Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum9540110.26442/20751753.2021.1.200607ArticlesСтатьиReview ArticleHemostasis disorders, thrombosis, antiphospholipid antibodies in patients with COVID-19Нарушения гемостаза, тромбозы, антифосфолипидные антитела у пациентов с COVID-19ReshetnyakTatiana M.РешетнякТатьяна Магомедалиевна

д-р мед. наук, проф., зав. лаб. сосудистой ревматологии

t_reshetnyak@yahoo.comChel'dievaFariza A.ЧельдиеваФариза Алановна

мл. науч. сотр. лаб. сосудистой ревматологии

LilaAleksandr M.ЛилаАлександр Михайлович

д-р мед. наук, проф., дир.

NasonovEvgenii L.НасоновЕвгений Львович

акад. РАН, д-р мед. наук, проф., гл. науч. сотр.

Nasonova Research Institute of RheumatologyФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»Russian Medical Academy of Continuous Professional EducationФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииSechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)15012021231VOL 23, NO1 (2021)ТОМ 23, №1 (2021)354228122021Copyright ©; 2021, Consilium MedicumCopyright ©; 2021, ООО "Консилиум Медикум"2021Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/95401

The article provides an overview of main blood clotting disorders in coronavirus infection 2019 (COVID-19), which is associated with several hematological changes. Patients with COVID-19 develop typically two hemostasis disorders - an increased D-dimer levels and moderate thrombocytopenia, which occur in more than 40% of cases. Other hemostasis abnormalities, which are frequently reported in COVID-19, included prolonged prothrombin time (PT), also expressed as international normalized ratio, prolonged thrombin time, and activated partial thromboplastin time (APTT), which were typical acute phase reactions. Prolonged APTT or PT, and thrombocytopenia are common, especially in patients with severe clinical course. It has been hypothesized that increased D-dimer concentration and prolongation of PT, APTT are associated with higher mortality in patients with COVID-19. Disseminated intravascular coagulation occurs most often in severe cases of COVID-19 (about 2% of all hospitalized patients) and indicates a poor prognosis, i.e. about 90% mortality. It remains unclear whether SARS-CoV-2 can induce antiphospholipid antibodies. An increased incidence of positive lupus anticoagulants was observed in patients with COVID-19, it can be assumed that all patients with COVID-19 in whom antiphospholipid antibodies are revealed should be monitored and receive thromboprophylaxis even with no history of thromboembolism.

Приведен обзор основных нарушений свертывания крови при коронавирусной болезни 2019 г. (COVID-19), которая связана с несколькими гематологическими изменениями. У пациентов с COVID-19 наблюдаются два типичных нарушения гемостаза - это повышенный уровень D-димера и умеренная тромбоцитопения, которые зарегистрированы в более чем 40% случаев. Другие аномалии гемостаза, часто сообщаемые при COVID-19, включали пролонгированное протромбиновое время (ПВ), выраженное также как международное нормализованное отношение, пролонгированное тромбиновое время и активированное частичное тромбопластиновое время (АЧТВ), которые являлись типичными острофазовыми реакциями. Пролонгация АЧТВ, ПВ и тромбоцитопения встречаются часто, особенно у пациентов с тяжелым клиническим течением. Высказано предположение, что повышенная концентрация D-димера и удлинение ПВ, АЧТВ связаны с более высокой смертностью у пациентов с COVID-19. Диссеминированное внутрисосудистое свертывание крови наблюдается чаще всего в тяжелых случаях COVID-19 (около 2% всех госпитализированных пациентов) и свидетельствует о плохом прогнозе, т.е. о 90% летальности. Остается неясным, может ли SARS-CoV-2 индуцировать антифосфолипидные антитела. Повышенную частоту положительных волчаночных антикоагулянтов наблюдали у пациентов с COVID-19, можно предположить, что все пациенты с COVID-19, у которых обнаружены антифосфолипидные антитела, должны находиться под пристальным наблюдением и получать тромбопрофи-лактику даже без каких-либо тромбоэмболий в анамнезе.

