Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC136810.15690/vramn1368CARDIOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ КАРДИОЛОГИИResearch ArticleCOVID-19, hemostasis disorders and risk of thrombotic complicationsCOVID-19, нарушения гемостаза и риск тромботических осложненийhttps://orcid.org/0000-0001-7415-46336602363216M-5660-20167538-2966MakatsariyaAlexander D.МакацарияАлександр Давидович
Russian Federation

MD, PhD, Professor

д.м.н., профессор, член-корр. РАН

gemostasis@mail.ruhttps://internist.ru/lectors/detail/makatsariya-/https://orcid.org/0000-0001-7441-27787423-8944SlukhanchukEkaterina V.СлуханчукЕкатерина Викторовна
Russian Federation

MD, PhD, Assistant Professor

к.м.н., доцент

beloborodova@rambler.ruhttps://orcid.org/0000-0001-8404-10426506003478F-8409-20175930-0859BitsadzeVictoria O.БицадзеВиктория Омаровна
Russian Federation

MD, PhD, Professor

д.м.н., профессор, профессор РАН

vikabits@mail.ruhttps://orcid.org/0000-0002-0725-968657194547147F-8384-20178225-4976KhizroevaJamilya Kh.ХизроеваДжамиля Хизриевна
Russian Federation

MD, PhD, Professor

доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья Сеченовского Университета

jamatotu@gmail.comhttps://orcid.org/0000-0002-3628-08041463-0065TretyakovaMaria V.ТретьяковаМария Владимировна
Russian Federation

MD, PhD, Assistant Professor

к.м.н., доцент

tretyakova777@yandex.ruhttps://orcid.org/0000-0001-5888-0774TsibizovaValentina I.ЦибизоваВалентина Ивановна
Russian Federation

Doctor, Departments of Functional and Ultrasound Diagnostics

врач отделения функциональной и ультразвуковой диагностики=

tsibizova.v@gmail.comhttps://orcid.org/0000-0002-9783-1796ShkodaAndrei S.ШкодаАндрей Сергеевич
Russian Federation

MD, PhD

д.м.н.

67gkb@mail.ruhttps://orcid.org/0000-0002-8980-97837006391091GrandoneElviraГрандонеЭльвира
Russian Federation

MD, PhD, Professor

д.м.н., профессор

grandoneelvira@gmail.comhttps://orcid.org/0000-0002-9576-13687003652413ElalamyIsmailЭлаламиИсмаил
Russian Federation

MD, PhD, Professor

д.м.н., профессор

ismail.elalamy@aphp.frhttps://orcid.org/0000-0002-5525-43537102724281G-8234-2018RizzoGiuseppeРиццоДжузеппе
Russian Federation

MD, PhD, Professor

д.м.н., профессор

giuseppe.rizzo@uniroma2.ithttps://orcid.org/0000-0002-9899-99107005114260GrisJean-Christophe R.ГриcЖан-Кристоф Р.
France

MD, PhD, Professor

д.м.н., профессор

jean.christophe.gris@chu-nimes.frhttps://orcid.org/0000-0002-8512-904355792310000SchulmanSamШульманСэм
Canada

