akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2021.216akusherstvo-1010Research ArticleREVIEW ARTICLESНАУЧНЫЕ ОБЗОРЫAnticoagulant, anti-inflammatory, antiviral and antitumor properties of heparinsАнтикоагулянтные, противовоспалительные, противовирусные и противоопухолевые свойства гепариновhttps://orcid.org/0000-0001-8404-1042БицадзеВ. О.BitsadzeV. O.

Бицадзе Виктория Омаровна – д.м.н., профессор РАН, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова

Scopus Author ID: 6506003478; Researcher ID: F-8409-2017

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Victoria O. Bitsadze – MD, Dr Sci Med, Professor of RAS, Professor, Department of Obstetrics and Gynecology, Filatov Institute of Children’s Health

Scopus Author ID: 6506003478; Researcher ID: F-8409-2017

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

https://orcid.org/0000-0001-7441-2778СлуханчукЕ. В.SlukhanchukE. V.

Слуханчук Екатерина Викторовна – к.м.н., зав. отделением гинекологии

119991 Москва, Абрикосовский пер., д. 2

Ekaterina V. Slukhanchuk – MD, PhD, Head of the Department of Gynecology

2 Abrikosovskiy Lane, Moscow 119991

beloborodova@rambler.ruhttps://orcid.org/0000-0002-0725-9686ХизроеваД. Х.KhizroevaJ. Kh.

Хизроева Джамиля Хизриевна – д.м.н., профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова

Scopus Author ID: 57194547147; Researcher ID: F-8384-2017

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Jamilya Kh. Khizroeva – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

Scopus Author ID: 57194547147; Researcher ID: F-8384-2017

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

https://orcid.org/0000-0002-3628-0804ТретьяковаМ. В.TretyakovaM. V.

Третьякова Мария Владимировна – к.м.н., врач акушер-гинеколог отделения гинекологии

119021 Москва, ул. Тимура Фрунзе, д. 15/1

Maria V. Tretyakova – MD, PhD, Obstetrician-Gynecologist, Department of Gynecology

15/1 Timura Frunze Str., Moscow 119021

https://orcid.org/0000-0003-4901-4625ПятигорскаяН. В.PyatigorskayaN. V.

Пятигорская Наталья Валерьевна – д.фарм.н., профессор, зав. кафедрой промышленной фармации

SPIN-код: 8128-1725

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Natalia V. Pyatigorskaya – MD, Dr Sci Pharm, Professor, Head of the Department of Industrial Pharmacy

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

https://orcid.org/0000-0001-6012-453XАкиньшинаС. В.AkinshinaS. V.

Акиньшина Светлана Владимировна – к.м.н., научный сотрудник кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Svetlana V. Akinshina – MD, PhD, Researcher, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

https://orcid.org/0000-0002-2541-3843МакацарияН. А.MakatsariyaN. A.

Макацария Наталия Александровна – к.м.н., доцент кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова

Researcher ID: F-8406-2017

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Nataliya A. Makatsariya – MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

ГоциридзеК. Э.GotsiridzeK. E.

Гоциридзе Кетеван Элгуджевна – врач акушер-гинеколог, руководитель Центра репродуктивного здоровья «Клиники Чачава»

Тбилиси 0179, ул. Мераба Костава, д. 38

Ketevan E. Gotsiridze – MD, Obstetrician-Gynecologist, Head of the Center for Reproductive Health

38 Merab Kostava Str., Tbilisi 0179

https://orcid.org/0000-0002-2965-4169БабаеваН. Н.BabaevaN. N.

Бабаева Нигяр Наби кызы – врач акушер-гинеколог, ООО «Альтамед+»

143006, Московская область, Одинцово, Союзная ул. 32Б

Nigar N. Babaeva – MD, Obstetrician Obstetrician-Gynecologist

32B Soyuznaya Str., Odintsovo, Moscow Region 143006

https://orcid.org/0000-0002-7756-8935ГригорьеваК. Н.GrigorevaK. N.

Григорьева Кристина Николаевна – ординатор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

Kristina N. Grigoreva – MD, Medical Resident, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

https://orcid.org/0000-0002-9783-1796ШкодаА. С.ShkodaA. S.

Шкода Андрей Сергеевич – д.м.н., профессор, главный врач

123423 Москва, ул. Саляма Адиля, д.2/44

Andrey S. Shkoda – MD, Dr Sci Med, Professor, Chief Physician

2/44 Salyama Adilya Str., Moscow 123423

https://orcid.org/0000-0002-9576-1368ЭлаламиИ.ElalamyI.

Элалами Исмаил – д.м.н., профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова ФГАОУ ВО Первый Московский государственный медицинский университет имени И. М. Сеченова Министерства здравоохранения Российской Федерации, (Сеченовский университет); профессор медицинского Университета Сорбонны; директор гематологии Центра Тромбозов

Scopus Author ID: 7003652413; Researcher ID: AAC-9695-2019

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

75006 Париж, Улица медицинского факультета, д. 12

75020 Париж, Китайская улица, д. 4

 

Ismail Elalamy – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health, Sechenov University; Professor, Medicine Sorbonne University; Director of Hematology, Department of Thrombosis Center, Hospital Tenon

Scopus Author ID: 7003652413; Researcher ID: AAC-9695-2019

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

12 Rue de l’École de Médecine, 75006 Paris

4 Rue de la Chine, 75020 Paris

https://orcid.org/0000-0002-9899-9910ГриЖ.-К.GrisJ.-C.

