akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2021.238akusherstvo-1067Research ArticleEDITORIALРЕДАКЦИОННАЯ СТАТЬЯNeutrophil extracellular traps: a role in inflammation and dysregulated hemostasis as well as in patients with COVID-19 and severe obstetric pathologyВнеклеточные ловушки нейтрофилов участие в процессах воспаления и дизрегуляции гемостаза, в том числе у пациентов с COVID-19 и тяжелой акушерской патологиейhttps://orcid.org/0000-0001-7415-4633МакацарияА. Д.MakatsariyaA. D.

Макацария Александр Давидович - доктор медицинских наук, профессор, академик РАН, заведующий кафедрой акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова.

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

Scopus Author ID: 57222220144.

Researcher ID: M-5660-2016.

Alexander D. Makatsariya - MD, Dr Sci Med, Academician of RAS, Professor, Head of the Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University.

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

Scopus Author ID: 57222220144.

Researcher ID: M-5660-2016.

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

Слуханчук Екатерина Викторовна - кандидат медицинских наук, доцент кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова ПМГМУ им. И.М. Сеченова МЗ РФ; врач акушер-гинеколог отделения абдоминальной хирургии и онкологии 2, РНЦХ им. акад. Б.В. Петровского.

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4; 119991 Москва, Абрикосовский пер., д. 2.

Ekaterina V. Slukhanchuk - MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University, Moscow Russia; Obstetrician-Gynecologist, Department of Abdominal Surgery and Oncology 2, Petrovsky National Research Centre of Surgery.

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991; 2 Abrikosovskiy Lane, Moscow 119991.

beloborodova@rambler.ruhttps://orcid.org/0000-0001-8404-1042БицадзеВ. О.BitsadzeV. O.

Бицадзе Виктория Омаровна - доктор медицинских наук, профессор РАН, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова.

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

Scopus Author ID: 6506003478.

Researcher ID: F-8409-2017.

Victoria O. Bitsadze - MD, Dr Sci Med, Professor of RAS, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University.

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

Scopus Author ID: 6506003478.

Researcher ID: F-8409-2017.

https://orcid.org/0000-0002-0725-9686ХизроеваД. Х.KhizroevaJ. Kh.

Хизроева Джамиля Хизриевна - доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова.

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

Scopus Author ID: 57194547147.

Researcher ID: F-8384-2017.

Jamilya Kh. Khizroeva - MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University.

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

Scopus Author ID: 57194547147.

Researcher ID: F-8384-2017.

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

Третьякова Мария Владимировна - кандидат медицинских наук, врач акушер-гинеколог отделения гинекологии.

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

Maria V. Tretyakova - MD, PhD, Obstetrician-Gynecologist, Department of Gynecology, «Medical Center» LLC.

15/1 Timura Frunze Str., Moscow 119021.

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

Макацария Наталия Александровна - кандидат медицинских наук, доцент кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова.

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

Researcher ID: F-8406-2017.

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

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

Researcher ID: F-8406-2017.

https://orcid.org/0000-0002-1388-5827АкиньшинаС. В.AkinshinaS. V.

Акиньшина Светлана Владимировна - кандидат медицинских наук, врач акушер-гинеколог, гематолог.

109004 Москва, ул. Земляной Вал, д. 62.

Svetlana V. Akinshina - MD, PhD, Obstetrician-Gynecologist, Hematologist, «Medical Centre for Women» LLC.

62 Str. Zemlyanoi Val, Moscow 109004.

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

Шкода Андрей Сергеевич - доктор медицинских наук, профессор, главный врач.

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

Andrey S. Shkoda - MD, Dr Sci Med, Professor, Chief Physician, Vorokhobov City Clinical Hospital № 67.

2/44 Salyama Adilya Str., Moscow 123423.

https://orcid.org/0000-0002-1339-4155ПанкратьеваЛ. Л.PankratyevaL. L.

Панкратьева Людмила Леонидовна - доктор медицинских наук, руководитель научно-клинического центра ГКБ № 67 им. Л.А. Ворохобова ДЗ г. Москвы; врач-неонатолог, врач-гематолог, доцент, профессор кафедры педиатрии и организации здравоохранения НМИЦ ДГОИ им. Дмитрия Рогачева МЗ РФ.

123423 Москва, ул. Саляма Адиля, д.2/44; 117997 Москва, ул. Саморы Машела, д. 1.

Scopus Author ID: 7006391091.

Author ID: 697284.

Liudmila L. Pankratyeva - MD, Dr Sci Med, Head of the Clinical Research Center, Vorokhobov City Clinical Hospital № 67; Neonatologist, Hematologist, Associate Professor, Professor of the Department of Pediatrics and Health Organization, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

2/44 Salyama Adilya Str., Moscow 123423; 1 Samora Machel Str., Moscow 117997.

Scopus Author ID: 7006391091.

Author ID: 697284.

https://orcid.org/0000-0003-4467-240XДи РенцоД. К.Di RenzoG. C.

Ди Ренцо Джан Карло - доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова ПМГМУ им. И.М. Сеченова МЗ РФ; директор Центра пренатальной и репродуктивной медицины Университета Перуджи; почетный генеральный секретарь Международной федерации акушеров-гинекологов (FIGO).

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4; Умбрия, Перуджа, Piazza Italia.

Scopus Author ID: 7103191096.

Researcher ID: P-3819-2017.

Gian C. Di Renzo - MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University; Director of the Center for Prenatal and Reproductive Medicine, University of Perugia, Italy; Honorary Secretary General of the International Federation of Gynecology and Obstetrics (FIGO).

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991; Umbria, Perugia, Piazza Italia.

Scopus Author ID: 7103191096.

Researcher ID: P-3819-2017.

https://orcid.org/0000-0002-5525-4353РиццоД.RizzoG.

Риццо Джузеппе - доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова ПМГМУ им. И.М. Сеченова МЗ РФ; профессор, директор департамента перинатологии, Римский университет Тор Вергата.

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

Scopus Author ID: 7102724281.

Researcher ID: G-8234-2018.

Giuseppe Rizzo - MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health, Sechenov University; Professor, Director, Division of Maternal and Fetal Medicine, Ospedale Cristo Re, University of Rome Tor Vergata.

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

Scopus Author ID: 7102724281.

Researcher ID: G-8234-2018.

https://orcid.org/0000-0002-7756-8935ГригорьеваК. Н.GrigorievaK. 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, Sechenov University.

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

https://orcid.org/0000-0001-5888-0774ЦибизоваВ. И.TsibizovaV. I.

Цибизова Валентина Ивановна - кандидат медицинских наук, акушер-гинеколог НИЛ оперативной гинекологии Института перинатологии и педиатрии; врач отделения функциональной и ультразвуковой диагностики НМИЦ им. В.А. Алмазова МЗ РФ.

197341 Санкт-Петербург, ул. Аккуратова, д. 2.

Valentina I. Tsibizova - MD, PhD, Obstetrician-Gynecologist, Research Laboratory of Operative Gynecology, Institute of Perinatology and Pediatrics; Physician, Department of Functional and Ultrasound Diagnostics, Almazov National Medical Research Centre.

2 Akkuratova Str., Saint Petersburg 197341.

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

Гри Жан-Кристоф - доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова; профессор гематологии, университет Монпелье.

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4; 34090 Монпелье, Rue Auguste Broussonnet, 163.

Researcher ID: AAA-2923-2019.

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.

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991; 163 Rue Auguste Broussonnet, Montpellier 34090.

Researcher ID: AAA-2923-2019.

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

Элалами Исмаил - доктор медицинских наук, профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова ПМГМУ им. И.М. Сеченова МЗ РФ; профессор медицинского Университета Сорбонны; директор гематологии Центра Тромбозов, Госпиталь Тенон.

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4; 75006 Париж, Улица медицинского факультета, д. 12; 75020 Париж, Китайская улица, д. 4.

Scopus Author ID: 7003652413.

Researcher ID: AAC-9695-2019.

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, Paris, France; Director of Hematology, Department of Thrombosis Center, Hospital Tenon.