д.м.н., профессор

schulms@mcmaster.caBrennerBenjaminБреннерБенджамин
Russian Federation

MD, PhD, Professor

д.м.н., профессор

b_brenner@rambam.health.gov.ilI.M. Sechenov First Moscow State Medical University (Sechenov University)Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)Petrovsky National Research Center of SurgeryРоссийский научный центр хирургии им. акад. Б.В. ПетровскогоMedical Center LLCООО «Лечебный Центр»Almazov National Medical Research CentreНациональный медицинский исследовательский центр имени В.А. АлмазоваLA Vorokhobov City Clinical Hospital 67Городская клиническая больница № 67 им. Л.А. ВорохобоваI.M. Sechenov Moscow State Medical University, (Sechenov University)Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет)Thrombosis and Haemostasis Research Unit, Fondazione I.R.C.C.S. “Casa Sollievo della Soff erenza”Научно-исследовательская больница Casa Sollievo della SofferenzaI.M. Sechenov Moscow State Medical University (Sechenov University)Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет)Medicine Sorbonne University, University Hospital TenonМедицинский Университет Сорбонна, Университетский Госпиталь ТенонI.M. Sechenov First Moscow State Medical University (Sechenov University)Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет)University of Roma Tor VergataРимский Университет Тор ВергатаUniversity MontpellierУниверситет МонпельеThrombosis and Atherosclerosis Research Institute, McMaster UniversityНаучно-исследовательский институт изучения тромбоза и атеросклероза, Университет МакМастерRambam Health Care CampusМногопрофильный лечебно-диагностический и реабилитационный центр «Рамбам»141020207543063170506202024082020Copyright ©; 2020, "Paediatrician" Publishers LLCCopyright ©; 2020, Издательство "Педиатръ"2020"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/1368

The spread of a new coronavirus infection worldwide since the end of 2019 has becomes a pandemic. Thrombotic complications are the leading cause of death in this disease. After entering the human body, the virus starts a cascade of reactions leading to the development of a cytokine storm, activation of all parts of the hemostasis and complement systems and other changes that result in disturbances in the circulation system with the development of multiple organ failures. Numerous studies have shown that a predictor of a severe course of COVID-19 is a sharp increase of D-dimer concentration in the blood and rise of some other markers of hemostasis activation. Based on the pathogenesis, the developed schemes for the prevention and treatment of COVID-19 severe complications include low molecular weight heparins (LMWH) which are also recommended for an outpatient COVID-19 patient. The prescription of low molecular weight heparin, the duration of their use and doses should be decided on the basis of a risk assessment of factors for each individual patient in combination with laboratory monitoring.

Распространение новой коронавирусной инфекции по всему миру с конца 2019 г. превратилось в пандемию. Тромботические осложнения являются ведущей причиной смерти при этом заболевании. После попадания в организм человека вирус запускает каскад реакций, приводящих к развитию цитокинового «шторма», активации всех звеньев системы гемостаза и комплемента, другим изменениям, приводящим к нарушениям в системе кровообращения с развитием полиорганных нарушений. Многочисленные исследования показали, что предиктором тяжелого течения заболевания является резкое повышение концентрации D-димера в крови и некоторых других маркеров активации гемостаза. Исходя из патогенеза, разработанные схемы профилактики и лечения тяжелых осложнений COVID-19 включают низкомолекулярные гепарины, которые также рекомендуют для применения в амбулаторных условиях. Назначение низкомолекулярных гепаринов, длительность их применения и дозы должны определяться на основе оценки факторов риска для каждого отдельного пациента в сочетании с лабораторным мониторингом.