coronavirus infection (COVID-19)hemostasis disorderantiphospholipid antibodiesantiphospholipid syndromethrombosisanticoagulantsкоронавирусная инфекция (COVID-19)нарушение гемостазаантифосфолипидные антителаантифосфолипидный синдромтромбозыантикоагулянтыCenters for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19) in the U.S, 2020. Available at: https://www.cdc.goV/coronavirus/2019-ncov/cases-in-us.html# investigationNational Institute of Allergy and Infectious Diseases. Coronaviruses, 2020. Available at: https://www.niaid.nih.gov/di-seases-conditions/coronavirusesCenters for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-managementpatientshtmlНасонов Е.Л. Коронавирусная болезнь 2019 (COVID-19): размышления ревматолога. Научно-практическая ревматология. 2020; 58 (2): 123-32Насонов Е.Л., Бекетова Т.В., Решетняк Т.М., и др. Коронавирусная болезнь 2019 (COVID-19) и иммуновоспалительные ревматические заболевания на перекрестке проблем тромбовоспаления и аутоиммунитета. Научно-практическая ревматология. 2020; 58: (4) 353-67Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 2020. DOI: 10.1016/ S2352-3026(20)30145-149Макацария А.Д., Григорьева К.Н., Мингалимов М.А., и др. Коронавирусная инфекция (COVID-19) и синдром диссеминированного внутрисосудистого свертывания. Акушерство, Г инекология и Репродукция. 2020; 14 (2)Loof TG, Schmidt O, Herwald H, et al. Coagulation systems of invertebrates and vertebrates and their roles in innate immunity: the same side of two coins? J Innate Immun 2011; 3 (1): 34-40. DOI:10.1159/000321641. PMID: 21051879Esmon CT, Esmon NL. The link between vascular features and thrombosis. Ann Rev Physiol 2011; 73: 503-14. DOI: 10.1146/annurev-physiol-012110-142300; PMID: 20887194Струкова С.М. Основы физиологии гемостаза. Учеб. пособие. 2-е изд., перераб. и доп. М.: МГУ, 2013; c. 148-84Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131: 417-30. DOI: 10.1111/j.1365-2141.2005.05753.xЧельдиева Ф.А., Решетняк Т.М. Ревматоидный артрит, некоторые компоненты гемостаза и воспаление. Соврем. ревматология. 2019; 13 (3): 87-94Henry BM, Santos de Oliveira MH, Stefanie Benoit S, et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med 2020. DOI: 10.1515/cclm-2020-0369Guan WJ, Ni ZY, Hu Y, et al. China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382 (18): 1708-20. DOI: 10.1056/NEJMoa2002032; PMID: 32109013; PMCID: PMC7092819Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (4): 844-7. DOI: 10.1111/jth.14768; PMID: 32073213; PMCID: PMC7166509Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506. DOI: 10.1016/S0140-6736(20)30183-5; PMID:31986264; PMCID: PMC7159299Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-62. DOI: 10.1016/S0140-6736(20)30566-3; PMID: 32171076; PMCID: PMC7270627Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J He-matol 2020. DOI: 10.1002/ajh.25829Thachil J, Wada H, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020. DOI: 10.1111/jth.14810Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020; 506: 145-8. DOI: 10.1016/j.cca.2020.03.022; PMID: 32178975; PMCID: PMC7102663Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395 (10229): 1033-4. DOI: 10.1016/S0140-6736(20)30628-0; PMID: 32192578; PMCID: PMC7270045Thachil J. Platelets in Inflammatory Disorders: A Pathophysiological and Clinical Perspective. Semin Thromb Hemost 2015; 41 (6): 572-81. DOI: 10.1055/s-0035-1556589Borensztajn KS, von der Thusen JH, Spek CA. The role of coagulation in chronic inflammatory disorders: A jack of all trades. Curr Pharm Des 2011; 17 (1): 9-16. DOI:10.2174/138161211795049813Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. DOI: 10.1016/j.thromres.2020.04.013Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (2): 295-306. DOI: 10.1111/j.1538-7836.2006.01753; PMID: 16420554Насонов Е.Л. Антифосфолипидный синдром. Монография. М.: Литтера, 2004; с. 36Решетняк Т.М. Антифосфолипидный синдром: диагностика и клинические проявления (лекция). Научнопрактическая ревматология. 