akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2022.293akusherstvo-1319Research ArticleREVIEW ARTICLEНАУЧНЫЙ ОБЗОРAnticoagulants: dose control methods and inhibitorsАнтикоагулянты: методы контроля дозы и ингибиторыhttps://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: 6506003478Researcher 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 Clinical Institute of Children’s Health

Scopus Author ID: 6506003478Researcher 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., доцент кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова; врач акушер-гинеколог отделения абдоминальной хирургии и онкологии 2

119991 Москва, ул. Большая Пироговская, д. 2, стр. 4119991 Москва, Абрикосовский пер., д. 2

Ekaterina V. Slukhanchuk – MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 1199912 Abrikosovskiy Lane, Moscow 119991

ekaterina@ginekologhirurg.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: 57194547147Researcher 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: 57194547147Researcher 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, ассистент кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова

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

Maria V. Tretyakova – MD, PhD, Obstetrician-Gynecologist, Assistant, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

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

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

Цибизова Валентина Ивановна – к.м.н., врач акушер-гинеколог НИЛ оперативной гинекологии Института перинатологии и педиатрии, врач отделения функциональной ультразвуковой диагностики

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

2 Akkuratova Str., Saint Petersburg 197341

https://orcid.org/0000-0003-0764-4477ГашимоваН. Р.GashimovaN. R.

Гашимова Нилуфар Рамиль кызы – аспирант кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова

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

Nilufar R. Gashimova – MD, Postgraduate Student, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

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

https://orcid.org/0000-0003-2245-2852НакаидзеИ. А.NakaidzeI. A.

Накаидзе Инга Александровна – аспирант кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова

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

Inga A. Nakaidze – MD, Postgraduate Student, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health

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

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

Элалами Исмаил – д.м.н., профессор кафедры акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова; профессор медицинского Университета Сорбонны; директор гематологии Центра Тромбозов

Scopus Author ID: 7003652413Researcher ID: AAC-96952019.

119991 Москва, ул. Большая Пироговская, д. 2, стр. 475006 Париж, Улица медицинского факультета, д. 1275020 Париж, Китайская улица, д. 4

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

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

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 11999112 Rue de l’Ecole de Medecine, Paris 750064 Rue de la Chine, Paris 75020

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; профессор гематологии, зав. лабораторией гематологии факультета биологических и фармацевтических наук Университета Монпелье и Университетской больницы Нима

Scopus Author ID: 7005114260Researcher ID: AAA-2923-2019

119991 Москва, ул. Большая Пироговская, д. 2, стр. 434090 Монпелье, ул. Огюста Бруссоне, д. 163

Jean-Christophe Gris – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health; Professor of Haematology, Head of the Laboratory of Haematology, Faculty of Biological and Pharmaceutical Sciences, Montpellier University and University Hospital of Nimes

Scopus Author ID: 7005114260Researcher ID: AAA-2923-2019

2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991163 Rue Auguste Broussonnet, Montpellier 34090

https://orcid.org/0000-0001-7415-4633МакацарияА. Д.MakatsariyaA. D.

Макацария Александр Давидович – д.м.н., профессор, академик РАН, зав. кафедрой акушерства и гинекологии Клинического института детского здоровья имени Н.Ф. Филатова

Scopus Author ID: 57222220144Researcher ID: M-5660-2016

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

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

Scopus Author ID: 57222220144Researcher ID: M-5660-2016.

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

ФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияSechenov UniversityRussian FederationФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет); ФГБНУ «Российский научный центр хирургии имени академика Б.В. Петровского»РоссияSechenov University; Petrovsky National Research Centre of SurgeryRussian FederationФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения Российской ФедерацииРоссияAlmazov National Medical Research Centre, Health Ministry of Russian FederationRussian 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 MontpellierFrance202219052022162158175Copyright © Bitsadze V.O., Slukhanchuk E.V., Khizroeva J.K., Tretyakova M.V., Tsibizova V.I., Gashimova N.R., Nakaidze I.A., Elalamy I., Gris J., Makatsariya A.D., 20222022Бицадзе В.О., Слуханчук Е.В., Хизроева Д.Х., Третьякова М.В., Цибизова В.И., Гашимова Н.Р., Накаидзе И.А., Элалами И., Гри Ж., Макацария А.Д.Bitsadze V.O., Slukhanchuk E.V., Khizroeva J.K., Tretyakova M.V., Tsibizova V.I., Gashimova N.R., Nakaidze I.A., Elalamy I., Gris J., Makatsariya A.D.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/1319

These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.