Гри Жан-Кристоф – д.м.н., профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н. Ф. Филатова ФГАОУ ВО Первый Московский государственный медицинский университет имени И. М. Сеченова Министерства здравоохранения Российской Федерации, (Сеченовский университет); профессор гематологии, университет Монпелье

Researcher ID: AAA-2923-2019

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4

163 Rue Auguste Broussonnet, Монпелье, Париж 34090

Jean-Christophe Gris – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health, Sechenov University; University of Montpellier

Researcher ID: AAA-2923-2019

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991

163 Rue Auguste Broussonnet, Montpellier, Paris 34090

https://orcid.org/0000-0002-8512-9043ШульманС.ShulmanS.

Шульман Сэм – д.м.н., профессор отделения гематологии и тромбоэмболий медицинского факультета Университета Макмастера; директор программы по тромбоэмболиям, многопрофильный госпиталь Гамильтона; профессор Каролинского института

1280 Main Street West, Гамильтон, Онтарио L8S 4K1

40 Wellington Street North, Гамильтон, Онтарио L8R 1M8, Канада

1 Solnavägen, Стокгольм 17177, Швеция

Sam Shulman – MD, Dr Sci Med, Professor, Department of Hematology and Thromboembolism, Faculty of Medicine, McMaster University; Director, Clinical Thromboembolism Program, Hamilton General Hospital; Professor, Karolinska Institutet

1280 Main Street West, Hamilton, Ontario L8S 4K1

40 Wellington Street North, Hamilton, Ontario L8R 1M8

1 Solnavägen, Stockholm, 17177, Sweden

ФГАОУ ВО Первый Московский государственный медицинский университет имени И. М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет)РоссияSechenov UniversityRussian FederationФГБНУ «Российский научный центр хирургии имени академика Б. В. Петровского»РоссияPetrovsky National Research Centre of SurgeryRussian FederationООО «Лечебный Центр»Россия«Medical Center» LLCRussian FederationКлиника ЧачаваГрузияChachava ClinicGeorgiaООО «Альтамед+»Россия«Altamed+» LLCRussian FederationГБУЗ «Городская клиническая больница № 67 имени Л. А. Ворохобова Департамента здравоохранения города Москвы»РоссияVorokhobov City Clinical Hospital № 67, Moscow Healthcare DepartmentRussian FederationФГАОУ ВО Первый Московский государственный медицинский университет имени И. М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет); Медицинский Университет Сорбонны; Госпиталь ТенонФранцияSechenov University; Medicine Sorbonne University; Hospital TenonFranceФГАОУ ВО Первый Московский государственный медицинский университет имени И. М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет); Университет МонпельеФранцияSechenov University; University of MontpellierFranceУниверситет Макмастера; Многопрофильный Госпиталь Гамильтона; Каролинский институтКанадаMcMaster University; Hamilton General Hospital; Karolinska InstituteCanada202109072021153295312Copyright © Bitsadze V.O., Slukhanchuk E.V., Khizroeva J.K., Tretyakova M.V., Pyatigorskaya N.V., Akinshina S.V., Makatsariya N.A., Gotsiridze K.E., Babaeva N.N., Grigoreva K.N., Shkoda A.S., Elalamy I., Gris J., Shulman S., 20212021Бицадзе В.О., Слуханчук Е.В., Хизроева Д.Х., Третьякова М.В., Пятигорская Н.В., Акиньшина С.В., Макацария Н.А., Гоциридзе К.Э., Бабаева Н.Н., Григорьева К.Н., Шкода А.С., Элалами И., Гри Ж., Шульман С.Bitsadze V.O., Slukhanchuk E.V., Khizroeva J.K., Tretyakova M.V., Pyatigorskaya N.V., Akinshina S.V., Makatsariya N.A., Gotsiridze K.E., Babaeva N.N., Grigoreva K.N., Shkoda A.S., Elalamy I., Gris J., Shulman S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/1010

Our knowledge regarding chemical structure and properties of heparin and its derivatives, including biological properties in blood plasma, on the cell surface and while interacting with receptors, has been progressively growing. New insights are followed by the expansion of therapeutic opportunities and indications for the use of heparins. There are prerequisites for the creation of new generation drugs with modified properties that reduce a bleeding risk while applied for a non-anticoagulant goal. The non-anticoagulant heparin properties allow to consider it as a candidate for pathogenetic treatment of patients with COVID-19. This review focuses on the anticoagulant and non-anticoagulant heparin properties as well as the underlying molecular mechanisms.

Наши знания относительно химической структуры гепарина и его производных, а также всей палитры их свойств, включая биологические свойства в плазме крови, на клеточной поверхности и во взаимодействии с рецепторами, прогрессивно растут. За новыми знаниями следует расширение терапевтических возможностей и показаний к использованию гепаринов. Возникают предпосылки к созданию препаратов нового поколения с модифицированными свойствами, снижающими риск развития кровотечений при использовании с неантикоагулянтной целью. Неантикоагулянтные свойства гепаринов делают их кандидатами для патогенетического лечения пациентов с COVID-19. Данный обзор посвящен антикоагулянтным и неантикоагулянтным свойствам гепаринов, а также лежащим в их основе молекулярным механизмам.