COVID-19SARS-COV-2coagulopathyDIC-syndromeD-dimerfibrinogenhyperferritinemiahypercytokinemiacytokine stormantiphospholipid antibodieslow molecular weight heparinCOVID-19SARS-CoV-2коагулопатияДВС-синдромД-димерфибриногенгиперферритинемиягиперцитокинемияцитокиновый «шторм»антифосфолипидные антителанизкомолекулярные гепариныHuang C, Wang Y, Li X, Ren L, Zhao J, Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395:(10223):497–506. doi: https://doi.org/10.1016/S0140-6736(20)30183-5.Tang 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):844–847 doi: https://doi.org/10.1111/jth.14768.Klok FA, Kruip M, van der Meer N, Arbous M, Gommers D, Kant K, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020;191:148–150. doi: https://doi.org/10.1016/j.thromres.2020.04.041.Poissy J, Goutay J, Caplan M, Parmentier E, Duburcq T, Lassalle F, et al. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation. 2020;142(2):184–186. doi: https://doi.org/10.1161/circulationaha.120.047430.Rivellese F, Prediletto E. ACE2 at the centre of COVID-19 from paucisymptomatic infections to severe pneumonia. Autoimmun Rev. 2020;19(6):102536. doi: https://doi.org/10.1016/j.autrev.2020.102536.McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. The Lancet Rheumatology. 2020;2(7);e437–e445. doi: https://doi.org/10.1016/S2665-9913(20)30121-1.Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Trans Res. 2020;220;1–13. doi: https://doi.org/10.1016/j.trsl.2020.04.007.Iba T, Levi M, Levy JH. Sepsis-induced coagulopathy and disseminated intravascular coagulation. Semin Thromb Hemost. 2020;46(1):89–95. doi: https://doi.org/10.1055/s-0039-1694995Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, et al. Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19. medRxiv. 2020. (In Print). doi: https://doi.org/10.1101/2020.04.09.20059626.Schönrich G, Raftery MJ, Samstag Y. Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression. Advances in Biological Regulation. 2020:100741. doi: https://doi.org/10.1016/j.jbior.2020.100741.Stakos D, Skendros P, Konstantinides S, Ritis K. Traps N’Clots: NET-Mediated Thrombosis and Related Diseases. Thromb Haemost. 2020;120(3):373–383. doi: https://doi.org/10.1055/s-0039-3402731.Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in thrombosis —the journey of TF through NETs. Front Immunol. 2012;3:385. doi: https://doi.org/10.3389/fimmu.2012.00385.He Y, Yang F-Y, Sun E-W. Neutrophil extracellular traps in autoimmune diseases. Chin Med J (Engl). 2018;131(13):1513–1519. doi: https://doi.org/10.4103/0366-6999.235122.Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. In: Seminars in thrombosis and hemostasis. Thieme Medical Publishers; 2013. Р. 559–566.Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38–44. doi: https://doi.org/10.1016/j.thromres.2016.11.007.Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975–979.Khizroeva J, Makatsariya A, Bitsadze V, Tretyakova M, Slukhanchuk E, Elalamy I, et al. Laboratory monitoring of COVID-19 patients and the significance of coagulopathy markers. Obstetrics, Gynecology and Reproduction. 2020;14;2. doi: https://doi.org/10.17749/2313-7347.141.Shoenfeld Y. Corona (COVID-19) time musings: our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020; 9(6):102538. doi: https://doi.org/10.1016/j.autrev.2020.102538.Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–848. doi: https://doi.org/10.1007/s00134-020-05991-x.Cao W, Krishnaswamy S, Camire RM, Lenting PJ, Zheng XL. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS-13. Proc Natl Acad Sci U S A. 2008;105(21):7416–7421. doi: https://doi.org/10.1073/pnas.0801735105.Hyun J, Kim HK, Kim J-E, Lim M-G, Jung JS, Park S, et al. Correlation between plasma activity of ADAMTS-13 and coagulopathy, and prognosis in disseminated intravascular coagulation. Thromb Res. 2009;124(1):75–79. doi: https://doi.org/10.1016/j.thromres.2008.11.020.Schwameis M, Schörgenhofer C, Assinger A, Steiner MM, Jilma B. Von VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP. Thromb Haemost. 2015;113(4):708–718. doi: https://doi.org/10.1160/th14-09-0731.Bitsadze VO, Khizroeva J, Makatsariya AD. The acquired form of ADAMTS-13 deficiency as the cause of thrombotic microangiopathy in a pregnant woman with recurrent cerebral circulation disorders, venous thromboembolism, preeclampsia and fetal loss syndrome. Case Reports in Perinatal Medicine. 2017;6. doi: https://doi.org/10.1515/crpm-2017-0023.Katneni UK, Alexaki A, Hunt R, Schiller T, DiCuccio M, Buehler PW, et al. Consumptive Coagulopathy and Thrombosis during severe COVID-19 infection: Potential Involvement of VWF/ADAMTS-13. 2020. InPress. doi: https://doi.org/10.20944/preprints202005.0385.v2.Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7:e438. doi: https://doi.org/10.1016/s2352-3026(20)30145-9.Escher R, Breakey N, Lämmle B. ADAMTS-13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients. Thromb Res. 2020;192:174–175. doi: https://doi.org/10.1016/j.thromres.2020.05.032.Makatsariya A, Slukhanchuk E, Bitsadze V, Khizroeva J, Tretyakova M., Tsibizova V, et al. COVID-19, neutrophil extracellular traps and vascular complications in obstetric practice. 2020. J Perinat Med. 2020:000010151520200280. doi: https://doi.org/10.1515/jpm-2020-0280.Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38. doi: https://doi.org/10.1056/nejmc2007575.Harzallah I, Debliquis A, Drénou B. Lupus anticoagulant is frequent in patients with Covid‐19. J Thromb Haemost. 2020; doi: https://doi.org/10.1111/jth.14867.Rodríguez-Pintó I, Espinosa G, Cervera R. Catastrophic APS in the context of other thrombotic microangiopathies. Curr Rheumatol Rep. 2015;17(1):482. https://doi.org/10.1007/s11926-014-0482-z.Yang Z, Shi J, He Z, Lü Y, Xu Q, Ye C, et al. Predictors for imaging progression on chest CT from coronavirus disease 2019 (COVID-19) patients. Aging (Albany NY). 2020;12:6037–6048. doi: https://doi.org/10.18632/aging.102999.Gavriilaki E, Chrysanthopoulou A, Sakellari I, Batsis I, Mallouri D, Touloumenidou T, et al. Linking Complement activation, coagulation, and neutrophils in transplant-associated thrombotic microangiopathy. Thromb Haemost. 2019;119:1433–1440. doi: https://doi.org/10.1055/s-0039-1692721.Abike F, Engin AB, Dunder İ, Tapisiz OL, Aslan C, Kutluay L. Human papilloma virus persistence and neopterin, folate and homocysteine levels in cervical dysplasias. Arch Gynecol Obstet. 2011;284(1):209–214. doi: https://doi.org/10.1007/s00404-010-1650-7.Ziegler TR, Judd SE, Ruff JH, McComsey GA, Eckard AR. Amino acid concentrations in HIV-infected youth compared to healthy controls and associations with CD4 counts and inflammation. AIDS Research and Human retroviruses. 2017;33:681–689.Zhai Z, Li C, Chen Y, Gerotziafas G, Zhang Z, Wan J, et al. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost. 2020;120(6):937. doi: https://doi.org/10.1055/s-0040-1710019.Ranucci M, Ballotta A, Di Dedda U, Bayshnikova E, Dei Poli M, et al. The procoagulant pattern of patients with COVID‐19 acute respiratory distress syndrome. J Thromb Haemost. 2020;18(7):1747–1751. doi: https://doi.org/10.1111/jth.14854.Ciceri F, Beretta L, Scandroglio AM, Colombo S, Landoni G, Ruggeri A, et al. Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc. 2020;22(2):95–97.Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmunity Reviews. 2020;19(5):102523. doi: https://doi.org/10.1016/j.autrev.2020.102523.Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118(9):1340–1347. doi: https://doi.org/10.1161/circresaha.115.306841.Arora G, Kassir M, Jafferany M, Galadari H, Lotti T, Satolli F, et al. The COVID‐19 Outbreak and Rheumatologic Skin Diseases. Dermatol Ther. 2020: e13357. doi: https://doi.org/10.1111/dth.13357юMehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in COVID-19. N Engl J Med. 2020;382:e102. doi: https://doi.org/10.1056/NEJMoa2007621.Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol. 2020;75(18):2352–2371. doi: https://doi.org/10.1016/j.jacc.2020.03.031.Aso Y, Wakabayashi S, Yamamoto R, Matsutomo R, Takebayashi K, Inukai T. Metabolic syndrome accompaned by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care. 2005;28(9):2211–2216. doi: https://doi.org/10.2337/diacare.28.9.2211.Gerotziafas G, Sergentanis TN, Voiriot G, Lassel L, Vandreden P, Papageorgiou L, et al. Derivation and Validation of a Predictive Score for Disease Worsening in Patients with COVID-19: The COMPASS-COVID-19 Prospective Observational Cohort Study. SSRN Electronic Journal. 2020:38. doi: https://doi.org/10.2139/ssrn.3592640.Olausson N, Discacciati A, Nyman AI, Lundberg F, Hovatta O, Westerlund E, et al. Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilization with fresh respectively frozen‐thawed embryo transfer: Nationwide cohort study. J Thromb Haemost. 2020;18(8):1965–1973. doi: https://doi.org/10.1111/jth.14840.Ramírez I, De la Viuda E, Baquedano L, Coronado P, Llaneza P, Mendoza N, et al. Managing thromboembolic risk with menopausal hormone therapy and hormonal contraception in the COVID-19 pandemic: Recommendations from the Spanish Menopause Society, Sociedad Española de Ginecología y Obstetricia and Sociedad Española de Trombosis y Hemostasia. Maturitas; 2020;137:57–62. doi: https://doi.org/10.1016/j.maturitas.2020.04.019.Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992;41(10):1257–1266. doi: https://doi.org/10.2337/diab.41.10.1257.Mannerås-Holm L, Baghaei F, Holm G, Janson PO, Ohlsson C, Lönn M, et al. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2011;96(4):1068–1076. doi: https://doi.org/10.1210/jc.2010-2279.Oral B, Mermi B, Dilek M, Alanoğlu G, Sütçü R. Thrombin activatable fibrinolysis inhibitor and other hemostatic parameters in patients with polycystic ovary syndrome. Gynecol Endocrinol. 2009;25(2):110–116. doi: https://doi.org/10.1080/09513590802549874.Макацария А.Д., Элалами И., Воробьев А.В., Бахтина А.С., Мэн М., Бицадзе В.О., и др. Тромботическая микроангиопатия у онкологических больных // Вестник Российской академии медицинских наук. — 2019. — Т. 74. — № 5. — С. 323–332. [Makatsariya AD, Elalamy I, Vorobev AV, Bakhtina AS, Meng M, Bitsadze VO, Khizroeva DKh. Thrombotic microangiopa-thy in cancer patients. Annals of the Russian Academy of Medical Sciences. 2019;74(5):323–332. (In Russ.)]. doi: https://doi.org/10.15690/vramn1204.Воробьев А.В., Макацария А.Д., Бреннер Б. Синдром Труссо: забытое прошлое или актуальное настоящее? // Акушерство и гинекология. — 2018. — № 2. — С. 27–34. [Vorobyex AV, Makatsaria AD, Brebber B. Trousseau’s syndrome: the forgotten past or actual present? Obstetrics and gynecology. 2018;(2):27–34 (In Russ.)] doi: https://doi.org/10.18565/aig.2018.2.27–34.Reese JA, Bougie DW, Curtis BR, Terrell DR, Vesely SK, Aster RH, et al. Drug‐induced thrombotic microangiopathy: Experience of the Oklahoma registry and the BloodCenter of Wisconsin. Am J Hematol. 2015;90(5):406–410. doi: https://doi.org/10.1002/ajh.23960.Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335–337. doi: https://doi.org/10.1016/s1470-2045(20)30096-6.Gris J-C, Mousty È, Bouvier S, Ripart S, Cochery-Nouvellon É, Fabbro-Peray P, et al. Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort. Haematologica. 