Антикоагулянты – крайне востребованные препараты в наши дни. Они используются в качестве профилактики тромбоэмболических осложнений при различных заболеваниях и состояниях в общетерапевтической практике, в кардиологии, неврологии, а также в акушерстве при ведении беременности высокого риска. Актуальность вопроса грамотного использования антикоагулянтов вышла на передний план в связи с появлением нового заболевания – коронавирусной инфекции COVID-19 и ее серьезных осложнений в виде развития тромботического шторма, при котором своевременное назначение антикоагулянтной терапии является залогом успеха терапии. Риск кровотечения следует учитывать при использовании любых антикоагулянтов. Пожилой возраст, нарушение функции почек и одновременный прием антиагрегантов являются общими факторами риска кровотечений. При этом лишь для антагонистов витамина К и гепарина имеются специфические антидоты – витамин К и протамин, соответственно. Ингибиторы остальных антикоагулянтов универсальны – это неактивированный или активированный концентрат протромбинового комплекса и рекомбинантный фактор VIIa. Гемодиализ эффективно снижает концентрацию дабигатрана, активированный уголь эффективен в случае недавнего перорального приема липофильных препаратов. Исследования новых антидотов имеющихся в настоящее время антикоагулянтов продолжаются, также как испытания новых видов антикоагулянтов, обладающих достаточной эффективностью в профилактике и лечении тромбоэмболических осложнений при минимальном риске геморрагических. Основным противопоказанием к использованию антикоагулянтов является незнание врачом механизмов действия препарата и возможности подавления его эффекта.