гепаринантикоагулянтыметастазывоспалениеCOVID-19heparinanticoagulantsmetastasesinflammationCOVID-19Обзор выполнен при финансовой поддержке РФФИ в рамках научного проекта номер 20-04-60274 (№ ЦИТИСАААА-А-20-120091790046-5).The review was funded by RFBR project number 20-04-60274 (№ ЦИТИСАААА-А-20-120091790046-5).ReferencesMulloy B., Hogwood J., Gray E. et al. Pharmacology of heparin and related drugs. Pharmacol Rev. 2016;68(1):76–141. https://doi.org/10.1124/pr.115.011247.Mulloy B., Hogwood J., Gray E. et al. Pharmacology of heparin and related drugs. Pharmacol Rev. 2016;68(1):76–141. https://doi.org/10.1124/pr.115.011247.Shriver Z., Capila I., Venkataraman G., Sasisekharan R. Heparin and heparan sulfate: analyzing structure and microheterogeneity. Handb Exp Pharmacol. 2012;(207):159–76. https://doi.org/10.1007/978-3-642-23056-1_8.Shriver Z., Capila I., Venkataraman G., Sasisekharan R. Heparin and heparan sulfate: analyzing structure and microheterogeneity. Handb Exp Pharmacol. 2012;(207):159–76. https://doi.org/10.1007/978-3-642-23056-1_8.Smith S.A., Morrissey J.H. Heparin is procoagulant in the absence of antithrombin. Thromb Haemost. 2008;100(1):160–2. https://doi.org/10.1160/TH08-05-0275.Smith S.A., Morrissey J.H. Heparin is procoagulant in the absence of antithrombin. Thromb Haemost. 2008;100(1):160–2. https://doi.org/10.1160/TH08-05-0275.Oduah E.I., Linhardt R.J., Sharfstein S.T. Heparin: past, present, and future. Pharmaceuticals (Basel). 2016;9(3):38. https://doi.org/10.3390/ph9030038.Oduah E.I., Linhardt R.J., Sharfstein S.T. Heparin: past, present, and future. Pharmaceuticals (Basel). 2016;9(3):38. https://doi.org/10.3390/ph9030038.Bertini S., Fareed J., Madaschi L. et al. Characterization of PF4-heparin complexes by photon correlation spectroscopy and zeta potential. Clin Appl Thromb Hemost. 2017;23(7):725–34. https://doi.org/10.1177/1076029616685430.Bertini S., Fareed J., Madaschi L. et al. Characterization of PF4-heparin complexes by photon correlation spectroscopy and zeta potential. Clin Appl Thromb Hemost. 2017;23(7):725–34. https://doi.org/10.1177/1076029616685430.Walenga J.M., Lyman G.H. Evolution of heparin anticoagulants to ultra-low-molecular-weight heparins: a review of pharmacologic and clinical differences and applications in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):1–18. https://doi.org/10.1016/j.critrevonc.2013.06.007.Walenga J.M., Lyman G.H. Evolution of heparin anticoagulants to ultra-low-molecular-weight heparins: a review of pharmacologic and clinical differences and applications in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):1–18. https://doi.org/10.1016/j.critrevonc.2013.06.007.Laporte S., Liotier J., Bertoletti L. et al. Individual patient data meta-analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients. J Thromb Haemost. 2011;9(3):464–72. https://doi.org/10.1111/j.1538-7836.2011.04182.x.Laporte S., Liotier J., Bertoletti L. et al. Individual patient data meta-analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients. J Thromb Haemost. 2011;9(3):464–72. https://doi.org/10.1111/j.1538-7836.2011.04182.x.Hirsh J., Warkentin T.E., Shaughnessy S.G. et al. Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S– 94S. https://doi.org/10.1378/chest.119.1_suppl.64s.Hirsh J., Warkentin T.E., Shaughnessy S.G. et al. Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S– 94S. https://doi.org/10.1378/chest.119.1_suppl.64s.Sculpher M.J., Lozano-Ortega G., Sambrook J. et al. Fondaparinux versus Enoxaparin in non–ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J. 2009;157(5):845–52. https://doi.org/10.1016/j.ahj.2009.02.017.Sculpher M.J., Lozano-Ortega G., Sambrook J. et al. Fondaparinux versus Enoxaparin in non–ST-elevation acute coronary syndromes: short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J. 2009;157(5):845–52. https://doi.org/10.1016/j.ahj.2009.02.017.Cassinelli G., Naggi A. Old and new applications of non-anticoagulant heparin. Int J Cardiol. 2016;212(Suppl):S14–21. https://doi.org/10.1016/S0167-5273(16)12004-2.Cassinelli G., Naggi A. Old and new applications of non-anticoagulant heparin. Int J Cardiol. 2016;212(Suppl):S14–21. https://doi.org/10.1016/ S0167-5273(16)12004-2.Quinsey N.S., Whisstock J.C., Le Bonniec B. et al. Molecular determinants of the mechanism underlying acceleration of the interaction between antithrombin and factor Xa by heparin pentasaccharide. J Bioll Chem. 2002;277(18):15971–8. https://doi.org/10.1074/jbc.M108131200.Quinsey N.S., Whisstock J.C., Le Bonniec B. et al. Molecular determinants of the mechanism underlying acceleration of the interaction between antithrombin and factor Xa by heparin pentasaccharide. J Bioll Chem. 2002;277(18):15971–8. https://doi.org/10.1074/jbc.M108131200.Cassinelli G., Torri G., Naggi A. Non-anticoagulant heparins as heparanase inhibitors. Adv Exp Med Biol. 2020;1221:493–522. https://doi.org/10.1007/978-3-030-34521-1_20.Cassinelli G., Torri G., Naggi A. Non-anticoagulant heparins as heparanase inhibitors. Adv Exp Med Biol. 2020;1221:493–522. https://doi.org/10.1007/978-3-030-34521-1_20.Cole G.J., Loewy A., Glaser L. Neuronal cell–cell adhesion depends on interactions of N-CAM with heparin-like molecules. Nature. 