2020;105(2):490–497. doi: https://doi.org/10.3324/haematol.2018.213991.Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010;8(11):2450–2457. doi: https://doi.org/10.1111/j.1538-7836.2010.04044.x.Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069. doi: https://doi.org/10.1001/jama.2020.1585.Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta. 2020;506:145–148. doi: https://doi.org/10.1016/j.cca.2020.03.022.Wang R, He M, Yue J, Bai L, Liu D, Huang Z, et al. CONUT score is associated with mortality in patients with COVID-19: a retrospective study in Wuhan. 2020. doi: https://doi.org/10.21203/rs.3.rs-32889/v1 .Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395:1054–1062. doi: https://doi.org/10.1016/S0140-6736(20)30566-3.Crowther M, Lim W. Use of low molecular weight heparins in patients with renal failure; time to re-evaluate our preconceptions. Springer; 2016.Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775–787. doi: https://doi.org/10.1001/jama.2016.0289.Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017;117(3):437–444. doi: https://doi.org/10.1160/th16-08-0620.Nagata K, Suto Y, Cognetti J, Browne KD, Kumasaka K, Johnson VE, et al. Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury. J Trauma Acute Care Surg. 2018;84(5):727–735. doi: https://doi.org/10.1097/ta.0000000000001819.Seeds E, Page C. Heparin inhibits allergen-induced eosinophil infiltration into guinea-pig lung via a mechanism unrelated to its anticoagulant activity. Pulm Pharmacol Ther. 2001;14(2):111–119. doi: https://doi.org/10.1006/pupt.2000.0277.Evans R, Wong VS, Morris A, Rhodes J. Treatment of corticosteroid‐resistant ulcerative colitis with heparin — a report of 16 cases. Alimentary Pharmacology & Therapeutics. 1997;11:1037–1040. doi: https://doi.org/10.1046/j.1365-2036.1997.00252.x.Vancheri C, Mastruzzo C, Armato F, Tomaselli V, Magrì S, Pistorio MP, LaMicela M, D’Amico L, Crimi N. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol. 2001;108(5):703–708. doi: https://doi.org/10.1067/mai.2001.118785.Diamant Z, Timmers MC, Van der Veen H, Page CP, Van der Meer F, Sterk PJ. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med. 1996;153(6):1790–1795. doi: https://doi.org/10.1164/ajrccm.153.6.8665036.Lever R, Page CP. Novel drug development opportunities for heparin. Nat Rev Drug Discov. 2002;1(2):140–148. doi: https://doi.org/10.1038/nrd724.Gori A, Pepe G, Attanasio M, Falciani M, Abbate R, Prisco D, et al. Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration. Thrombosis and Haemostasis. 1999;81:589–593.Bazargani F, Albrektsson A, Yahyapour N, Braide M. Low molecular weight heparin improves peritoneal ultrafiltration and blocks complement and coagulation. Peritoneal Dialysis International. 2005;25(4):394–404. doi: https://doi.org/10.1177/089686080502500416.Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Advances. 2018;2(22):3360–3392. doi: https://doi.org/10.1182/bloodadvances.2018024489.Wang L, Brown JR, Varki A, Esko JD. Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L-and P-selectins. The Journal of Clinical Investigation. 2002;110:127–136. doi: https://doi.org/10.1172/jci14996.Helfer H, Siguret V, Mahé I. Tinzaparin Sodium Pharmacokinetics in Patients with Chronic Kidney Disease: Practical Implications. Am J Cardiovasc Drugs. 2020;20(3):223–228. doi: https://doi.org/10.1007/s40256-019-00382-0.Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19: A Comment. Journal of Thrombosis and Haemostasis. 2020;08;2060. doi: https://doi.org/10.1111/jth.14860.Arabi YM, Al-Hameed F, Burns KE, Mehta S, Alsolamy SJ, Alshahrani MS, et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. New England Journal of Medicine. 2019;380:1305–1315. doi: https://doi.org/10.1056/NEJMoa1816150.