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991; 12 Rue de l’École de Médecine, 75006 Paris; 4 Rue de la Chine, 75020 Paris.

Scopus Author ID: 7003652413.

Researcher ID: AAC-9695-2019.

Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияSechenov UniversityRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); Российский научный центр хирургии имени академика Б.В. ПетровскогоРоссияSechenov University; Petrovsky National Research Centre of SurgeryRussian FederationООО «Лечебный Центр»Россия«Medical Center» LLCRussian FederationООО «Медицинский женский центр»Россия«Medical Centre for Women» LLCRussian FederationГородская клиническая больница № 67 имени Л.А. Ворохобова Департамента здравоохранения города МосквыРоссияVorokhobov City Clinical Hospital № 67, Moscow Healthcare DepartmentRussian FederationГородская клиническая больница № 67 имени Л.А. Ворохобова Департамента здравоохранения города Москвы; Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии имени Дмитрия Рогачева Министерства здравоохранения Российской ФедерацииРоссияVorokhobov City Clinical Hospital № 67, Moscow Healthcare Department; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Health Ministry of Russian FederationRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); Центр пренатальной и репродуктивной медицины Университета ПеруджиРоссияSechenov University; Center for Prenatal and Reproductive Medicine, University of PerugiaRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); Римский университет Тор ВергатаРоссияSechenov University; University of Rome Tor VergataRussian FederationНациональный медицинский исследовательский центр имени В.А. Алмазова Министерства здравоохранения Российской ФедерацииРоссияAlmazov National Medical Research Centre, Health Ministry of Russian FederationRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); Университет МонпельеРоссияSechenov University; University of MontpellierRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); Медицинский Университет Сорбонны; Госпиталь ТенонРоссияSechenov University; Medicine Sorbonne University; Hospital TenonRussian Federation202108092021154335350Copyright © Makatsariya A.D., Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.K., Tretyakova M.V., Makatsariya N.A., Akinshina S.V., Shkoda A.S., Pankratyeva L.L., Di Renzo G.C., Rizzo G., Grigorieva K.N., Tsibizova V.I., Gris J., Elalamy I., 20212021Макацария А.Д., Слуханчук Е.В., Бицадзе В.О., Хизроева Д.Х., Третьякова М.В., Макацария Н.А., Акиньшина С.В., Шкода А.С., Панкратьева Л.Л., Ди Ренцо Д.К., Риццо Д., Григорьева К.Н., Цибизова В.И., Гри Ж., Элалами И.Makatsariya A.D., Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.K., Tretyakova M.V., Makatsariya N.A., Akinshina S.V., Shkoda A.S., Pankratyeva L.L., Di Renzo G.C., Rizzo G., Grigorieva K.N., Tsibizova V.I., Gris J., Elalamy I.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/1067

Numerous studies have proven a close relationship between inflammatory diseases and the state of hypercoagulability. In fact, thromboembolic complications represent one of the main causes of disability and mortality in acute and chronic inflammatory diseases, cancer and obstetric complications. Despite this, the processes of hemostasis and immune responses have long been considered separately; currently, work is underway to identify the molecular basis for a relationship between such systems. It has been identified that various pro-inflammatory stimuli are capable of triggering a coagulation cascade, which in turn modulates inflammatory responses. Neutrophil extracellular traps (NETs) are the networks of histones of extracellular DNA generated by neutrophils in response to inflammatory stimuli. The hemostasis is activated against infection in order to minimize the spread of infection and, if possible, inactivate the infectious agent. Another molecular network is based on fibrin. Over the last 10 years, there has been accumulated a whole body of evidence that NETs and fibrin are able to form a united network within a thrombus, stabilizing each other. Similarities and molecular cross-reactions are also present in the processes of fibrinolysis and lysis of NETs. Both NETs and von Willebrand factor (vWF) are involved in thrombosis as well as inflammation. During the development of these conditions, a series of events occurs in the microvascular network, including endothelial activation, NETs formation, vWF secretion, adhesion, aggregation, and activation of blood cells. The activity of vWF multimers is regulated by the specific metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Studies have shown that interactions between NETs and vWF can lead to arterial and venous thrombosis and inflammation. In addition, the contents released from activated neutrophils or NETs result in decreased ADAMTS-13 activity, which can occur in both thrombotic microangiopathies and acute ischemic stroke. Recently, NETs have been envisioned as a cause of endothelial damage and immunothrombosis in COVID-19. In addition, vWF and ADAMTS-13 levels predict COVID-19 mortality. In this review, we summarize the biological characteristics and interactions of NETs, vWF, and ADAMTS-13, the effect of NETs on hemostasis regulation and discuss their role in thrombotic conditions, sepsis, COVID-19, and obstetric complications.

Многочисленными исследованиями доказана тесная связь воспалительных заболеваний с состоянием гиперкоагуляции. Фактически, тромбоэмболические осложнения являются одной из основных причин инвалидности и смертности при острых и хронических воспалительных заболеваниях, онкологических заболеваниях и при акушерских осложнениях. Несмотря на это, процессы гемостаза и иммунные реакции долгое время рассматривались по отдельности; в настоящее время идет работа по выявлению молекулярных основ взаимосвязи между этими системами. Уже известно, что различные провоспа-лительные стимулы способны запускать коагуляционный каскад, который в свою очередь модулирует воспалительные реакции. Внеклеточные ловушки нейтрофилов (англ. neutrophil extracellular traps, NETs) представляют собой сети из гистонов внеклеточной ДНК, генерируемые нейтрофилами в ответ на воспалительные стимулы. Система гемостаза активируется в ответ на инфицирование с целью минимизировать распространение инфекции и по возможности инактивировать инфекционный агент. Еще одну молекулярную сеть представляет собой фибрин. За последние 10 лет появилось много данных о том, что NETs и фибрин способны формировать единую сеть внутри тромба, стабилизируя друг друга. Сходства и перекрестные молекулярные реакции присутствуют также и в процессах фибринолиза и лизиса NETs. Как NETs, так и фактор фон Виллебранда (vWF) являются участниками и тромбоза и воспаления. В процессе развития этих состояний в микросо-судистой сети происходит серия событий, включающая активацию эндотелия, образование NETs, секрецию vWF, адгезию, агрегацию и активацию клеток крови. Активность мультимеров vWF регулируется специфической металлопротеиназой ADAMTS-13 (англ. a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Исследования показали, что взаимодействия между NETs и vWF могут приводить к артериальному и венозному тромбозу, а также воспалению. Кроме того, содержимое, высвобождаемое из активированных нейтрофилов или NETs, вызывает снижение активности ADAMTS-13, что может происходить как при тромботических микроангиопатиях, так и при остром ишемическом инсульте. В последнее время NETs рассматривают как причину повреждения эндотелия и иммунотромбоза при COVID-19. Кроме того, уровни vWF и ADAMTS-13 позволяют прогнозировать смертность от COVID-19. В данном обзоре мы суммируем биологические характеристики и взаимодействия NETs, vWF и ADAMTS-13, влияние NETs на регуляцию системы гемостаза, а также обсуждаем их роль в тромботических состояниях, при сепсисе, COVID-19 и акушерских осложнениях.