1986;320(6061):445–7. https://doi.org/10.1038/320445a0.Cole G.J., Loewy A., Glaser L. Neuronal cell–cell adhesion depends on interactions of N-CAM with heparin-like molecules. Nature. 1986;320(6061):445–7. https://doi.org/10.1038/320445a0.Klebe R.J., Escobedo L.V., Bentley K.L., Thompson L.K. Regulation of cell motility, morphology, and growth by sulfated glycosaminoglycans. Cell Motil Cytoskeleton. 1986;6(3):273–81. https://doi.org/10.1002/cm.970060304.Klebe R.J., Escobedo L.V., Bentley K.L., Thompson L.K. Regulation of cell motility, morphology, and growth by sulfated glycosaminoglycans. Cell Motil Cytoskeleton. 1986;6(3):273–81. https://doi.org/10.1002/cm.970060304.Sandset P.M., Abildgaard U., Larsen M.L. Heparin induces release of extrinsic: coagulation pathway inhibitor (EPI). Thromb Res. 1988;50(6):803–13. https://doi.org/10.1016/0049-3848(88)90340-4.Sandset P.M., Abildgaard U., Larsen M.L. Heparin induces release of extrinsic: coagulation pathway inhibitor (EPI). Thromb Res. 1988;50(6):803–13. https://doi.org/10.1016/0049-3848(88)90340-4.Webb L., Ehrengruber M.U., Clark-Lewis I. et al. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc Natl Acad Sci U S A. 1993;90(15):7158–62. https://doi.org/10.1073/pnas.90.15.7158.Webb L., Ehrengruber M.U., Clark-Lewis I. et al. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc Natl Acad Sci U S A. 1993;90(15):7158–62. https://doi.org/10.1073/pnas.90.15.7158.Wildhagen K.C., de Frutos P.C., Reutelingsperger C.P. et al. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014;123(7):1098–101. https://doi.org/10.1182/blood-2013-07-514984.Wildhagen K.C., de Frutos P.C., Reutelingsperger C.P. et al. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014;123(7):1098–101. https://doi.org/10.1182/blood-2013-07-514984.Chang G.M., Atkinson H.M., Berry L.R., Chan A.K. Inhibition of plasmin generation in plasma by heparin, low molecular weight heparin, and a covalent antithrombin–heparin complex. Blood Coagul Fibrinolysis. 2017;28(6):431–7. https://doi.org/10.1097/MBC.0000000000000611.Chang G.M., Atkinson H.M., Berry L.R., Chan A.K. Inhibition of plasmin generation in plasma by heparin, low molecular weight heparin, and a covalent antithrombin–heparin complex. Blood Coagul Fibrinolysis. 2017;28(6):431–7. https://doi.org/10.1097/MBC.0000000000000611.Lam L., Silbert J., Rosenberg R. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun. 1976;69(2):570–7. https://doi.org/10.1016/0006-291x(76)90558-1.Lam L., Silbert J., Rosenberg R. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun. 1976;69(2):570–7. https://doi.org/10.1016/0006-291x(76)90558-1.Friedl A., Filla M., Rapraeger A.C. Tissue-specific binding by FGF and FGF receptors to endogenous heparan sulfates. Methods Mol Biol. 2001;171:535–46. https://doi.org/10.1385/1-59259-209-0:535.Friedl A., Filla M., Rapraeger A.C. Tissue-specific binding by FGF and FGF receptors to endogenous heparan sulfates. Methods Mol Biol. 2001;171:535–46. https://doi.org/10.1385/1-59259-209-0:535.Li J., Guo Z.Y., Gao X.H. et al. Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1, VEGF and TGF-1. PLoS One. 2015;10(2):e0118481. https://doi.org/10.1371/journal.pone.0118481.Li J., Guo Z.Y., Gao X.H. et al. Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1, VEGF and TGF-1. PLoS One. 2015;10(2):e0118481. https://doi.org/10.1371/journal.pone.0118481.Yang Y., Long Y., Wang Y. et al. Enhanced anti-tumor and anti-metastasis therapy for triple negative breast cancer by CD44 receptor-targeted hybrid self-delivery micelles. Int J Pharm. 2020;577:119085. https://doi.org/10.1016/j.ijpharm.2020.119085.Yang Y., Long Y., Wang Y. et al. Enhanced anti-tumor and anti-metastasis therapy for triple negative breast cancer by CD44 receptor-targeted hybrid self-delivery micelles. Int J Pharm. 2020;577:119085. https://doi.org/10.1016/j.ijpharm.2020.119085.Sanford D., Naidu A., Alizadeh N., Lazo-Langner A. The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost. 2014;12(7):1076–85. https://doi.org/10.1111/jth.12595.Sanford D., Naidu A., Alizadeh N., Lazo-Langner A. The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. J Thromb Haemost. 2014;12(7):1076–85. https://doi.org/10.1111/jth.12595.Ettelaie C., Fountain D., Collier M.E.W. et al. Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-B. Biochim Biophys Acta. 2011;1812(12):1591–600. https://doi.org/10.1016/j.bbadis.2011.09.007.Ettelaie C., Fountain D., Collier M.E.W. et al. Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-B. Biochim Biophys Acta. 2011;1812(12):1591–600. https://doi.org/10.1016/j.bbadis.2011.09.007.Alonso D., Bertolesi G., Farias E. et al. Antimetastatic effects associated with anticoagulant properties of heparin and chemically modified heparin species in a mouse mammary tumor model. Oncol Rep. 1996;3(1):219–22. https://doi.org/10.3892/or.3.1.219.Alonso D., Bertolesi G., Farias E. et al. Antimetastatic effects associated with anticoagulant properties of heparin and chemically modified heparin species in a mouse mammary tumor model. Oncol Rep. 1996;3(1):219–22. https://doi.org/10.3892/or.3.1.219.Koenig A., Norgard-Sumnicht K., Linhardt R., Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest. 1998;101(4):877–89. https://doi.org/10.1172/JCI1509.Koenig A., Norgard-Sumnicht K., Linhardt R., Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest. 1998;101(4):877–89. https://doi.org/10.1172/JCI1509.Ma L., Qiao H., He C. et al. Modulating the interaction of CXCR4 and CXCL12 by low-molecular-weight heparin inhibits hepatic metastasis of colon cancer. Invest New Drugs. 2012;30(2):508–17. https://doi.org/10.1007/s10637-010-9578-0.Ma L., Qiao H., He C. et al. Modulating the interaction of CXCR4 and CXCL12 by low-molecular-weight heparin inhibits hepatic metastasis of colon cancer. Invest New Drugs. 2012;30(2):508–17. https://doi.org/10.1007/s10637-010-9578-0.Schlesinger M., Roblek M., Ortmann K. et al. The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin. Thromb Res. 2014;133(5):855–62. https://doi.org/10.1016/j.thromres.2014.02.020.Schlesinger M., Roblek M., Ortmann K. et al. The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin. Thromb Res. 2014;133(5):855–62. https://doi.org/10.1016/j.thromres.2014.02.020.Joseph P.R.B., Sawant K.V., Rajarathnam K. Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking. Open Biol. 2017;7(11):170168. https://doi.org/10.1098/rsob.170168.Joseph P.R.B., Sawant K.V., Rajarathnam K. Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking. Open Biol. 2017;7(11):170168. https://doi.org/10.1098/rsob.170168.Gomes A.M, Kozlowski E.O., Borsig L. et al. Antitumor properties of a new non-anticoagulant heparin analog from the mollusk Nodipecten nodosus: Effect on P-selectin, heparanase, metastasis and cellular recruitment. Glycobiology. 2015;25(4):386–93. https://doi.org/10.1093/glycob/cwu119.Gomes A.M, Kozlowski E.O., Borsig L. et al. Antitumor properties of a new non-anticoagulant heparin analog from the mollusk Nodipecten nodosus: Effect on P-selectin, heparanase, metastasis and cellular recruitment. Glycobiology. 2015;25(4):386–93. https://doi.org/10.1093/glycob/cwu119.Pfankuchen D.B., Baltes F., Batool T. et al. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway. Oncotarget. 2017;8(40):67553–66. https://doi.org/10.18632/oncotarget.18738.Pfankuchen D.B., Baltes F., Batool T. et al. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway. Oncotarget. 2017;8(40):67553–66. https://doi.org/10.18632/oncotarget.18738.Sindrewicz P., Yates E.A., Turnbull J.E. et al. Interaction with the heparin-derived binding inhibitors destabilizes galectin-3 protein structure. Biochem Biophys Res Commun. 2020;523(2):336–41. https://doi.org/10.1016/j.bbrc.2019.12.054Sindrewicz P., Yates E.A., Turnbull J.E. et al. Interaction with the heparin-derived binding inhibitors destabilizes galectin-3 protein structure. Biochem Biophys Res Commun. 2020;523(2):336–41. https://doi.org/10.1016/j.bbrc.2019.12.054.Yu Y., Lv Q., Zhang B. et al. Adjuvant therapy with heparin in patients with lung cancer without indication for anticoagulants: A systematic review of the literature with meta-analysis. J Cancer Res Ther. 2016;12(Suppl):37–42. https://doi.org/10.4103/0973-1482.191627.Yu Y., Lv Q., Zhang B. et al. Adjuvant therapy with heparin in patients with lung cancer without indication for anticoagulants: A systematic review of the literature with meta-analysis. J Cancer Res Ther. 2016;12(Suppl):37–42. https://doi.org/10.4103/0973-1482.191627.Groen H.J., van der Heijden E.H., Klinkenberg T.J. et al. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019;121(5):372–7. https://doi.org/10.1038/s41416-019-0533-3.Groen H.J., van der Heijden E.H., Klinkenberg T.J. et al. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. Br J Cancer. 2019;121(5):372–7. https://doi.org/10.1038/s41416-019-0533-3.Meyer G., Besse B., Doubre H. et al. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Res J. 2018;52(4). https://doi.org/10.1183/13993003.01220-2018.Meyer G., Besse B., Doubre H. et al. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Res J. 2018;52(4). https://doi.org/10.1183/13993003.01220-2018.Klerk C.P., Smorenburg S.M., Otten H.-M. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23(10):2130–5. https://doi.org/10.1200/JCO.2005.03.134.Klerk C.P., Smorenburg S.M., Otten H.-M. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23(10):2130–5. https://doi.org/10.1200/JCO.2005.03.134.Lee A.Y., Rickles F.R., Julian J.A. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23(10):2123–9. https://doi.org/10.1200/JCO.2005.03.133.Lee A.Y., Rickles F.R., Julian J.A. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23(10):2123–9. https://doi.org/10.1200/JCO.2005.03.133.Kakkar A.K., Levine M.N., Kadziola Z. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004;22(10):1944–8. https://doi.org/10.1200/JCO.2004.10.002.Kakkar A.K., Levine M.N., Kadziola Z. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004;22(10):1944–8. https://doi.org/10.1200/JCO.2004.10.002.Liao W.Y., Ho C.C., Hou H.H. et al. Heparin co-factor II enhances cell motility and promotes metastasis in non-small cell lung cancer. J Pathology. 