-200220-0773Ye Q., Wang B., Mao J. The pathogenesis and treatment of the «Cytokine Storm» in COVID-19. J. Infect. 2020; 80 (6): 607-13. https://doi.org/10.1016/jjinf.2020.03.037.Ulrich H., Pillat M.M. CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement. Stem Cell Reviews and Reports. 2020; 16: 434-40.Lippi G., Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020. https://doi.org/10.1515/cclm-2020-0198.Giannis D., Ziogas I.A., Gianni P Coagulation Disorders in Coronavirus Infected Patients: COVID-19, SARS-CoV-1, MERS-CoV and Lessons From the Past. J. Clin. Virol. 2020; 127: 104362. https://doi.org/10.1016/jjcv2020.104362.Bikdeli B., Madhavan M.V, Jimenez D., Chuich T., Dreyfus I., Driggin E., Der Nigoghossian C. , Ageno W., Madjid M., Guo Y et al. COV-ID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J. Am. Coll. Cardiol. 2020; S0735-1097 (20) 35008-7. https://doi.org/10.1016/jjacc.2020.04.031.Bikdeli B., Madhavan M.V., Gupta A., Jimenez D. , Burton J.R., Der Nigoghossian C. et al. (Global COVID-19 Thrombosis Collaborative Group) Pharmacological Agents Targeting Thromboin-flammation in COVID-19: Review and Implications for Future Research. Thromb. Haemost. 2020. https://doi.org/10.1055/s-0040-1713152.Bohm M., Frey N., Giannitsis E., Sliwa K., Zeiher A.M. Coronavirus Disease 2019 (COVID-19) and Its Implications for Cardiovascular Care: Expert Document From the German Cardiac Society and the World Heart Federation. Clin. Res. Cardiol. 2020; 1-14. https://doi. org/10.1007/s00392-020-01656-3.Vivas D., Roldán V., Esteve-Pastor M.A., Roldán I., Tello-Montoliu A., Ruiz-Nodar J.M., Cosin-Sales J., Gámez J.M., Consuegra L., Ferreiro J.L., Marin F, Arrarte V., Anguita M., Cequier Á., Pérez-Villacastin J. Recommendations on Antithrombotic Treatment During the COVID-19 Pandemic. Position Statement of the Working Group on Cardiovascular Thrombosis of the Spanish Society of Cardiology Rev Esp. Cardiol. 2020. https://doi.org/10.1016/j.recesp.2020.04.006.Watson R.A., Johnson D.M., Dharia R.N., Merli G.J., Doherty J.U. Anti-Coagulant and AntiPlatelet Therapy in the COVID-19 Patient: A Best Practices Quality Initiative Across a Large Health System. Hosp. Pract. 2020. https://doi.org/10.1080/21548331.2020.1772639.Lorenzo C., Francesca B., Francesco P, Elena C., Luca S., Paolo S. Acute Pulmonary Embolism in COVID-19 Related Hypercoagulability. J. Thromb. Thrombolysis. 2020; 1-4. https://doi.org/10.1007/s11239-020-02160-1.Emert R., Shah P, Zampella J.G. COVID-19 and Hypercoagulability in the Outpatient Setting. Thromb. Res. 2020; 192: 122-3. htt-ps://doi.org/10.1016/j.thromres.2020.05.031.Spyropoulos A.C., Ageno W., Barnathan E.S. Hospital-based Use of Thromboprophylaxis in Patients With COVID-19. Lancet. 2020; 395 (10234): e75. https://doi.org/10.1016/S0140-6736(20)30926-0.Mei H., Hu Y. Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19. Zhonghua Xue Ye Xue Za Zhi. 2020; 41 (3): 185-91. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0002.Zhang Y, Cao W., Xiao M., Li Y.J., Yang Y, Zhao J. et al. Clinical and Coagulation Characteristics of 7 Patients With Critical COVID-2019 Pneumonia and Acro-Ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020; 41 (0): E006. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.Thachil J. The Versatile Heparin in COVID-19. J. Thromb. Haemost. 2020; 18 (5): 1020-2. https://doi.org/10.1111/jth.14821.Zhang Y, Xiao M., Zhang S., Xia P, Cao W., Jiang W., Chen H., Ding X., Zhao H., Zhang H. et al. Coagulopathy and Antiphospholipid Antibodies in Patients With Covid-19. N. Engl. J. Med. 2020; 382 (17): e38. https://doi.org/10.1056/NEJMc2007575.Gavillet M., Rufer N., Grandoni F, Klappert J.C., Zermatten M.G., Cairoli A., Canellini G., Alberio L., Duchosal M.A., Spertini O., Blum S. Hematology in the Time of COVID-19. Rev Med. Suisse. 2020; 16 (691-2): 823-6.Lippi G., Plebani M., Henry B.M. Thrombocytopenia Is Associated With Severe Coronavirus Disease 2019 (COVID-19) Infections: A Meta-Analysis. Clin. Chim. Acta. 2020; 506: 145-8. https://doi.org/10.1016/j.cca.2020.03.022.Tan L., Wang Q., Zhang D., Ding J., Huang Q., Tang Y-Q., Wang Q., Miao H. Lymphopenia Predicts Disease Severity of COVID-19: A Descriptive and Predictive Study Signal Transduct. Target. Ther. 2020; 5 (1): 33. https://doi.org/10.1038/s41392-020-0148-4.Lippi G., Plebani M. Procalcitonin in Patients With Severe Coronavirus Disease 2019 (COV-ID-19): A Meta-Analysis. Clin. Chim. Acta. 2020; 505: 190-1. https://doi.org/10.1016/j.cca.2020.03.004.Ji H.-L., Zhao R., Matalon S., Matthay M.A. Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility. Physiol. Rev 2020; 100 (3): 1065-75. https://doi.org/10.1152/physrev.00013.2020.Barnes B.J., Adrover J.M., Baxter-Stoltzfus A., Borczuk A., Cools-Lartigue J., Crawford J.M., Daβler-Plenker J., Guerci P., Huynh C., Knight J.S. et al. Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps. J. Exp. Med. 2020; 217 (6): e20200652. https://doi.org/10.1084/jem.20200652.Lu G., Wang J. Dynamic Changes in Routine Blood Parameters of a Severe COVID-19 Case. Clin Chim Acta. 2020; 508: 98-102. https://doi.org/10.1016/j.cca.2020.04.034.Luo Y., Yuan X., Xue Y., Mao L., Lin Q., Tang G., Song H., Liu W., Hou H., Wang F., Sun Z. Using a Diagnostic Model Based on Routine Laboratory Tests to Distinguish Patients Infected With SARS-CoV-2 From Those Infected With Influenza Virus. Int. J. Infect. Dis. 2020; 95: 436-40. https://doi.org/10.1016/j.ijid.2020.04.078.Lapic I., Rogić D., Plebani M. Erythrocyte Sedimentation Rate Is Associated With Severe Coronavirus Disease 2019 (COVID-19): A Pooled Analysis. Clin. Chem. Lab. Med. 2020. https://doi.org/10.1515/cclm-2020-0620.Wang Z., Du Z., Zhu F Glycosylated Hemoglobin Is Associated With Systemic Inflammation, Hypercoagulability, and Prognosis of COVID-19 Patients. Diabetes Res Clin Pract. 2020; 164: 108214. https://doi.org/10.1016/j. diabres.2020.108214.Lehene M., Fischer-Fodor E., Scurtu F., Hâdade N.D., Gal E., Mot A.C., Matei A., Silaghi-Dumitrescu R. Excess ascorbate is a chemical stress agent against proteins and cells. Pharmaceuticals (Basel). 2020; 13 (6): E107. https://doi.org/10.3390/ph13060107.