2014; 52 (1): 56-71Буланов Н.М., Козловская Н.Л., Моисеев С.В., и др. Сочетание АНЦА-ассоциированного васкулита и атипичного гемолитико-уремического синдрома у пациентки с мутацией гена диацилглицеролкиназы-эпсилон (Клинический разбор). Нефрология и диализ. 2018. 20 (2): 212-24Hess DC, Sethi K, Awad E. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus and antiphospholipid antibodies: effective treatment with plasma exchange and immunosuppression. J Rheumatol 1992; 19: 1474-8. PMID: 14 33020.Harzallah I, Debliquis A, Drenou B. Lupus anticoagulant is frequent in patients with Covid-19. J Thromb Haemost 2020; 18: 2064-5. DOI: 10.1111/ jth.14867Pineton de Chambrun M, Frere C, Miyara M, et al. High Frequency of Antiphospholipid Antibodies in Critically-ill COVID-19 Patients: a Link with Hypercoagulability? J Int Med 2020; 12. DOI: 10.1111/joim.13126Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med 2020; 382: e38. DOI: 10.1056/NEJMc2007575Zuo Y, Estes SK, Gandhi AA, et al. Prothrombotic antiphospholipid antibodies in COVID-19. medRxiv 2020; 17. DOI: 10.1101/ 2020.06.15.20131607Xiao M, Zhang Y, Zhang S, et al. Brief Report: Antiphospholipid antibodies in critically ill patients with Coronavirus Disease 2019 (COVID-19). Arthritis Rheumatol 2020. DOI: 10.1002/art.41425Leroy V, Arvieux J, Jacob MC, et al. Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol 1998; 101 (3): 468-74. DOI: 10.1046/j.1365-2141.1998.00722; PMID: 9633888Gharavi EE, Chaimovich H, Cucurull E, et al. Induction of antiphospholipid antibodies by immunization with syntetic viral and bacterial peptidies. Lupus 1999; 8: 449-55. DOI: 10.1177/096120339900800607Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31 (4): 256-63. DOI: 10.1053/sarh.2002.28303Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Ne-urosurg Psychiatry 2020; 91 (8): 889-91. DOI: 10.1136/jnnp-2020-323586Devreese KMJ, Ortel TL, Pengo V, et al. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (4): 809-13. DOI:10.1111/jth.13976Kelchtermans H, Pelkmans L, de Laat B, Devreese KM. IgG/IgM antiphospholipid antibodies present in the classification criteria for the antiphospholipid syndrome: a critical review of their association with thrombosis. J Thromb Haemost 2016; 14 (8): 1530-48. DOI: 10.1111/jth.13379Chayoua W, Kelchtermans H, Gris JC, et al. The (non-)sense of detecting anti-cardiolipin and anti-beta2glycoprotein I IgM antibodies in the antiphospholipid syndrome. J Thromb Haemost 2020; 18 (1): 169-79. DOI: 10.1111/jth.14633Schouwers SM, Delanghe JR, Devreese KM. Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010; 125 (1): 102-4. DOI: 10.1016/j.thromres.2009.09.001; PMID: 19782388.Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: A relevant observation? J Thromb Haemost 2020; 18 (9): 2191-201. DOI: 10.1111/jth.14994Devreese KM. Antiphospholipid antibody testing and standardization. International Journal of Laboratory Hematology 2014; 36 (3): 352-63. DOI: 10.1111/ijlh.12234Schouwers SM, Delanghe JR, Devreese KM. Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results? Thromb Res 2010; 125 (1): 102-4. DOI: 10.1016/j.thromres.2009.09.001De Kesel PM, Devreese KMJ. The effect of unfractionated heparin, enoxaparin and danaparoid on lupus anticoagulant testing. Can activated carbon eliminate false positive results? Res Practice Thromb Haemost 2019. DOI: 10.1002/rth1002.12264Tripodi A, Cohen H, Devreese KMJ. Lupus anticoagulant detection in anticoagulated patients. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020. DOI: 10.1111/jth.14846Galeano-Valle F, Oblitas CM, Ferreiro-Mazon MM, et al. Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism. Thromb Res 2020; 192: 113-5. DOI: 10.1016/ j.thromres.2020.05.017Borghi MO, Beltagy A, Garrafa E, et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol 2020; 15; 11: 584241. DOI: 10.3389/fimmu.2020.584241Tincani A, Morozzi G, Afeltra A, et al. Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). Antiprothrombin antibodies: a comparative analysis of homemade and commercial methods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). Clin Exp Rheumatol 2007; 25 (2): 268-74. PMID: 17543152.Bowles L, Platton S, Yartey N, et al. Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19. New Engl J Med 2020. DOI: 10.1056/NEJMc2013656Sanchez-Zamora P, de la Flor-Robledo M. Acute lung injury as a consequence of fresh frozen plasma administration in a patient with factor XII deficiency. Rev Esp Anestesiol Reanim 2014; 61 (8): 446-50. DOI: 10.1016/j.redar.2013.09.012; PMID: 24252352.Cornudella R, Puente F, Hortells JL, Gutierrez M. Moderate deficiency of Factor XII associated with postoperative deep venous thrombosis. Sangre (Barc) 1989; 34 (2): 144-6. PMID: 2756451.Cugno M, Meroni PL, Gualtierotti R, et al. Complement activation in patients with COVID-19: A novel therapeutic target. J Allergy Clin Immunol 2020; 146: 215-17. DOI: 10.1016/j.jaci.2020.05.006Garcia-Carrasco M, Galarza-Maldonado C, Mendoza-Pinto C, et al. Infections and the Antiphospholipid Syndrome. Clin Rev Allergy Immunol 2009; 36: 104-8. DOI: 10.1007/s12016-008-8103-0Wyman B, Perl A. Metabolic pathways mediate pathogenesis and offer targets for treatment in rheumatic diseases. Curr Opin Rheumatol 2020; 32: 184-91. DOI: 10.1097/BOR.0000000000000687Available from: https://www.outcomesumassmed.org/IMPROVE/risk_score/index.htmlTapson VF, Decousus H, Pini M, et al. IMPROVE Investigators. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132 (3): 936-45. DOI: 10.1378/chest.06-2993; PMID: 17573514.Spyropoulos AC, Anderson FA Jr, Fitzgerald G, et al. IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (3): 706-14. DOI: 10.1378/chest.10-1944; PMID: 21436241.Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (4): 489-500. DOI: 10.1182/blood.2020006520; PMID: 32492712; PMCID: PMC7378457.Conti CB, Henchi S, Coppeta GP, et al. Bleeding in COVID-19 severe pneumonia: The other side of abnormal coagulation pattern? Eur J Intern Med 2020; 77: 147-9. DOI: 10.1016/j.ejim.2020.05.002Jang JY, Lim YS, Woo JH, et al. Spontaneous rupture of intercostal artery after severe cough. Am J Emerg Med 2015; 33 (1): 131. DOI: 10.1016/j.ajem.2014.06.033Lee CH, Lan CC, Wang CC, et al. Spontaneous rupture of gastroduodenal artery pseudoaneurysm following vigorous cough. Am J Gastroenterol 2009; 104 (2): 529-30. DOI: 10.1038/ajg.2008.52Dorgalaleh A. Bleeding and Bleeding Risk in COVID-19. Semin Thromb Hemost 2020; 46 (7): 815-8. DOI: 10.1055/s-0040-1713434Joob B, Wiwanitkit V. Hemorrhagic Problem Among the Patients With COVID-19: Clinical Summary of 41 Thai Infected Patients. Clin Appl Thromb Hemost 2020; 26: 1076029620918308. DOI: 10.1177/1076029620918308Poyiadji N, Shahin G, Noujaim D, et al. COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features. Radiology 2020; 296 (2): E119-20. DOI: 10.1148/radiol.2020201187Zulfiqar AA, Lorenzo-Villalba N, Hassler P, Andres E. Immune Thrombocytopenic Purpura in a Patient with Covid-19. N Engl J Med 2020; 382 (18): e43. DOI: 10.1056/NEJMc2010472; PMID: 32294340; PMCID: PMC7179995.Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020. DOI: 10.1016/j.jacc.2020.04.031Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment. J Thromb Haemost 2020. DOI: 10.1111/jth.14860Testa S, Prandoni P, Paoletti O, et al. Direct oral anticoagulant plasma levels’ striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience. J Thromb Haemost 2020. DOI: 10.1111/jth.14871Liu X, Zhang X, Xiao Y, et al. Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment. medRxiv 2020. DOI: 10.1101/2020.04.23.20076851Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020. DOI: 10.2450/2020.0083-20Preventing Hospital-Associated Venous Thromboembolism. A Guide for Effective Quality Improvement. Available at: https://www.ahrq.gov/sites/default/files/publications/files/vteguide.pdf