кровотечениеантидотпрямые ингибиторы тромбинаингибиторы Xa фактораварфарингепариннизкомолекулярные гепариныантикоагулянтыbleedingantidotedirect thrombin inhibitorsfactor Xa inhibitorswarfarinheparinlow molecular weight heparinsanticoagulantsОбзор выполнен при финансовой поддержке РФФИ в рамках научного проекта РФФИ №20-04-60274.The review was funded by RFBR, project number 20-04-60274.ReferencesLopes L., Spencer F.A., Neumann I. et al. Bleeding risk in atrial fibrillation patients taking vitamin K antagonists: systematic review and metaanalysis. Clin Pharmacol Ther. 2013;94(3):367–75. https://doi.org/10.1038/clpt.2013.99.Lopes L., Spencer F.A., Neumann I. et al. Bleeding risk in atrial fibrillation patients taking vitamin K antagonists: systematic review and metaanalysis. Clin Pharmacol Ther. 2013;94(3):367–75. https://doi.org/10.1038/clpt.2013.99.Chai-Adisaksopha C., Crowther M., Isayama T., Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450–8. https://doi.org/10.1182/blood-2014-07-590323.Chai-Adisaksopha C., Crowther M., Isayama T., Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450–8. https://doi.org/10.1182/blood-2014-07-590323.Garcia D.A., Baglin T.P., Weitz J.I., Samama M.M. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S–e43S. https://doi.org/10.1378/chest.11-2291.Garcia D.A., Baglin T.P., Weitz J.I., Samama M.M. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S–e43S. https://doi.org/10.1378/chest.11-2291.Buller H.R., Davidson B.L., Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140(11):867–73. https://doi.org/10.7326/0003-4819-140-11-200406010-00007.Buller H.R., Davidson B.L., Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140(11):867–73. https://doi.org/10.7326/0003-4819-140-11-200406010-00007.Beyer-Westendorf J., Michalski F., Tittl L. et al. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol. 2016;3(10):e480–e488. https://doi.org/10.1016/S2352-3026(16)30111-9.Beyer-Westendorf J., Michalski F., Tittl L. et al. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol. 2016;3(10):e480–e488. https://doi.org/10.1016/S2352-3026(16)30111-9.Gong I.Y., Schwarz U.I., Crown N. et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PloS One. 2011;6(11):e27808. https://doi.org/10.1371/journal.pone.0027808.Gong I.Y., Schwarz U.I., Crown N. et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PloS One. 2011;6(11):e27808. https://doi.org/10.1371/journal.pone.0027808.Pirmohamed M., Burnside G., Eriksson N. et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369(24):2294– 303. https://doi.org/10.1056/NEJMoa1311386.Pirmohamed M., Burnside G., Eriksson N. et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369(24):2294– 303. https://doi.org/10.1056/NEJMoa1311386.Hirsh J., Anand S.S., Halperin J.L., Fuster V. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;103(24):2994–3018. https://doi.org/10.1161/01.cir.103.24.2994.Hirsh J., Anand S.S., Halperin J.L., Fuster V. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;103(24):2994–3018. https://doi.org/10.1161/01.cir.103.24.2994.Olsson S.B., Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–8. https://doi.org/10.1016/s0140-6736(03)14841-6.Olsson S.B., Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691–8. https://doi.org/10.1016/s0140-6736(03)14841-6.Stangier J., Rathgen K., Stahle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. https://doi.org/10.1111/j.1365-2125.2007.02899.x.Stangier J., Rathgen K., Stahle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. https://doi.org/10.1111/j.1365-2125.2007.02899.x.Eriksson B.I., Dahl O.E., Huo M.H. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). Thromb Haemost. 2011;105(4):721–9. https://doi.org/10.1160/TH10-10-0679.Eriksson B.I., Dahl O.E., Huo M.H. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). Thromb Haemost. 2011;105(4):721–9. https://doi.org/10.1160/TH10-10-0679.Eriksson B., Dahl O., Rosencher N. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178–85. https://doi.org/10.1111/j.1538-7836.2007.02748.x.Eriksson B., Dahl O., Rosencher N. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178–85. https://doi.org/10.1111/j.1538-7836.2007.02748.x.Schulman S., Kearon C., Kakkar A.K. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52. https://doi.org/10.1056/NEJMoa0906598.Schulman S., Kearon C., Kakkar A.K. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52. https://doi.org/10.1056/NEJMoa0906598.Schulman S., Kearon C., Kakkar A.K. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–18. https://doi.org/10.1056/NEJMoa1113697.Schulman S., Kearon C., Kakkar A.K. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–18. https://doi.org/10.1056/NEJMoa1113697.Connolly S.J., Ezekowitz M.D., Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. https://doi.org/10.1056/NEJMoa0905561.Connolly S.J., Ezekowitz M.D., Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. https://doi.org/10.1056/NEJMoa0905561.Samama M.M. The mechanism of action of rivaroxaban – an oral, direct Factor Xa inhibitor – compared with other anticoagulants. Thromb Res. 2011;127(6):497–504. https://doi.org/10.1016/j.thromres.2010.09.008.Samama M.M. The mechanism of action of rivaroxaban – an oral, direct Factor Xa inhibitor – compared with other anticoagulants. Thromb Res. 2011;127(6):497–504. https://doi.org/10.1016/j.thromres.2010.09.008.Kakkar A.K., Brenner B., Dahl O.E. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31–9. https://doi.org/10.1016/S0140-6736(08)60880-6.Kakkar A.K., Brenner B., Dahl O.E. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31–9. https://doi.org/10.1016/S0140-6736(08)60880-6.Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in nonvalvular Atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638.Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in nonvalvular Atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638.Lassen M.R., Raskob G.E., Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807–15. https://doi.org/10.1016/S0140-6736(09)62125-5..Lassen M.R., Raskob G.E., Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807–15. https://doi.org/10.1016/S0140-6736(09)62125-5..Lassen M.R., Gallus A., Raskob G.E. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487–98. https://doi.org/10.1056/NEJMoa1006885.Lassen M.R., Gallus A., Raskob G.E. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487–98. https://doi.org/10.1056/NEJMoa1006885.Granger C.B., Alexander J.H., McMurray J.J. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039.Granger C.B., Alexander J.H., McMurray J.J. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039.Agnelli G., Buller H.R., Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808. https://doi.org/10.1056/NEJMoa1302507.Agnelli G., Buller H.R., Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808. https://doi.org/10.1056/NEJMoa1302507.Hokusai-VTE Investigators; Buller H.R., Decousus H., Grosso M.A. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15. https://doi.org/10.1056/NEJMoa1306638.Hokusai-VTE Investigators; Buller H.R., Decousus H., Grosso M.A. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15. https://doi.org/10.1056/NEJMoa1306638.Giugliano R.P., Ruff C.T., Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104. https://doi.org/10.1056/NEJMoa1310907.Giugliano R.P., Ruff C.T., Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104. https://doi.org/10.1056/NEJMoa1310907.Weitz J.I., Chan N.C. Advances in antithrombotic therapy. Arterioscler Thromb Vasc Biol. 2019;39(1):7–12. https://doi.org/10.1161/ ATVBAHA.118.310960.Weitz J.I., Chan N.C. Advances in antithrombotic therapy. Arterioscler Thromb Vasc Biol. 2019;39(1):7–12. https://doi.org/10.1161/ ATVBAHA.118.310960.Pirlog A.-M., Pirlog C.D., Maghiar M.A. DOACs vs vitamin K antagonists: a comparison of phase III clinical trials and a prescriber support tool. Open Access Maced J Med Sci. 2019;7(7):1226–32. https://doi.org/10.3889/oamjms.2019.289.Pirlog A.-M., Pirlog C.D., Maghiar M.A. DOACs vs vitamin K antagonists: a comparison of phase III clinical trials and a prescriber support tool. Open Access Maced J Med Sci. 2019;7(7):1226–32. https://doi.org/10.3889/oamjms.2019.289.Hellenbart E.L., Faulkenberg K.D., Finks S.W. Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:325–42. https://doi.org/10.2147/VHRM.S121661.Hellenbart E.L., Faulkenberg K.D., Finks S.W. Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:325–42. https://doi.org/10.2147/VHRM.S121661.Wheeler A.P., Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol. 2016;9(7):629–37. https://doi.org/10.1080/17474086.2016.1191944.Wheeler A.P., Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol. 2016;9(7):629–37. https://doi.org/10.1080/17474086.2016.1191944.Gomez K., Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14(6):1183–9. https://doi.org/10.1111/j.1365-2516.2008.01667.x.Gomez K., Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14(6):1183–9. https://doi.org/10.1111/j.1365-2516.2008.01667.x.Preis M., Hirsch J., Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood. 2017;129(9):1210–5. https://doi.org/10.1182/blood-2016-09742262.Preis M., Hirsch J., Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood. 2017;129(9):1210–5. https://doi.org/10.1182/blood-2016-09742262.Georgi B., Mielke J., Chaffin M. et al. Leveraging human genetics to estimate clinical risk reductions achievable by inhibiting factor XI. Stroke. 2019;50(11):3004–12. https://doi.org/10.1161/STROKEAHA.119.026545.Georgi B., Mielke J., Chaffin M. et al. Leveraging human genetics to estimate clinical risk reductions achievable by inhibiting factor XI. Stroke. 2019;50(11):3004–12. https://doi.org/10.1161/STROKEAHA.119.026545.Mavromanoli A.C., Barco S., Konstantinides S.V. Antithrombotics and new interventions for venous thromboembolism: Exploring possibilities beyond factor IIa and factor Xa inhibition. Res Pract Thromb Haemost. 2021;5(4):10.1002/rth2.12509. https://doi.org/10.1002/rth2.12509.Mavromanoli A.C., Barco S., Konstantinides S.V. Antithrombotics and new interventions for venous thromboembolism: Exploring possibilities beyond factor IIa and factor Xa inhibition. Res Pract Thromb Haemost. 2021;5(4):10.1002/rth2.12509. https://doi.org/10.1002/rth2.12509.Yau J.W., Liao P., Fredenburgh J.C. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood. 2014;123(13):2102–7. https://doi.org/10.1182/blood-2013-12-540872.Yau J.W., Liao P., Fredenburgh J.C. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood. 2014;123(13):2102–7. https://doi.org/10.1182/blood-2013-12-540872.Crosby J.R., Marzec U., Revenko A.S. et al. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol. 2013;33(7):1670–8. https://doi.org/10.1161/ATVBAHA.113.301282.Crosby J.R., Marzec U., Revenko A.S. et al. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Thromb Vasc Biol. 2013;33(7):1670–8. https://doi.org/10.1161/ATVBAHA.113.301282.Buller H.R., Bethune C., Bhanot S. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–40. https://doi.org/10.1056/NEJMoa1405760.Buller H.R., Bethune C., Bhanot S. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–40. https://doi.org/10.1056/NEJMoa1405760.Eikelboom J., Floege J., Thadhani R. et al. Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target. Kidney Int. 2021;100(6):1199–207. https://doi.org/10.1016/j.kint.2021.08.028.Eikelboom J., Floege J., Thadhani R. et al. Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target. Kidney Int. 2021;100(6):1199–207. https://doi.org/10.1016/j.kint.2021.08.028.Verhamme P., Yi B.A., Segers A. et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385(7):609–17. https://doi.org/10.1056/NEJMoa2105872.Verhamme P., Yi B.A., Segers A. et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385(7):609–17. https://doi.org/10.1056/NEJMoa2105872.Weitz J.I., Bauersachs R., Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA. 2020;323(2):130–9. https://doi.org/10.1001/jama.2019.20687.Weitz J.I., Bauersachs R., Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA. 2020;323(2):130–9. https://doi.org/10.1001/jama.2019.20687.Eikelboom J.W., Connolly S.J., Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–14. https://doi.org/10.1056/NEJMoa1300615.Eikelboom J.W., Connolly S.J., Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–14. https://doi.org/10.1056/NEJMoa1300615.Jaffer I.H., Stafford A.R., Fredenburgh J.C. et al. Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation. J Am Heart Assoc. 2015;4(8):e002322. https://doi.org/10.1161/JAHA.115.002322.Jaffer I.H., Stafford A.R., Fredenburgh J.C. et al. Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation. J Am Heart Assoc. 2015;4(8):e002322. https://doi.org/10.1161/JAHA.115.002322.Bethune C., Walsh M., Jung B. et al. Pharmacokinetics and pharmacodynamics of Ionis-FXIRx, an antisense inhibitor of factor XI, in patients with end-stage renal disease on hemodialysis. Blood. 2017;130(Suppl 1):1116. https://doi.org/10.1182/BLOOD.V130.SUPPL_1.1116.1116.Bethune C., Walsh M., Jung B. et al. Pharmacokinetics and pharmacodynamics of Ionis-FXIRx, an antisense inhibitor of factor XI, in patients with end-stage renal disease on hemodialysis. Blood. 2017;130(Suppl 1):1116. https://doi.org/10.1182/BLOOD.V130.SUPPL_1.1116.1116.Kearon C., Akl E.A., Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315–52. https://doi.org/10.1016/j.chest.2015.11.026.Kearon C., Akl E.A., Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315–52. https://doi.org/10.1016/j.chest.2015.11.026.Tripodi A. D-dimer testing in laboratory practice. Clin Chem. 2011;57(9):1256–62. https://doi.org/10.1373/clinchem.2011.166249.Tripodi A. D-dimer testing in laboratory practice. Clin Chem. 2011;57(9):1256–62. https://doi.org/10.1373/clinchem.2011.166249.Palareti G., Cosmi B., Legnani C. et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355(17):1780–9. https://doi.org/10.1056/NEJMoa054444.Palareti G., Cosmi B., Legnani C. et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355(17):1780–9. https://doi.org/10.1056/NEJMoa054444.Douketis J., Tosetto A., Marcucci M. et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med. 2010;153(8):523–31. https://doi.org/10.7326/0003-4819-153-8-201010190-00009.Douketis J., Tosetto A., Marcucci M. et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med. 2010;153(8):523–31. https://doi.org/10.7326/0003-4819-153-8-201010190-00009.Palareti G., Cosmi B., Legnani C. et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196–203. https://doi.org/10.1182/blood-2014-01-548065.Palareti G., Cosmi B., Legnani C. et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196–203. https://doi.org/10.1182/blood-2014-01-548065.Rodger M.A., Kahn S.R., Wells P.S. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417–26. https://doi.org/10.1503/cmaj.080493.Rodger M.A., Kahn S.R., Wells P.S. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417–26. https://doi.org/10.1503/cmaj.080493.Douxfils J., Gosselin R.C. Laboratory assessment of direct oral anticoagulants. Semin Thromb Hemost. 2017;43(3):277–90. https://doi.org/10.1055/s-0036-1597296.Douxfils J., Gosselin R.C. Laboratory assessment of direct oral anticoagulants. Semin Thromb Hemost. 2017;43(3):277–90. https://doi.org/10.1055/s-0036-1597296.Schulman S., Kearon C., Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x.Schulman S., Kearon C., Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x.Kaatz S., Ahmad D., Spyropoulos A., Schulman S., Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119–26. https://doi.org/10.1111/jth.13140.Kaatz S., Ahmad D., Spyropoulos A., Schulman S., Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119–26. https://doi.org/10.1111/jth.13140.Douketis J.D., Arneklev K., Goldhaber S.Z. et al. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med. 2006;166(8):853–9. https://doi.org/10.1001/archinte.166.8.853.Douketis J.D., Arneklev K., Goldhaber S.Z. et al. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med. 2006;166(8):853–9. https://doi.org/10.1001/archinte.166.8.853.Schulman S., Beyth R.J., Kearon C., Levine M.N. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6):257S–298S. https://doi.org/10.1378/chest.08-0674.Schulman S., Beyth R.J., Kearon C., Levine M.N. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6):257S–298S. https://doi.org/10.1378/chest.08-0674.Crowther M., Lim W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr Opin Pulm Med. 2007;13(5):409– 13. https://doi.org/10.1097/MCP.0b013e328216430d.Crowther M., Lim W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr Opin Pulm Med. 2007;13(5):409– 13. https://doi.org/10.1097/MCP.0b013e328216430d.Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators; Yusuf S., Mehta S.R., Chrolavicius S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464–76. https://doi.org/10.1056/NEJMoa055443.Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators; Yusuf S., Mehta S.R., Chrolavicius S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464–76. https://doi.org/10.1056/NEJMoa055443.Yusuf S., Mehta S.R., Chrolavicius S. et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519–30. https://doi.org/10.1001/jama.295.13.joc60038.Yusuf S., Mehta S.R., Chrolavicius S. et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519–30. https://doi.org/10.1001/jama.295.13.joc60038.Turpie A.G., Bauer K.A., Eriksson B.I., Lassen M.R. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833–40. https://doi.org/10.1001/archinte.162.16.1833.Turpie A.G., Bauer K.A., Eriksson B.I., Lassen M.R. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833–40. https://doi.org/10.1001/archinte.162.16.1833.Reilly P.A., Lehr T., Haertter S. et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–8. https://doi.org/10.1016/j.jacc.2013.07.104.Reilly P.A., Lehr T., Haertter S. et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–8. https://doi.org/10.1016/j.jacc.2013.07.104.Connolly S.J., Wallentin L., Ezekowitz M.D. et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237–43. https://doi.org/10.1161/CIRCULATIONAHA.112.001139.Connolly S.J., Wallentin L., Ezekowitz M.D. et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237–43. https://doi.org/10.1161/CIRCULATIONAHA.112.001139.Dans A.L., Connolly S.J., Wallentin L. et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127(5):634–40. https://doi.org/10.1161/CIRCULATIONAHA.112.115386.Dans A.L., Connolly S.J., Wallentin L. et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127(5):634–40. https://doi.org/10.1161/CIRCULATIONAHA.112.115386.Halperin J.L., Halperin JL, Wojdyla D. et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130(2):138–46. https://doi.org/10.1161/CIRCULATIONAHA.113.005008.Halperin J.L., Halperin JL, Wojdyla D. et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130(2):138–46. https://doi.org/10.1161/CIRCULATIONAHA.113.005008.Crowther M.A., Douketis J.D., Schnurr T. et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med. 2002;137(4):251–4. https://doi.org/10.7326/0003-4819-137-4-200208200-00009.Crowther M.A., Douketis J.D., Schnurr T. et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med. 2002;137(4):251–4. https://doi.org/10.7326/0003-4819-137-4-200208200-00009.DeZee K.J., Shimeall W.T., Douglas K.M. et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. 2006;166(4):391–7. https://doi.org/10.1001/.391.DeZee K.J., Shimeall W.T., Douglas K.M. et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. 2006;166(4):391–7. https://doi.org/10.1001/.391.Watson H.G., Baglin T., Laidlaw S.L. et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115(1):145–9. https://doi.org/10.1046/j.1365-2141.2001.03070.x.Watson H.G., Baglin T., Laidlaw S.L. et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115(1):145–9. https://doi.org/10.1046/j.1365-2141.2001.03070.x.Holbrook A., Schulman S., Witt D.M. et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S– e184S. https://doi.org/10.1378/chest.11-2295.Holbrook A., Schulman S., Witt D.M. et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S– e184S. https://doi.org/10.1378/chest.11-2295.Makris M., Greaves M., Phillips W.S. et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77(3):477–80.Makris M., Greaves M., Phillips W.S. et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77(3):477–80.Holland .L, Warkentin T.E., Refaai M. et al. Suboptimal effect of a threefactor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6):1171–7. https://doi.org/10.1111/j.1537-2995.2008.02080.x.Holland .L, Warkentin T.E., Refaai M. et al. Suboptimal effect of a threefactor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6):1171–7. https://doi.org/10.1111/j.1537-2995.2008.02080.x.Dentali F., Marchesi C., Pierfranceschi M.G. et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106(3):429–38. https://doi.org/10.1160/TH11-01-0052.Dentali F., Marchesi C., Pierfranceschi M.G. et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106(3):429–38. https://doi.org/10.1160/TH11-01-0052.Nishijima D.K., Dager W.E., Schrot R.J., Holmes J.F. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17(3):244– 51. https://doi.org/10.1111/j.1553-2712.2010.00666.x.Nishijima D.K., Dager W.E., Schrot R.J., Holmes J.F. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17(3):244– 51. https://doi.org/10.1111/j.1553-2712.2010.00666.x.Pinner N.A., Hurdle A.C., Oliphant C. et al. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg. 2010;74(6):631–5. https://doi.org/10.1016/j.wneu.2010.06.030.Pinner N.A., Hurdle A.C., Oliphant C. et al. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg. 2010;74(6):631–5. https://doi.org/10.1016/j.wneu.2010.06.030.Levi M., Levy J.H., Andersen H.F., Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–800. https://doi.org/10.1056/NEJMoa1006221.Levi M., Levy J.H., Andersen H.F., Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–800. https://doi.org/10.1056/NEJMoa1006221.Wojcik C., Schymik M.L., Cure E.G. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009;2(4):217–25. https://doi.org/10.1007/s12245-009-0125-8.Wojcik C., Schymik M.L., Cure E.G. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009;2(4):217–25. https://doi.org/10.1007/s12245-009-0125-8.Pai M., Crowther M.A. Neutralization of heparin activity. Handb Exp Pharmacol. 2012;(207):265-77. https://doi.org/10.1007/978-3-64223056-1_11.Pai M., Crowther M.A. Neutralization of heparin activity. Handb Exp Pharmacol. 2012;(207):265-77. https://doi.org/10.1007/978-3-64223056-1_11.van Veen J.J., Maclean R.M., Hampton K.K. et al. Protamine reversal of low molecular weight heparin: clinically effective? Blood Coagul Fibrinolysis. 2011;22(7):565–70. https://doi.org/10.1097/MBC.0b013e3283494b3c.van Veen J.J., Maclean R.M., Hampton K.K. et al. Protamine reversal of low molecular weight heparin: clinically effective? Blood Coagul Fibrinolysis. 2011;22(7):565–70. https://doi.org/10.1097/MBC.0b013e3283494b3c.Nybo M., Madsen J.S. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103(2):192–6. https://doi.org/10.1111/j.1742-7843.2008.00274.x.Nybo M., Madsen J.S. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103(2):192–6. https://doi.org/10.1111/j.1742-7843.2008.00274.x.Horrow J.C. Protamine: a review of its toxicity. Anesth Analg. 1985;64(3):348–61.Horrow J.C. Protamine: a review of its toxicity. Anesth Analg. 1985;64(3):348–61.Bakchoul T., Zollner H., Amiral J. et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013;121(15):2821–7. https://doi.org/10.1182/blood-2012-10-460691.Bakchoul T., Zollner H., Amiral J. et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013;121(15):2821–7. https://doi.org/10.1182/blood-2012-10-460691.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.Chan S., Kong M., Minning D. et al. Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin. J Thromb Haemost. 2003;1(4):760–5. https://doi.org/10.1046/j.1538-7836.2003.00101.x.Chan S., Kong M., Minning D. et al. Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin. J Thromb Haemost. 2003;1(4):760–5. https://doi.org/10.1046/j.1538-7836.2003.00101.x.Lauritzen B., Hedner U., Johansen P. et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost. 2008;6(5):804–11. https://doi.org/10.1111/j.1538-7836.2008.02933.x.Lauritzen B., Hedner U., Johansen P. et al. Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats. J Thromb Haemost. 2008;6(5):804–11. https://doi.org/10.1111/j.1538-7836.2008.02933.x.Bijsterveld N.R., Moons A.H., Boekholdt S.M. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–4. https://doi.org/10.1161/01.cir.0000038501.87442.02.Bijsterveld N.R., Moons A.H., Boekholdt S.M. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–4. https://doi.org/10.1161/01.cir.0000038501.87442.02.Bijsterveld N.R., Vink R., van Aken B.E. et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol. 2004;124(5):653–8. https://doi.org/10.1111/j.1365-2141.2003.04811.x.Bijsterveld N.R., Vink R., van Aken B.E. et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol. 2004;124(5):653–8. https://doi.org/10.1111/j.1365-2141.2003.04811.x.Firozvi K., Deveras R.A.E., Kessler C.M. Reversal of low-molecular-weight heparin-induced bleeding in patients with pre-existing hypercoagulable states with human recombinant activated factor VII concentrate. Am J Hematol. 2006;81(8):582–9. https://doi.org/0.1002/ajh.2065.Firozvi K., Deveras R.A.E., Kessler C.M. Reversal of low-molecular-weight heparin-induced bleeding in patients with pre-existing hypercoagulable states with human recombinant activated factor VII concentrate. Am J Hematol. 2006;81(8):582–9. https://doi.org/0.1002/ajh.2065.Nagler M., Haslauer M., Wuillemin W.A. Fondaparinux – data on efficacy and safety in special situations. Thromb Res. 2012;129(4):407–17. https://doi.org/10.1016/j.thromres.2011.10.037.Nagler M., Haslauer M., Wuillemin W.A. Fondaparinux – data on efficacy and safety in special situations. Thromb Res. 2012;129(4):407–17. https://doi.org/10.1016/j.thromres.2011.10.037.Gerotziafas G.T., Depasse F., Chakroun T. et al. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb Haemost. 2004;91(3):531–7. https://doi.org/10.1160/TH03-07-0483.Gerotziafas G.T., Depasse F., Chakroun T. et al. Recombinant factor VIIa partially reverses the inhibitory effect of fondaparinux on thrombin generation after tissue factor activation in platelet rich plasma and whole blood. Thromb Haemost. 