нейтрофилывнеклеточные ловушки нейтрофиловNETsтромбозфибринфибринолизфактор фон ВиллебрандаvWFADAMTS-13COVID-19neutrophilsneutrophil extracellular trapsNETsthrombosisfibrinfibrinolysisvon Willebrand factorvWFADAMTS-13COVID-19ReferencesAntoniak S. The coagulation system in host defense. Res Pract Thromb Haemost. 2018;2(3):549-57. https://doi.org/10.1002/rth2.12109.Antoniak S. The coagulation system in host defense. Res Pract Thromb Haemost. 2018;2(3):549-57. https://doi.org/10.1002/rth2.12109.Engelmann B., Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34—45. https://doi.org/10.1038/nri3345.Engelmann B., Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34—45. https://doi.org/10.1038/nri3345.Jenne C.N., Kubes P. Platelets in inflammation and infection. Platelets. 2015;26(4):286-92. https://doi.org/10.3109/09537104.2015.1010441.Jenne C.N., Kubes P. Platelets in inflammation and infection. Platelets. 2015;26(4):286-92. https://doi.org/10.3109/09537104.2015.1010441.Rendu F., Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions. Platelets. 2001;12(5):261-73. https://doi.org/10.1080/09537100120068170.Rendu F., Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions. Platelets. 2001;12(5):261-73. https://doi.org/10.1080/09537100120068170.Kenny E.F., Herzig A., Kruger R. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017;6:e24437. https://doi.org/10.7554/eLife.24437.Kenny E.F., Herzig A., Kruger R. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017;6:e24437. https://doi.org/10.7554/eLife.24437.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.1092385.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.1092385.Metchnikoff E. Immunity in infective diseases. Cambridge: University Press, 1907.Metchnikoff E. Immunity in infective diseases. Cambridge: University Press, 1907.Ehrlich P. Methodologische beitrage zur physiologie und pathologie der verschiedenen formen der leukocyten. The Collected Papers of Paul Ehrlich: Elsevier, 2013. 124-9.Ehrlich P. Methodologische beitrage zur physiologie und pathologie der verschiedenen formen der leukocyten. The Collected Papers of Paul Ehrlich: Elsevier, 2013. 124-9.Fuchs T.A., Abed U., Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231-41. https://doi.org/10.1083/jcb.200606027.Fuchs T.A., Abed U., Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231-41. https://doi.org/10.1083/jcb.200606027.Martinod K., Wagner D.D. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-76. https://doi.org/10.1182/blood-2013-10-463646.Martinod K., Wagner D.D. Thrombosis: tangled up in NETs. Blood. 2014;123(18):2768-76. https://doi.org/10.1182/blood-2013-10-463646.Budnik I., Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol. 2018;39(8):610-23. https://doi.org/10.1016/j.it.2018.04.010.Budnik I., Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol. 2018;39(8):610-23. https://doi.org/10.1016/j.it.2018.04.010.Brill A., Fuchs T., Savchenko A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10(1):136-44. https://doi.org/10.1111/j.1538-7836.2011.04544.x.Brill A., Fuchs T., Savchenko A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10(1):136-44. https://doi.org/10.1111/j.1538-7836.2011.04544.x.Darbousset R., Thomas G.M., Mezouar S. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood. 2012;120(10):2133-43. https://doi.org/10.1182/blood-2012-06-437772.Darbousset R., Thomas G.M., Mezouar S. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood. 2012;120(10):2133-43. https://doi.org/10.1182/blood-2012-06-437772.Savchenko A., Martinod K., Seidman M. et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost. 2014;12(6):860-70. https://doi.org/10.1111/jth.12571.Savchenko A., Martinod K., Seidman M. et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost. 2014;12(6):860-70. https://doi.org/10.1111/jth.12571.Mangold A., Alias S., Scherz T. et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. 2015;116(7):1182-92. https://doi.org/10.1161/CIRCRESAHA.116.304944.Mangold A., Alias S., Scherz T. et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. 2015;116(7):1182-92. https://doi.org/10.1161/CIRCRESAHA.116.304944.Ducroux C., Di Meglio L., Loyau S. et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke. 2018;49(3):754-7. https://doi.org/10.1161/STROKEAHA.117.019896.Ducroux C., Di Meglio L., Loyau S. et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke. 2018;49(3):754-7. https://doi.org/10.1161/STROKEAHA.117.019896.Farkas A.Z., Farkas V.J., Gubucz I. et al. Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases. Thromb Res. 2019;175:46-52. https://doi.org/10.1016/j.thromres.2019.01.006.Farkas A.Z., Farkas V.J., Gubucz I. et al. Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases. Thromb Res. 2019;175:46-52. https://doi.org/10.1016/j.thromres.2019.01.006.Abrams S.T., Zhang N., Manson J. et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2):160-9. https://doi.org/10.1164/rccm.201206-1037OC.Abrams S.T., Zhang N., Manson J. et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2):160-9. https://doi.org/10.1164/rccm.201206-1037OC.Garcia-Gimenez J., Roma-Mateo C., Carbonell N. et al. A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients. Sci Rep. 2017;7(1):10643. https://doi.org/10.1038/s41598-017-10830-z.Garcia-Gimenez J., Roma-Mateo C., Carbonell N. et al. A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients. Sci Rep. 2017;7(1):10643. https://doi.org/10.1038/s41598-017-10830-z.Alhamdi Y., Abrams S.T., Cheng Z. et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10):2094-103. https://doi.org/10.1097/CCM.0000000000001162.Alhamdi Y., Abrams S.T., Cheng Z. et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10):2094-103. https://doi.org/10.1097/CCM.0000000000001162.Thalin C., Hisada Y., Lundstrom S. et al. Neutrophil extracellular traps: villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(9):1724-38. https://doi.org/10.1161/ATVBAHA.119.312463.Thalin C., Hisada Y., Lundstrom S. et al. Neutrophil extracellular traps: villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(9):1724-38. https://doi.org/10.1161/ATVBAHA.119.312463.Laridan E., Martinod K., De Meyer S.F. Neutrophil extracellular traps in arterial and venous thrombosis. Semin Thromb Hemost. 2019;45(1):86-93. https://doi.org/10.1055/s-0038-167704.Laridan E., Martinod K., De Meyer S.F. Neutrophil extracellular traps in arterial and venous thrombosis. Semin Thromb Hemost. 2019;45(1):86-93. https://doi.org/10.1055/s-0038-167704.Gould T., Lysov Z., Liaw P. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;(13 Suppl 1):S82-91. https://doi.org/10.1111/jth.12977.Gould T., Lysov Z., Liaw P. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;(13 Suppl 1):S82-91. https://doi.org/10.1111/jth.12977.Jimenez-Alcazar M., Napirei M., Panda R. et al. Impaired DN ase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost. 2015;13(5):732-42. https://doi.org/10.1111/jth.12796.Jimenez-Alcazar M., Napirei M., Panda R. et al. Impaired DN ase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost. 2015;13(5):732-42. https://doi.org/10.1111/jth.12796.Fuchs T.A., Brill A., Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-5. https://doi.org/10.1073/pnas.1005743107.Fuchs T.A., Brill A., Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880-5. https://doi.org/10.1073/pnas.1005743107.Ley K., Laudanna C., Cybulsky M.I., Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678-89. https://doi.org/10.1038/nri2156.Ley K., Laudanna C., Cybulsky M.I., Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678-89. https://doi.org/10.1038/nri2156.Yago T., Liu Z., Ahamed .J, McEver R.P. Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice. Blood. 2018;132(13):1426-37. https://doi.org/10.1182/blood-2018-05-850859.Yago T., Liu Z., Ahamed .J, McEver R.P. Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice. Blood. 2018;132(13):1426-37. https://doi.org/10.1182/blood-2018-05-850859.Palabrica T., Lobb R., Furie B.C. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992;359(6398):848-51. https://doi.org/10.1038/359848a0.Palabrica T., Lobb R., Furie B.C. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992;359(6398):848-51. https://doi.org/10.1038/359848a0.Wakefield T.W., Myers D.D., Henke P.K. Role of selectins and fibrinolysis in VTE. Thromb Res. 2009;123(Suppl 4):S35-40. https://doi.org/10.1016/S0049-3848(09)70141-0.Wakefield T.W., Myers D.D., Henke P.K. Role of selectins and fibrinolysis in VTE. Thromb Res. 2009;123(Suppl 4):S35-40. https://doi.org/10.1016/S0049-3848(09)70141-0.Ataga K.I., Kutlar A., Kanter J. et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-39. https://doi.org/10.1056/NEJMoa1611770.Ataga K.I., Kutlar A., Kanter J. et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-39. https://doi.org/10.1056/NEJMoa1611770.Hakkim A., Fuchs T.A., Martinez N.E. et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7(2):75-7. https://doi.org/10.1038/nchembio.496.Hakkim A., Fuchs T.A., Martinez N.E. et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7(2):75-7. https://doi.org/10.1038/nchembio.496.Bianchi M., Hakkim A., Brinkmann V. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619-22. https://doi.org/10.1182/blood-2009-05-221606.Bianchi M., Hakkim A., Brinkmann V. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619-22. https://doi.org/10.1182/blood-2009-05-221606.Naudin C., Burillo E., Blankenberg S. et al. Factor XII contact activation. Semin Thromb Hemost. 2017;43(8):814-26. https://doi.org/10.1055/s-0036-1598003.Naudin C., Burillo E., Blankenberg S. et al. Factor XII contact activation. Semin Thromb Hemost. 2017;43(8):814-26. https://doi.org/10.1055/s-0036-1598003.Delabranche X., Helms J., Meziani F. Immunohaemostasis: a new view on haemostasis during sepsis. Ann Intensive Care. 2017;7(1):1—14. https://doi.org/10.1186/s13613-017-0339-5.Delabranche X., Helms J., Meziani F. Immunohaemostasis: a new view on haemostasis during sepsis. Ann Intensive Care. 2017;7(1):1—14. https://doi.org/10.1186/s13613-017-0339-5.Semeraro F., Ammollo C.T., Morrissey J.H. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952—61. https://doi.org/10.1182/blood-2011-03-343061.Semeraro F., Ammollo C.T., Morrissey J.H. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952—61. https://doi.org/10.1182/blood-2011-03-343061.Vu T.T., Leslie B.A., Stafford A.R. et al. Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway. Thromb Haemost. 2016;115(1):89—98. https://doi.org/10.1160/TH15-04-033.Vu T.T., Leslie B.A., Stafford A.R. et al. Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway. Thromb Haemost. 2016;115(1):89—98. https://doi.org/10.1160/TH15-04-033.Noubouossie D.F., Whelihan M.F., Yu Y.-B. et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood. 2017;129(8):1021—9. https://doi.org/10.1182/blood-2016-06-722298.Noubouossie D.F., Whelihan M.F., Yu Y.-B. et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood. 2017;129(8):1021—9. https://doi.org/10.1182/blood-2016-06-722298.Urban C.F., Ermert D., Schmid M. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10):e1000639. https://doi.org/10.1371/journal.ppat.1000639.Urban C.F., Ermert D., Schmid M. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5(10):e1000639. https://doi.org/10.1371/journal.ppat.1000639.Chen R., Kang R., Fan X., Tang D. Release and activity of histone in diseases. Cell Death Dis. 2014;5(8):e1370. https://doi.org/10.1038/cddis.2014.337Chen R., Kang R., Fan X., Tang D. Release and activity of histone in diseases. Cell Death Dis. 2014;5(8):e1370. https://doi.org/10.1038/cddis.2014.337Qi H., Yang S., Zhang L. Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol. 2017;8:928. https://doi.org/10.3389/fimmu.2017.00928.Qi H., Yang S., Zhang L. Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol. 2017;8:928. https://doi.org/10.3389/fimmu.2017.00928.Xu J., Zhang X., Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318—21. https://doi.org/10.1038/nm.2053.Xu J., Zhang X., Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318—21. https://doi.org/10.1038/nm.2053.Saffarzadeh M., Juenemann C., Queisser M.A. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PloS One. 2012;7(2):e32366. https://doi.org/10.1371/journal.pone.0032366.Saffarzadeh M., Juenemann C., Queisser M.A. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PloS One. 2012;7(2):e32366. https://doi.org/10.1371/journal.pone.0032366.Kleine T.J., Lewis P.N., Lewis S.A. Histone-induced damage of a mammalian epithelium: the role of protein and membrane structure. Am J Physiol. 1997;273(6):C1925-36. https://doi.org/10.1152/ajpcell.1997.273.6.C1925Kleine T.J., Lewis P.N., Lewis S.A. Histone-induced damage of a mammalian epithelium: the role of protein and membrane structure. Am J Physiol. 1997;273(6):C1925-36. https://doi.org/10.1152/ajpcell.1997.273.6.C1925Gamberucci A., Fulceri R., Marcolongo P. et al. Histones and basic polypeptides activate Ca2+/cation influx in various cell types. Biochem J. 1998;331(Pt 2):623-30. https://doi.org/10.1042/bj3310623.Gamberucci A., Fulceri R., Marcolongo P. et al. Histones and basic polypeptides activate Ca2+/cation influx in various cell types. Biochem J. 1998;331(Pt 2):623-30. https://doi.org/10.1042/bj3310623.Crittenden J.R., Bergmeier W., Zhang Y. et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10(9):982-6. https://doi.org/10.1038/nm1098.Crittenden J.R., Bergmeier W., Zhang Y. et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10(9):982-6. https://doi.org/10.1038/nm1098.Carestia A., Rivadeneyra L., Romaniuk M.A. et al. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost. 2013;110(5):1035-45. https://doi.org/10.1160/TH13-02-0174.Carestia A., Rivadeneyra L., Romaniuk M.A. et al. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost. 2013;110(5):1035-45. https://doi.org/10.1160/TH13-02-0174.Gersh K.C., Nagaswami C., Weisel J.W. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost. 2009;102(6):1169. https://doi.org/10.1160/TH09-03-0199.Gersh K.C., Nagaswami C., Weisel J.W. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost. 2009;102(6):1169. https://doi.org/10.1160/TH09-03-0199.Wohner N., Sotonyi P., Machovich R. et al. Lytic resistance of fibrin containing red blood cells. Arterioscler Thromb Vasc Biol. 2011;31(10):2306-13. https://doi.org/10.1161/ATVBAHA.111.229088.Wohner N., Sotonyi P., Machovich R. et al. Lytic resistance of fibrin containing red blood cells. Arterioscler Thromb Vasc Biol. 2011;31(10):2306-13. https://doi.org/10.1161/ATVBAHA.111.229088.Semeraro F., Ammollo C., Esmon N., Esmon C. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost. 2014;12(10):1697—702. https://doi.org/10.1111/jth.12677.Semeraro F., Ammollo C., Esmon N., Esmon C. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost. 2014;12(10):1697—702. https://doi.org/10.1111/jth.12677.Barranco-Medina S., Pozzi N., Vogt A.D., Di Cera E. Histone H4 promotes prothrombin autoactivation. J Biol Chem. 2013;288(50):35749-57. https://doi.org/10.1074/jbc.M113.509786.Barranco-Medina S., Pozzi N., Vogt A.D., Di Cera E. Histone H4 promotes prothrombin autoactivation. J Biol Chem. 2013;288(50):35749-57. https://doi.org/10.1074/jbc.M113.509786.Varju I., Longstaff C., Szabo L. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost. 2015;113(6):1289-98. https://doi.org/10.1160/TH14-08-0669.Varju I., Longstaff C., Szabo L. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost. 2015;113(6):1289-98. https://doi.org/10.1160/TH14-08-0669.Ammollo C.T., Semeraro F., Xu J. et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost. 2011;9(9):1795—803. https://doi.org/10.1111/j.1538-7836.2011.04422.x.Ammollo C.T., Semeraro F., Xu J. et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost. 2011;9(9):1795—803. https://doi.org/10.1111/j.1538-7836.2011.04422.x.Healy L.D., Puy C., Fernandez J.A. et al. Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem. 2017;292(21):8616-29. https://doi.org/10.1074/jbc.M116.768309.Healy L.D., Puy C., Fernandez J.A. et al. Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem. 2017;292(21):8616-29. https://doi.org/10.1074/jbc.M116.768309.Bajzar L., Morser J., Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombinthrombomodulin complex. J Biol Chem. 1996;271(28):16603—8. https://doi.org/10.1074/jbc.271.28.16603.Bajzar L., Morser J., Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombinthrombomodulin complex. J Biol Chem. 1996;271(28):16603—8. https://doi.org/10.1074/jbc.271.28.16603.Sakharov D.V., Plow E.F., Rijken D.C. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem. 1997;272(22):14477-82. https://doi.org/10.1074/jbc.272.22.14477.Sakharov D.V., Plow E.F., Rijken D.C. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem. 1997;272(22):14477-82. https://doi.org/10.1074/jbc.272.22.14477.Gould T.J., Vu T.T., Stafford A.R. et al. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol. 2015;35(12):2544-53. https://doi.org/10.1161/ATVBAHA.115.306035.Gould T.J., Vu T.T., Stafford A.R. et al. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol. 2015;35(12):2544-53. https://doi.org/10.1161/ATVBAHA.115.306035.Bustin M., Cole R.D. Regions of high and low cationic charge in a lysine-rich histone. J Biol Chem. 1970;245(6):1458-66.Bustin M., Cole R.D. Regions of high and low cationic charge in a lysine-rich histone. J Biol Chem. 1970;245(6):1458-66.Katchalski E., Bichovski-Slomnitzki L., Volcani B. Action of some watersoluble poly-a-amino-acids on bacteria. Nature. 1952;169(4313):1095-6. https://doi.org/10.1038/1691095b0.Katchalski E., Bichovski-Slomnitzki L., Volcani B. Action of some watersoluble poly-a-amino-acids on bacteria. Nature. 1952;169(4313):1095-6. https://doi.org/10.1038/1691095b0.Biezunski N., Shafrir E., De Vries A., Katchalski E. The action of polylysine on the conversion of fibrinogen into fibrin by coagulase thrombin. Biochem J. 1955;59(1):55-8. https://doi.org/10.1042/bj0590055.Biezunski N., Shafrir E., De Vries A., Katchalski E. The action of polylysine on the conversion of fibrinogen into fibrin by coagulase thrombin. Biochem J. 1955;59(1):55-8. https://doi.org/10.1042/bj0590055.Wolberg A.S. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131-42. https://doi.org/10.1016/j.blre.2006.11.001.Wolberg A.S. Thrombin generation and fibrin clot structure. Blood Rev. 2007;21(3):131-42. https://doi.org/10.1016/j.blre.2006.11.001.Mutch N.J., Engel R., de Willige S.U. et al. Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood. 2010;115(19):3980-8. https://doi.org/10.1182/blood-2009-11-254029.Mutch N.J., Engel R., de Willige S.U. et al. Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin. Blood. 2010;115(19):3980-8. https://doi.org/10.1182/blood-2009-11-254029.Locke M., Francis R.J., Tsaousi E., Longstaff C. Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin. Sci Rep. 2020;10(1):1-16. https://doi.org/10.1038/s41598-020-68584-0.Locke M., Francis R.J., Tsaousi E., Longstaff C. Fibrinogen protects neutrophils from the cytotoxic effects of histones and delays neutrophil extracellular trap formation induced by ionomycin. Sci Rep. 2020;10(1):1-16. https://doi.org/10.1038/s41598-020-68584-0.Longstaff C., Varju I., Sotonyi P. et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288(10):6946-56. https://doi.org/10.1074/jbc.M112.404301.Longstaff C., Varju I., Sotonyi P. et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288(10):6946-56. https://doi.org/10.1074/jbc.M112.404301.Muszbek L., Bereczky Z., Bagoly Z. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011;91(3):931-72. https://doi.org/10.1152/physrev.00016.2010.Muszbek L., Bereczky Z., Bagoly Z. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011;91(3):931-72. https://doi.org/10.1152/physrev.00016.2010.Byrnes J.R., Duval C., Wang Y. et al. Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin a-chain crosslinking. Blood. 2015;126(16):1940-8. https://doi.org/10.1182/blood-2015-06-652263.Byrnes J.R., Duval C., Wang Y. et al. Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin a-chain crosslinking. Blood. 2015;126(16):1940-8. https://doi.org/10.1182/blood-2015-06-652263.Wolberg A.S. Fibrinogen and factor XIII: newly-recognized roles in venous thrombosis formation and composition. Curr Opin Hematol. 2018;25(5):358-64. https://doi.org/10.1097/MOH.0000000000000445.Wolberg A.S. Fibrinogen and factor XIII: newly-recognized roles in venous thrombosis formation and composition. Curr Opin Hematol. 2018;25(5):358-64. https://doi.org/10.1097/MOH.0000000000000445.Locke M., Longstaff C. Extracellular histones inhibit fibrinolysis through noncovalent and covalent interactions with fibrin. Thromb Haemost. 2021;121(4):464-76. https://doi.org/10.1055/s-0040-1718760.Locke M., Longstaff C. Extracellular histones inhibit fibrinolysis through noncovalent and covalent interactions with fibrin. Thromb Haemost. 2021;121(4):464-76. https://doi.org/10.1055/s-0040-1718760.Longstaff C., Hogwood J., Gray E. et al. Neutralization of the anticoagulant effects of heparin by histones in blood plasma and purified systems. Thromb Haemost. 2016;115(3):591-9. https://doi.org/10.1160/TH15-03-0214.Longstaff C., Hogwood J., Gray E. et al. Neutralization of the anticoagulant effects of heparin by histones in blood plasma and purified systems. Thromb Haemost. 2016;115(3):591-9. https://doi.org/10.1160/TH15-03-0214.Wang F., Zhang N., Li B. et al. Heparin defends against the toxicity of circulating histones in sepsis. Front Biosci (Landmark Ed). 2015;20:1259-70. https://doi.org/10.2741/4370.Wang F., Zhang N., Li B. et al. Heparin defends against the toxicity of circulating histones in sepsis. Front Biosci (Landmark Ed). 2015;20:1259-70. https://doi.org/10.2741/4370.Fuchs T.A., Bhandari A.A., Wagner D.D. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-14. https://doi.org/10.1182/blood-2011-01-332676.Fuchs T.A., Bhandari A.A., Wagner D.D. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-14. https://doi.org/10.1182/blood-2011-01-332676.Komissarov A.A, Florova G., Idell S. Effects of extracellular DNA on plasminogen activation and fibrinolysis. J Biol Chem. 2011;286(49):41949-62. https://doi.org/10.1074/jbc.M111.301218.Komissarov A.A, Florova G., Idell S. Effects of extracellular DNA on plasminogen activation and fibrinolysis. J Biol Chem. 2011;286(49):41949-62. https://doi.org/10.1074/jbc.M111.301218.Eckle I., Seitz R., Egbring R. et al.Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler. 1991;372(11):1007-13. https://doi.org/10.1515/bchm3.1991.372.2.1007.Eckle I., Seitz R., Egbring R. et al.Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler. 1991;372(11):1007-13. https://doi.org/10.1515/bchm3.1991.372.2.1007.Levi M., Schultz M., van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost. 2013:39(5):559-66. https://doi.org/10.1055/s-0033-1343894.Levi M., Schultz M., van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost. 2013:39(5):559-66. https://doi.org/10.1055/s-0033-1343894.Gando S., Kameue T., Morimoto Y. et al. Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis. Crit Care Med. 2002;30(8):1729-34. https://doi.org/10.1097/00003246-200208000-00009.Gando S., Kameue T., Morimoto Y. et al. Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis. Crit Care Med. 2002;30(8):1729-34. https://doi.org/10.1097/00003246-200208000-00009.Collen D., Schetz J., de Cock F. et al. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest. 1977;7(1):27-35. https://doi.org/10.1111/j.1365-2362.1977.tb01566.x.Collen D., Schetz J., de Cock F. et al. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest. 1977;7(1):27-35. https://doi.org/10.1111/j.1365-2362.1977.tb01566.x.Iba T., Saitoh D. Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2014;2(1):66. https://doi.org/10.1186/s40560-014-0051-6.Iba T., Saitoh D. Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2014;2(1):66. https://doi.org/10.1186/s40560-014-0051-6.Sun H.-m., Hong L.-z., Shen X.-k. et al. Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase. Chin Med J (Engl). 2009;122(20):2466-71.Sun H.-m., Hong L.-z., Shen X.-k. et al. Antithrombin-III without concomitant heparin improves endotoxin-induced acute lung injury rats by inhibiting the activation of mitogen-activated protein kinase. Chin Med J (Engl). 2009;122(20):2466-71.Asakura H., Ontachi Y., Mizutani T. et al. Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Eur J Haematol. 2001;67(3):170-5. https://doi.org/10.1034/j.1600-0609.2001.5790508.x.Asakura H., Ontachi Y., Mizutani T. et al. Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Eur J Haematol. 2001;67(3):170-5. https://doi.org/10.1034/j.1600-0609.2001.5790508.x.Aibiki M., Fukuoka N., Umakoshi K. et al. Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation. Shock. 2007;27(2):139-44. https://doi.org/10.1097/01.shk.0000239762.90335.68.Aibiki M., Fukuoka N., Umakoshi K. et al. Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation. Shock. 2007;27(2):139-44. https://doi.org/10.1097/01.shk.0000239762.90335.68.Iba T., Miki T., Hashiguchi N. et al. Combination of antithrombin and recombinant thrombomodulin modulates neutrophil cell-death and decreases circulating DAMPs levels in endotoxemic rats. Thromb Res. 2014;134(1):169-73. https://doi.org/10.1016/j.thromres.2014.04.015.Iba T., Miki T., Hashiguchi N. et al. Combination of antithrombin and recombinant thrombomodulin modulates neutrophil cell-death and decreases circulating DAMPs levels in endotoxemic rats. Thromb Res. 2014;134(1):169-73. https://doi.org/10.1016/j.thromres.2014.04.015.Lof A., Muller J.P., Brehm M.A. A biophysical view on von Willebrand factor activation. J Cell Physiol. 2018;233(2):799-810. https://doi.org/10.1002/jcp.25887.Lof A., Muller J.P., Brehm M.A. A biophysical view on von Willebrand factor activation. J Cell Physiol. 2018;233(2):799-810. https://doi.org/10.1002/jcp.25887.Zhang C., Kelkar A., Neelamegham S. von Willebrand factor selfassociation is regulated by the shear-dependent unfolding of the A2 domain. Blood Adv. 2019;3(7):957-68. https://doi.org/10.1182/bloodadvances.2018030122.Zhang C., Kelkar A., Neelamegham S. von Willebrand factor selfassociation is regulated by the shear-dependent unfolding of the A2 domain. Blood Adv. 2019;3(7):957-68. https://doi.org/10.1182/bloodadvances.2018030122.South K., Lane D.A. ADAMTS-13 and von Willebrand factor: a dynamic duo. J Thromb Haemost. 2018;16(1):6-18. https://doi.org/10.1111/jth.13898.South K., Lane D.A. ADAMTS-13 and von Willebrand factor: a dynamic duo. J Thromb Haemost. 2018;16(1):6-18. https://doi.org/10.1111/jth.13898.Bernardo A., Ball C., Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood. 2004;104(1):100-6. https://doi.org/10.1182/blood-2004-01-0107.Bernardo A., Ball C., Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood. 2004;104(1):100-6. https://doi.org/10.1182/blood-2004-01-0107.Ono T., Mimuro J., Madoiwa S. et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood. 2006;107(2):528-34. https://doi.org/10.1182/blood-2005-03-1087.Ono T., Mimuro J., Madoiwa S. et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood. 2006;107(2):528-34. https://doi.org/10.1182/blood-2005-03-1087.Chen J., Fu X., Wang Y. et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood. 2010;115(3):706-12. https://doi.org/10.1182/blood-2009-03-213967.Chen J., Fu X., Wang Y. et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood. 2010;115(3):706-12. https://doi.org/10.1182/blood-2009-03-213967.Wang Y., Chen J., Ling M. et al. Hypochlorous acid generated by neutrophils inactivates ADAMTS13: an oxidative mechanism for regulating ADAMTS13 proteolytic activity during inflammation. J Biol Chem. 2015;290(3):1422-31. https://doi.org/10.1074/jbc.M114.599084.Wang Y., Chen J., Ling M. et al. Hypochlorous acid generated by neutrophils inactivates ADAMTS13: an oxidative mechanism for regulating ADAMTS13 proteolytic activity during inflammation. J Biol Chem. 2015;290(3):1422-31. https://doi.org/10.1074/jbc.M114.599084.Wong S.L., Wagner D.D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J. 2018;32(12):6258-370. https://doi.org/10.1096/fj.201800691R.Wong S.L., Wagner D.D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J. 2018;32(12):6258-370. https://doi.org/10.1096/fj.201800691R.Sorvillo N., Mizurini D.M., Coxon C. et al. Plasma peptidylarginine deiminase IV promotes VWF-platelet string formation and accelerates thrombosis after vessel injury. Circ Res. 2019;125(5):507-19. https://doi.org/10.1161/CIRCRESAHA.118.314571.Sorvillo N., Mizurini D.M., Coxon C. et al. Plasma peptidylarginine deiminase IV promotes VWF-platelet string formation and accelerates thrombosis after vessel injury. Circ Res. 2019;125(5):507-19. https://doi.org/10.1161/CIRCRESAHA.118.314571.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):844-7. https://doi.org/10.1111/jth.14768.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):844-7. https://doi.org/10.1111/jth.14768.Han H., Yang L., Liu R. et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020;58(7):1116-20. https://doi.org/10.1515/cclm-2020-0188.Han H., Yang L., Liu R. et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020;58(7):1116-20. https://doi.org/10.1515/cclm-2020-0188.Zuo Y., Yalavarthi S., Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999. https://doi.org/10.1172/jci.insight.138999.Zuo Y., Yalavarthi S., Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999. https://doi.org/10.1172/jci.insight.138999.Nicolai L., Leunig A., Brambs S. et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation. 2020;142(12):1176-89. https://doi.org/10.1161/CIRCULATIONAHA.120.048488.Nicolai L., Leunig A., Brambs S. et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation. 2020;142(12):1176-89. https://doi.org/10.1161/CIRCULATIONAHA.120.048488.Barnes B.J., Adrover J.M., Baxter-Stoltzfus A. et al. Targeting potential drivers of COVID-19: neutrophil extracellular traps. J Exp Med. 2020;217(6):e20200652. https://doi.org/10.1084/jem.20200652.Barnes B.J., Adrover J.M., Baxter-Stoltzfus A. et al. Targeting potential drivers of COVID-19: neutrophil extracellular traps. J Exp Med. 2020;217(6):e20200652. https://doi.org/10.1084/jem.20200652.Veras F.P., Pontelli M.C., Silva C.M. et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med. 2020;217(12):e20201129. https://doi.org/10.1084/jem.20201129.Veras F.P., Pontelli M.C., Silva C.M. et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med. 2020;217(12):e20201129. https://doi.org/10.1084/jem.20201129.Pfeiler S., Massberg S., Engelmann B. Biological basis and pathological relevance of microvascular thrombosis. Thromb Res. 2014;133(Suppl 1):S35-7. https://doi.org/10.1016/j.thromres.2014.03.016.Pfeiler S., Massberg S., Engelmann B. Biological basis and pathological relevance of microvascular thrombosis. Thromb Res. 2014;133(Suppl 1):S35-7. https://doi.org/10.1016/j.thromres.2014.03.016.Gould T.J., Vu T.T., Swystun L.L. et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and plateletindependent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977-84. https://doi.org/10.1161/ATVBAHA.114.304114.Gould T.J., Vu T.T., Swystun L.L. et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and plateletindependent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977-84. https://doi.org/10.1161/ATVBAHA.114.304114.Wang Y., Luo L., Braun O.O. et al. Neutrophil extracellular trap -microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci Rep. 2018;8(1):4020. https://doi.org/10.1038/s41598-018-22156-5.Wang Y., Luo L., Braun O.O. et al. Neutrophil extracellular trap -microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci Rep. 2018;8(1):4020. https://doi.org/10.1038/s41598-018-22156-5.Massberg S., Grahl L., von Bruehl M.