2015;235(1):50–64. https://doi.org/10.1002/path.4421.Liao W.Y., Ho C.C., Hou H.H. et al. Heparin co-factor II enhances cell motility and promotes metastasis in non-small cell lung cancer. J Pathology. 2015;235(1):50–64. https://doi.org/10.1002/path.4421.Alyahya R., Sudha T., Racz M. et al. Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models. Int J Oncol. 2015;46(3):1225–31. https://doi.org/10.3892/ijo.2014.2803.Alyahya R., Sudha T., Racz M. et al. Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models. Int J Oncol. 2015;46(3):1225–31. https://doi.org/10.3892/ijo.2014.2803.Oschatz C., Maas C., Lecher B. et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011;34(2):258–68. https://doi.org/10.1016/j.immuni.2011.02.008.Oschatz C., Maas C., Lecher B. et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011;34(2):258–68. https://doi.org/10.1016/j.immuni.2011.02.008.Stelmach I., Jerzynska J., Stelmach W. et al. The effect of inhaled heparin on airway responsiveness to histamine and leukotriene D4. Allergy Asthma Proc. 2003;24(1): 59–65.Stelmach I., Jerzynska J., Stelmach W. et al. The effect of inhaled heparin on airway responsiveness to histamine and leukotriene D4. Allergy Asthma Proc. 2003;24(1): 59–65.Vancheri C., Mastruzzo C., Armato F. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol. 2001;108(5):703–8. https://doi.org/10.1067/mai.2001.118785.Vancheri C., Mastruzzo C., Armato F. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol. 2001;108(5):703–8. https://doi.org/10.1067/mai.2001.118785.Becker R.C., Mahaffey K.W., Yang H. et al. Heparin-associated anti-Xa activity and platelet-derived prothrombotic and proinflammatory biomarkers in moderate to high-risk patients with acute coronary syndrome. J Thromb Thrombolysis. 2011;31(2):146–53. https://doi.org/10.1007/s11239-010-0532-y.Becker R.C., Mahaffey K.W., Yang H. et al. Heparin-associated anti-Xa activity and platelet-derived prothrombotic and proinflammatory biomarkers in moderate to high-risk patients with acute coronary syndrome. J Thromb Thrombolysis. 2011;31(2):146–53. https://doi.org/10.1007/s11239-010-0532-y.Rathbun S.W., Aston C.E., Whitsett T.L. A randomized trial of dalteparin compared with ibuprofen for the treatment of superficial thrombophlebitis. J Thromb Haemost. 2012;10(5):833–9. https://doi.org/10.1111/j.1538-7836.2012.04669.x.Rathbun S.W., Aston C.E., Whitsett T.L. A randomized trial of dalteparin compared with ibuprofen for the treatment of superficial thrombophlebitis. J Thromb Haemost. 2012;10(5):833–9. https://doi.org/10.1111/j.1538-7836.2012.04669.x.Weiler J.M., Edens R.E., Linhardt R., Kapelanski D. Heparin and modified heparin inhibit complement activation in vivo. J Immunol. 1992;148(10):3210–5.Weiler J.M., Edens R.E., Linhardt R., Kapelanski D. Heparin and modified heparin inhibit complement activation in vivo. J Immunol. 1992;148(10):3210–5.Linhardt R.J., Rice K.G., Kim Y.S. et al. Homogeneous, structurally defined heparin-oligosaccharides with low anticoagulant activity inhibit the generation of the amplification pathway C3 convertase in vitro. J Biol Chem. 1988;263(26):13090–6. https://doi.org/10.1016/S0021-9258(18)37675-0.Linhardt R.J., Rice K.G., Kim Y.S. et al. Homogeneous, structurally defined heparin-oligosaccharides with low anticoagulant activity inhibit the generation of the amplification pathway C3 convertase in vitro. J Biol Chem. 1988;263(26):13090–6. https://doi.org/10.1016/S0021-9258(18)37675-0.Proudfoot A.E., Fritchley S., Borlat F. et al. The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J Biol Chem. 2001;276(14):10620–6. https://doi.org/10.1074/jbc.M010867200.Proudfoot A.E., Fritchley S., Borlat F. et al. The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J Biol Chem. 2001;276(14):10620–6. https://doi.org/10.1074/jbc.M010867200.Young E., Podor T.J., Venner T., Hirsh J. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arterioscler Thromb Vas Biol. 1997;17(8):1568–74. https://doi.org/10.1161/01.atv.17.8.1568.Young E., Podor T.J., Venner T., Hirsh J. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arterioscler Thromb Vas Biol. 1997;17(8):1568–74. https://doi.org/10.1161/01.atv.17.8.1568.Brinkmann V., Reichard U., Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. https://doi.org/10.1126/science.109238.Brinkmann V., Reichard U., Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. https://doi.org/10.1126/science.109238.Iba T., Hashiguchi N., Nagaoka I. et al. Heparins attenuated histonemediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction. Intensive Care Med Exp. 2015;3(1):36. https://doi.org/10.1186/s40635-015-0072-z.Iba T., Hashiguchi N., Nagaoka I. et al. Heparins attenuated histonemediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction. Intensive Care Med Exp. 2015;3(1):36. https://doi.org/10.1186/s40635-015-0072-z.Redini F., Tixier J., Petitou M. et al. Inhibition of leucocyte elastase by heparin and its derivatives. Biochem J. 1988;252(2):515–9. https://doi.org/10.1042/bj2520515.Redini F., Tixier J., Petitou M. et al. Inhibition of leucocyte elastase by heparin and its derivatives. Biochem J. 1988;252(2):515–9. https://doi.org/10.1042/bj2520515.von Brühl M.