-L. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16(8):887-96. https://doi.org/10.1038/nm.2184.Massberg S., Grahl L., von Bruehl M.-L. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16(8):887-96. https://doi.org/10.1038/nm.2184.Nakazawa D., Ishizu A. Immunothrombosis in severe COVID-19. EBioMedicine. 2020;59:102942. https://doi.org/10.1016/j.ebiom.2020.102942.Nakazawa D., Ishizu A. Immunothrombosis in severe COVID-19. EBioMedicine. 2020;59:102942. https://doi.org/10.1016/j.ebiom.2020.102942.Ladikou E.E., Sivaloganathan H., Milne K.M. et al. Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clin Med (Lond). 2020;20(5):e178-e182. https://doi.org/10.7861/clinmed.2020-0346.Ladikou E.E., Sivaloganathan H., Milne K.M. et al. Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clin Med (Lond). 2020;20(5):e178-e182. https://doi.org/10.7861/clinmed.2020-0346.Tiscia G.L., Favuzzi G., De Laurenzo A. et al. Reduction of ADAMTS13 levels predicts mortality in SARS-CoV-2 patients. TH Open. 2020;4(03):e203-e206. https://doi.org/10.1055/s-0040-1716379.Tiscia G.L., Favuzzi G., De Laurenzo A. et al. Reduction of ADAMTS13 levels predicts mortality in SARS-CoV-2 patients. TH Open. 2020;4(03):e203-e206. https://doi.org/10.1055/s-0040-1716379.Kanthi Y., Knight J.S., Zuo Y., Pinsky D.J. New (re) purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm. JCI Insight. 2020;5(14):e140971. https://doi.org/10.1172/jci.insight.140971.Kanthi Y., Knight J.S., Zuo Y., Pinsky D.J. New (re) purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm. JCI Insight. 2020;5(14):e140971. https://doi.org/10.1172/jci.insight.140971.Okamoto K., Tamura T., Sawatsubashi Y. Sepsis and disseminated intravascular coagulation. J Intensive Care. 2016;4:23. https://doi.org10.1186/s40560-016-0149-0.Okamoto K., Tamura T., Sawatsubashi Y. Sepsis and disseminated intravascular coagulation. J Intensive Care. 2016;4:23. https://doi.org10.1186/s40560-016-0149-0.Iba T., Ito T., Maruyama I. et al. Potential diagnostic markers for disseminated intravascular coagulation of sepsis. Blood Rev. 2016;30(2):149-55. https://doi.org/10.1016/j.blre.2015.10.002.Iba T., Ito T., Maruyama I. et al. Potential diagnostic markers for disseminated intravascular coagulation of sepsis. Blood Rev. 2016;30(2):149-55. https://doi.org/10.1016/j.blre.2015.10.002.Levi M., van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38-44. https://doi.org/10.1016/j.thromres.2016.11.007.Levi M., van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38-44. https://doi.org/10.1016/j.thromres.2016.11.007.Semeraro N., Ammollo C.T., Semeraro F., Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res. 2012;129(3):290-5. https://doi.org/10.1016/j.thromres.2011.10.013.Semeraro N., Ammollo C.T., Semeraro F., Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res. 2012;129(3):290-5. https://doi.org/10.1016/j.thromres.2011.10.013.Ikeda M., Matsumoto H., Ogura H. et al. Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. J Crit Care. 2018;43:48-53. https://doi.org/10.1016/j.jcrc.2017.07.049.Ikeda M., Matsumoto H., Ogura H. et al. Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. J Crit Care. 2018;43:48-53. https://doi.org/10.1016/j.jcrc.2017.07.049.Aibar J., Castro P., Espinosa G. et al. ADAMTS-13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome. Shock. 2015;43(6):556-62. https://doi.org/10.1097/SHK.0000000000000341.Aibar J., Castro P., Espinosa G. et al. ADAMTS-13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome. Shock. 2015;43(6):556-62. https://doi.org/10.1097/SHK.0000000000000341.Russwurm S., Vickers J., Meier-Hellmann A. et al. Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock. 2002;17(4):263-8. https://doi.org/10.1097/00024382-200204000-00004.Russwurm S., Vickers J., Meier-Hellmann A. et al. Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock. 2002;17(4):263-8. https://doi.org/10.1097/00024382-200204000-00004.Wang Y., Ouyang Y., Liu B. et al. Platelet activation and antiplatelet therapy in sepsis: A narrative review. Thromb Res. 2018;166:28-36. https://doi.org/10.1016/j.thromres.2018.04.007.Wang Y., Ouyang Y., Liu B. et al. Platelet activation and antiplatelet therapy in sepsis: A narrative review. Thromb Res. 2018;166:28-36. https://doi.org/10.1016/j.thromres.2018.04.007.Delabranche X., Stiel L., Severac F. et al. Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock. 2017;47(3):313-7. https://doi.org/10.1097/SHK.0000000000000719.Delabranche X., Stiel L., Severac F. et al. Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock. 2017;47(3):313-7. https://doi.org/10.1097/SHK.0000000000000719.Gupta A.K., Hasler P., Holzgreve W. et al. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol. 2005;66(11):1146-54. https://doi.org/10.1016/j.humimm.2005.11.003.Gupta A.K., Hasler P., Holzgreve W. et al. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol. 2005;66(11):1146-54. https://doi.org/10.1016/j.humimm.2005.11.003.Redman C.W., Sargent I. Placental debris, oxidative stress and pre-eclampsia. Placenta. 2000;21(7):597-602. https://doi.org/10.1053/plac.2000.0560.Redman C.W., Sargent I. Placental debris, oxidative stress and pre-eclampsia. Placenta. 2000;21(7):597-602. https://doi.org/10.1053/plac.2000.0560.Bouvier S., Mousty E., Fortier M. et al. Placenta-mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes. J Thromb Haemost. 2020;18(12):3371-80. https://doi.org/10.1111/jth.15105.Bouvier S., Mousty E., Fortier M. et al. Placenta-mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes. J Thromb Haemost. 2020;18(12):3371-80. https://doi.org/10.1111/jth.15105.Sargent I., Germain S., Sacks G. et al. Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol. 2003;59(2):153-60. https://doi.org/10.1016/s0165-0378(03)00044-5.Sargent I., Germain S., Sacks G. et al. Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol. 2003;59(2):153-60. https://doi.org/10.1016/s0165-0378(03)00044-5.Sacks G., Studena K., Sargent I., Redman C. CD11b expression on circulating neutrophils in pre-eclampsia. Clin Sci (Lond). 1997;93(2):187-8. https://doi.org/10.1042/cs0930187.Sacks G., Studena K., Sargent I., Redman C. CD11b expression on circulating neutrophils in pre-eclampsia. Clin Sci (Lond). 1997;93(2):187-8. https://doi.org/10.1042/cs0930187.Giaglis S., Stoikou M., Chowdhury C.S. et al. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front Immunol. 2016;7:565. https://doi.org/10.3389/fimmu.2016.00565.Giaglis S., Stoikou M., Chowdhury C.S. et al. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front Immunol. 2016;7:565. https://doi.org/10.3389/fimmu.2016.00565.Giaglis S., Stoikou M., Grimolizzi F. et al. Neutrophil migration into the placenta: Good, bad or deadly? Cell Adh Migr. 2016;10(1-2):208-25. https://doi.org/10.1080/19336918.2016.1148866.Giaglis S., Stoikou M., Grimolizzi F. et al. Neutrophil migration into the placenta: Good, bad or deadly? Cell Adh Migr. 2016;10(1-2):208-25. https://doi.org/10.1080/19336918.2016.1148866.Hahn S., Huppertz B., Holzgreve W. Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation? Placenta. 2005;26(7):515-26. https://doi.org/10.1016/j.placenta.2004.10.017.Hahn S., Huppertz B., Holzgreve W. Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation? Placenta. 2005;26(7):515-26. https://doi.org/10.1016/j.placenta.2004.10.017.Hahn S., Gupta A.K., Troeger C., Rusterholz C, Holzgreve W, editors. Disturbances in placental immunology: ready for therapeutic interventions? Springer Semin Immunopathol. 2006;27(4):477-93. https://doi.org/10.1007/s00281-006-0016-5.Hahn S., Gupta A.K., Troeger C., Rusterholz C, Holzgreve W, editors. Disturbances in placental immunology: ready for therapeutic interventions? Springer Semin Immunopathol. 2006;27(4):477-93. https://doi.org/10.1007/s00281-006-0016-5.Erpenbeck L., Chowdhury C.S., Zsengeller Z.K. et al. PAD4 deficiency decreases inflammation and susceptibility to pregnancy loss in a mouse model. Biol Reprod. 2016;95(6):132. https://doi.org/10.1095/biolreprod.116.140293.Erpenbeck L., Chowdhury C.S., Zsengeller Z.K. et al. PAD4 deficiency decreases inflammation and susceptibility to pregnancy loss in a mouse model. Biol Reprod. 2016;95(6):132. https://doi.org/10.1095/biolreprod.116.140293.Gupta S., Agarwal A., Banerjee J., Alvarez J.G. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol Surv. 2007;62(5):335-47. https://doi.org/10.1097/01.ogx.0000261644.89300.df.Gupta S., Agarwal A., Banerjee J., Alvarez J.G. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol Surv. 2007;62(5):335-47. https://doi.org/10.1097/01.ogx.0000261644.89300.df.Paszkowski T., Lagod L., Sikorsi R., Rola R. The role of oxidative stress in the pathogenesis of early pregnancy loss. Poland J Gynecol Invest. 2001;3(3):135-8.Paszkowski T., Lagod L., Sikorsi R., Rola R. The role of oxidative stress in the pathogenesis of early pregnancy loss. Poland J Gynecol Invest. 2001;3(3):135-8.Choi J.W., Im M.W., Pai S.H. Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci. 2002;32(3):257-63.Choi J.W., Im M.W., Pai S.H. Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci. 2002;32(3):257-63.Omeljaniuk W.J., Jabtonska E., Garley M. et al. Biomarkers of neutrophil extracellular traps (NETs) and nitric oxide-(NO)-dependent oxidative stress in women who miscarried. Sci Rep. 2020;10(1):13088. https://doi.org/10.1038/s41598-020-70106-x.Omeljaniuk W.J., Jabtonska E., Garley M. et al. Biomarkers of neutrophil extracellular traps (NETs) and nitric oxide-(NO)-dependent oxidative stress in women who miscarried. Sci Rep. 2020;10(1):13088. https://doi.org/10.1038/s41598-020-70106-x.Girardi G., Berman J., Redecha P. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644-54. https://doi.org/10.1172/JCI18817.Girardi G., Berman J., Redecha P. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644-54. https://doi.org/10.1172/JCI18817.Redecha P., Tilley R., Tencati M. et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody-induced fetal injury. Blood. 2007;110(7):2423-31. https://doi.org/10.1182/blood-2007-01-070631.Redecha P., Tilley R., Tencati M. et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody-induced fetal injury. Blood. 2007;110(7):2423-31. https://doi.org/10.1182/blood-2007-01-070631.Redecha P., Franzke C.-W., Ruf W. et al. Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J Clin Invest. 2008;118(10):3453-61. https://doi.org/10.1172/JCI36089.Redecha P., Franzke C.-W., Ruf W. et al. Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J Clin Invest. 2008;118(10):3453-61. https://doi.org/10.1172/JCI36089.Yalavarthi S., Gould T.J., Rao A.N. et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015;67(11):2990-3003. https://doi.org/10.1002/art.39247.Yalavarthi S., Gould T.J., Rao A.N. et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015;67(11):2990-3003. https://doi.org/10.1002/art.39247.Meng H., Yalavarthi S., Kanthi Y. et al. In vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheumatol. 2017;69(3):655-67. https://doi.org/10.1002/art.39938.Meng H., Yalavarthi S., Kanthi Y. et al. In vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheumatol. 2017;69(3):655-67. https://doi.org/10.1002/art.39938.Zhao J., Kim K.D., Yang X. et al. Hyper innate responses in neonates lead to increased morbidity and mortality after infection. Proc Natl Acad Sci U S A. 2008;105(21):7528-33. https://doi.org/10.1073/pnas.0800152105.Zhao J., Kim K.D., Yang X. et al. Hyper innate responses in neonates lead to increased morbidity and mortality after infection. Proc Natl Acad Sci U S A. 2008;105(21):7528-33. https://doi.org/10.1073/pnas.0800152105.Heinemann A.S., Pirr S., Fehlhaber B. et al. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 2017;31(3):1153-64. https://doi.org/10.1096/fj.201601083R.Heinemann A.S., Pirr S., Fehlhaber B. et al. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 2017;31(3):1153-64. https://doi.org/10.1096/fj.201601083R.Annane D., Bellissant E., Cavaillon J.-M. Septic shock. Lancet. 2005;365(9453):63-78. https://doi.org/10.1016/S0140-6736(04)17667-8.Annane D., Bellissant E., Cavaillon J.-M. Septic shock. Lancet. 2005;365(9453):63-78. https://doi.org/10.1016/S0140-6736(04)17667-8.Schouten M., Wiersinga W.J., Levi M., van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536-45. https://doi.org/10.1189/jlb.0607373.Schouten M., Wiersinga W.J., Levi M., van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536-45. https://doi.org/10.1189/jlb.0607373.Nourshargh S., Renshaw S.A., Imhof B.A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 2016;37(5):273-86. https://doi.org/10.1016/j.it.2016.03.006.Nourshargh S., Renshaw S.A., Imhof B.A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 2016;37(5):273-86. https://doi.org/10.1016/j.it.2016.03.006.Souto F.O., Alves-Filho J.C., Turato W.M. et al. Essential role of CCR2 in neutrophil tissue infiltration and multiple organ dysfunction in sepsis. Am J Respir Crit Care Med. 2011;183(2):234-42. https://doi.org/10.1164/rccm.201003-0416OC.Souto F.O., Alves-Filho J.C., Turato W.M. et al. Essential role of CCR2 in neutrophil tissue infiltration and multiple organ dysfunction in sepsis. Am J Respir Crit Care Med. 2011;183(2):234-42. https://doi.org/10.1164/rccm.201003-0416OC.Colon D.F., Wanderley C.W., Franchin M. et al. Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis. Crit Care. 2019;23(1):113. https://doi.org/10.1186/s13054-019-2407-8.Colon D.F., Wanderley C.W., Franchin M. et al. Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis. Crit Care. 2019;23(1):113. https://doi.org/10.1186/s13054-019-2407-8.Stiel C.U., Ebenebe C.U., Trochimiuk M. et al. Markers of NETosis do not predict neonatal early onset sepsis: a pilot study. Front Pediatr. 2020;7:555. https://doi.org/10.3389/fped.2019.00555.Stiel C.U., Ebenebe C.U., Trochimiuk M. et al. Markers of NETosis do not predict neonatal early onset sepsis: a pilot study. Front Pediatr. 2020;7:555. https://doi.org/10.3389/fped.2019.00555.Yost C.C., Schwertz H., Cody M.Jet al. Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest. 2016;126(10):3783-98. https://doi.org/10.1172/JCI83873.Yost C.C., Schwertz H., Cody M.Jet al. Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest. 2016;126(10):3783-98. https://doi.org/10.1172/JCI83873.Adly A.A., Ismail E.A., Andrawes N.G., El-Saadany M.A. Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis. Cytokine. 2014;65(2):184-91. https://doi.org/10.1016/j.cyto.2013.11.004.Adly A.A., Ismail E.A., Andrawes N.G., El-Saadany M.A. Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis. Cytokine. 2014;65(2):184-91. https://doi.org/10.1016/j.cyto.2013.11.004.Camicia G., Pozner R., de Larranaga G. Neutrophil extracellular traps in sepsis. Shock. 2014;42(4):286-94. https://doi.org/10.1097/SHK.0000000000000221.Camicia G., Pozner R., de Larranaga G. Neutrophil extracellular traps in sepsis. Shock. 2014;42(4):286-94. https://doi.org/10.1097/SHK.0000000000000221.

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