-L., Stark K., Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819–35. https://doi.org/10.1084/jem.20112322.von Brühl M.-L., Stark K., Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819–35. https://doi.org/10.1084/jem.20112322.Levi M., van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38(2 Suppl):S26–34. https://doi.org/10.1097/CCM.0b013e3181c98d21.Levi M., van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38(2 Suppl):S26–34. https://doi.org/10.1097/CCM.0b013e3181c98d21.Connor W.E., Armstrong M.L. Plasma lipoprotein lipase after subcutaneous heparin. Circulation. 1961;24(1):87–93. https://doi.org/10.1161/01.cir.24.1.87.Connor W.E., Armstrong M.L. Plasma lipoprotein lipase after subcutaneous heparin. Circulation. 1961;24(1):87–93. https://doi.org/10.1161/01.cir.24.1.87.Wang L., Fuster M., Sriramarao P., Esko J.D. Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nature Immunol. 2005;6(9):902–10. https://doi.org/10.1038/ni1233.Wang L., Fuster M., Sriramarao P., Esko J.D. Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nature Immunol. 2005;6(9):902–10. https://doi.org/10.1038/ni1233.Kitamura N., Yamaguchi M., Shimabukuro K. et al. Heparin-like glycosaminoglycans inhibit leukocyte adhesion to endotoxin-activated human vascular endothelial cells under nonstatic conditions. Eur Surg Res. 1996;28(6):428–35. https://doi.org/10.1159/000129487.Kitamura N., Yamaguchi M., Shimabukuro K. et al. Heparin-like glycosaminoglycans inhibit leukocyte adhesion to endotoxin-activated human vascular endothelial cells under nonstatic conditions. Eur Surg Res. 1996;28(6):428–35. https://doi.org/10.1159/000129487.Miller S.J., Hoggatt A., Faulk W.P. Heparin regulates ICAM-1 expression in human endothelial cells: an example of non-cytokine-mediated endothelial activation. Thromb Haemost. 1998;80(3):481–7.Miller S.J., Hoggatt A., Faulk W.P. Heparin regulates ICAM-1 expression in human endothelial cells: an example of non-cytokine-mediated endothelial activation. Thromb Haemost. 1998;80(3):481–7.Coombe D.R., Stevenson S.M., Kinnear B.F. et al. Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 2. Biochemical analyses. Biochemistry. 2008;47(17):4863–75. https://doi.org/10.1021/bi7024595.Coombe D.R., Stevenson S.M., Kinnear B.F. et al. Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 2. Biochemical analyses. Biochemistry. 2008;47(17):4863–75. https://doi.org/10.1021/bi7024595.Kiselyov V.V., Berezin V., Maar T.E. et al. The first immunoglobulin-like neural cell adhesion molecule (NCAM) domain is involved in double-reciprocal interaction with the second immunoglobulin-like NCAM domain and in heparin binding. J Biol Chem. 1997;272(15):10125–34. https://doi.org/10.1074/jbc.272.15.10125.Kiselyov V.V., Berezin V., Maar T.E. et al. The first immunoglobulin-like neural cell adhesion molecule (NCAM) domain is involved in double-reciprocal interaction with the second immunoglobulin-like NCAM domain and in heparin binding. J Biol Chem. 1997;272(15):10125–34. https://doi.org/10.1074/jbc.272.15.10125.Diamond M.S., Alon R., Parkos C.A. et al. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol. 1995;130(6):1473–82. https://doi.org/10.1083/jcb.130.6.1473.Diamond M.S., Alon R., Parkos C.A. et al. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol. 1995;130(6):1473–82. https://doi.org/10.1083/jcb.130.6.1473.Hu Q.-Y., Fink E., Grant C.K., Elder J.H. Selective interaction of heparin with the variable region 3 within surface glycoprotein of laboratory-adapted feline immunodeficiency virus. PloS One. 2014;9(12):e115252. https://doi.org/10.1371/journal.pone.0115252.Hu Q.-Y., Fink E., Grant C.K., Elder J.H. Selective interaction of heparin with the variable region 3 within surface glycoprotein of laboratory-adapted feline immunodeficiency virus. PloS One. 2014;9(12):e115252. https://doi.org/10.1371/journal.pone.0115252.Luan Z., Hu B., Wu L. et al. Unfractionated heparin alleviates human lung endothelial barrier dysfunction induced by high mobility group box 1 through regulation of P38–GSK3–Snail signaling pathway. Cell Physiol Biochem. 2018;46(5):1907–18. https://doi.org/10.1159/000489375.Luan Z., Hu B., Wu L. et al. Unfractionated heparin alleviates human lung endothelial barrier dysfunction induced by high mobility group box 1 through regulation of P38–GSK3–Snail signaling pathway. Cell Physiol Biochem. 2018;46(5):1907–18. https://doi.org/10.1159/000489375.Morgan M.J., Liu Z.-G. Crosstalk of reactive oxygen species and NF-B signaling. Cell Res. 2011;21(1):103–15. https://doi.org/10.1038/cr.2010.178.Morgan M.J., Liu Z.-G. Crosstalk of reactive oxygen species and NF-B signaling. Cell Res. 2011;21(1):103–15. https://doi.org/10.1038/cr.2010.178.Blaukovitch C.I., Pugh R., Gilotti A.C. et al. Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual-specificity phosphatase MKP-1. J Cell Biochem. 2010;110(2):382–91. https://doi.org/10.1002/jcb.22543.Blaukovitch C.I., Pugh R., Gilotti A.C. et al. Heparin treatment of vascular smooth muscle cells results in the synthesis of the dual-specificity phosphatase MKP-1. J Cell Biochem. 2010;110(2):382–91. https://doi.org/10.1002/jcb.22543.Stewart E., Liu X., Clark G. et al. Inhibition of smooth muscle cell adhesion and proliferation on heparin-doped polypyrrole. Acta Biomater. 2012;8(1):194–200. https://doi.org/10.1016/j.actbio.2011.07.029.Stewart E., Liu X., Clark G. et al. Inhibition of smooth muscle cell adhesion and proliferation on heparin-doped polypyrrole. Acta Biomater. 2012;8(1):194–200. https://doi.org/10.1016/j.actbio.2011.07.029.Achilles A., Mohring A., Zeus T. et al. Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation: reply. J Thromb Haemost. 2017;15(7):1524–5. https://doi.org/10.1111/jth.13595.Achilles A., Mohring A., Zeus T. et al. Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation: reply. J Thromb Haemost. 2017;15(7):1524–5. https://doi.org/10.1111/jth.13595.Luan Z.-G., Naranpurev M., Ma X.-C. Treatment of low molecular weight heparin inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats. Inflammation. 2014;37(3):924–32. https://doi.org/10.1007/s10753-014-9812-6.Luan Z.-G., Naranpurev M., Ma X.-C. Treatment of low molecular weight heparin inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats. Inflammation. 2014;37(3):924–32. https://doi.org/10.1007/s10753-014-9812-6.Lipowsky H.H., Lescanic A. Inhibition of inflammation induced shedding of the endothelial glycocalyx with low molecular weight heparin. Microvasc Res. 2017;112:72–8. https://doi.org/10.1016/j.mvr.2017.03.007.Lipowsky H.H., Lescanic A. Inhibition of inflammation induced shedding of the endothelial glycocalyx with low molecular weight heparin. Microvasc Res. 2017;112:72–8. https://doi.org/10.1016/j.mvr.2017.03.007.Floer M., Götte M., Wild M.K. et al. Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice. Am J Pathol. 2010;176(1):146–57. https://doi.org/10.2353/ajpath.2010.080639.Floer M., Götte M., Wild M.K. et al. Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice. Am J Pathol. 2010;176(1):146–57. https://doi.org/10.2353/ajpath.2010.080639.Nelson A., Berkestedt I., Schmidtchen A. et al. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock. 2008;30(6):623–7. https://doi.org/10.1097/SHK.0b013e3181777da3.Nelson A., Berkestedt I., Schmidtchen A. et al. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock. 2008;30(6):623–7. https://doi.org/10.1097/SHK.0b013e3181777da3.Varga Z., Flammer A.J., Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8. https://doi.org/10.1016/S0140-6736(20)30937-5.Varga Z., Flammer A.J., Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8. https://doi.org/10.1016/S0140-6736(20)30937-5.Harenberg J., Jonas J.B., Trecca E.M. A liaison between sudden sensorineural hearing loss and SARS-CoV-2 infection. Thromb Haemost. 2020;120(9):1237–9. https://doi.org/10.1055/s-0040-1714370.Harenberg J., Jonas J.B., Trecca E.M. A liaison between sudden sensorineural hearing loss and SARS-CoV-2 infection. Thromb Haemost. 2020;120(9):1237–9. https://doi.org/10.1055/s-0040-1714370.Zhou P., Yin J.-X., Tao H.-L., Zhang H.-W. Pathogenesis and management of heparin-induced thrombocytopenia and thrombosis. Clin Chim Acta. 2020;504:73–-80. https://doi.org/10.1016/j.cca.2020.02.002.Zhou P., Yin J.-X., Tao H.-L., Zhang H.-W. Pathogenesis and management of heparin-induced thrombocytopenia and thrombosis. Clin Chim Acta. 2020;504:73–-80. https://doi.org/10.1016/j.cca.2020.02.002.Cuker A., Arepally G.M., Chong B.H. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360–92. https://doi.org/10.1182/bloodadvances.2018024489.Cuker A., Arepally G.M., Chong B.H. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360–92. https://doi.org/10.1182/bloodadvances.2018024489.Lefkou E., Khamashta M., Hampson G., Hunt B. Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus. 2010;19(1):3–12. https://doi.org/10.1177/0961203309353171.Lefkou E., Khamashta M., Hampson G., Hunt B. Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus. 2010;19(1):3–12. https://doi.org/10.1177/0961203309353171.Schindewolf M., Paulik M., Kroll H. et al. Low incidence of heparin-induced skin lesions in orthopedic surgery patients with low-molecularweight heparins. Clin Exp Allergy. 2018;48(8):1016–24. https://doi.org/10.1111/cea.13159.Schindewolf M., Paulik M., Kroll H. et al. Low incidence of heparin-induced skin lesions in orthopedic surgery patients with low-molecularweight heparins. Clin Exp Allergy. 2018;48(8):1016–24. https://doi.org/10.1111/cea.13159.Долгушина Н., Макацария А. Низкомолекулярные гепарины в лечении плацентарной недостаточности и других осложнений беременности у больных вирусными инфекциями. АГ-инфо. 2007;(3):5–1.Dolgushina N., Makatsariya A. Low molecular weight heparins in therapy of placental insufficiency and other complications of pregnancy in patients with viral infections. [Nizkomolekulyarnye gepariny v lechenii placentarnoj nedostatochnosti i drugih oslozhnenij beremennosti u bol'nyh virusnymi infekciyami]. AG-info. 2007;(3):5–1. (In Russ.).

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