2004;91(3):531–7. https://doi.org/10.1160/TH03-07-0483.Lisman T., Bijsterveld N., Adelmeijer J. et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb Haemost. 2003;1(11):2368–73. https://doi.org/10.1046/j.1538-7836.2003.00536.x.Lisman T., Bijsterveld N., Adelmeijer J. et al. Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb Haemost. 2003;1(11):2368–73. https://doi.org/10.1046/j.1538-7836.2003.00536.x.Akwaa F., Spyropoulos A.C. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med. 2013;15(3):288–98. https://doi.org/10.1007/s11936013-0238-5.Akwaa F., Spyropoulos A.C. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med. 2013;15(3):288–98. https://doi.org/10.1007/s11936013-0238-5.van Ryn J., Stangier J., Haertter S. et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–27. https://doi.org/10.1160/TH09-11-0758.van Ryn J., Stangier J., Haertter S. et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–27. https://doi.org/10.1160/TH09-11-0758.Stangier J., Rathgen K., Stahle H., Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68. https://doi.org/10.2165/11318170-000000000-00000.Stangier J., Rathgen K., Stahle H., Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68. https://doi.org/10.2165/11318170-000000000-00000.Khadzhynov D., Wagner F., Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605. https://doi.org/10.1160/TH12-08-0573.Khadzhynov D., Wagner F., Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605. https://doi.org/10.1160/TH12-08-0573.Zhou W., Schwarting S., Illanes S. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594–9. https://doi.org/10.1161/STROKEAHA.111.624650.Zhou W., Schwarting S., Illanes S. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594–9. https://doi.org/10.1161/STROKEAHA.111.624650.Eerenberg E.S., Kamphuisen P.W., Sijpkens M.K. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9. https://doi.org/10.1161/CIRCULATIONAHA.111.029017.Eerenberg E.S., Kamphuisen P.W., Sijpkens M.K. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9. https://doi.org/10.1161/CIRCULATIONAHA.111.029017.Marlu R., Hodaj E., Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108(2):217–24. https://doi.org/10.1160/TH12-03-0179.Marlu R., Hodaj E., Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108(2):217–24. https://doi.org/10.1160/TH12-03-0179.Dager W.E., Gosselin R.C., Roberts A.J. Reversing dabigatran in lifethreatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41(5):e42–6. https://doi.org/10.1097/CCM.0b013e31827caaa3.Dager W.E., Gosselin R.C., Roberts A.J. Reversing dabigatran in lifethreatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41(5):e42–6. https://doi.org/10.1097/CCM.0b013e31827caaa3.Schulman S., Ritchie B., Goy J.K. et al. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol. 2014;164(2):308–10. https://doi.org/10.1111/bjh.12620.Schulman S., Ritchie B., Goy J.K. et al. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol. 2014;164(2):308–10. https://doi.org/10.1111/bjh.12620.van Ryn J., Schurer J., Kink-Eiband M., Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood. 2011;118(21):2316. https://doi.org/10.1182/blood.V118.21.2316.2316.van Ryn J., Schurer J., Kink-Eiband M., Clemens A. The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood. 2011;118(21):2316. https://doi.org/10.1182/blood.V118.21.2316.2316.Pollack C.V., Reilly P.A., van Ryn J. et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431–41. https://doi.org/10.1056/NEJMoa1707278.Pollack C.V., Reilly P.A., van Ryn J. et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017;377(5):431–41. https://doi.org/10.1056/NEJMoa1707278.Zhang D., Frost C.E., He K. et al. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos. 2013;41(4):906–15. https://doi.org/10.1124/dmd.112.050575.Zhang D., Frost C.E., He K. et al. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos. 2013;41(4):906–15. https://doi.org/10.1124/dmd.112.050575.Godier A., Miclot A., Le Bonniec B. et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102. https://doi.org/10.1097/ALN.0b013e318238c036.Godier A., Miclot A., Le Bonniec B. et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102. https://doi.org/10.1097/ALN.0b013e318238c036.Fukuda T., Honda Y., Kamisato C. et al. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107(2):253–9. https://doi.org/10.1160/TH11-090668.Fukuda T., Honda Y., Kamisato C. et al. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107(2):253–9. https://doi.org/10.1160/TH11-090668.Majeed A., Agren A., Holmstrom M. et al. Management of rivaroxabanor apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706–12. https://doi.org/10.1182/blood-2017-05-782060.Majeed A., Agren A., Holmstrom M. et al. Management of rivaroxabanor apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706–12. https://doi.org/10.1182/blood-2017-05-782060.Schulman S., Gross P.L., Ritchie B. et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemosts. 2018;118(5):842–51. https://doi.org/10.1055/s-0038-1636541.Schulman S., Gross P.L., Ritchie B. et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemosts. 2018;118(5):842–51. https://doi.org/10.1055/s-0038-1636541.Gruber A., Marzec U.M., Buetehorn U., Hanson S., Perzborn E. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood. 2008;112(11):3825. https://doi.org/10.1182/blood.V112.11.3825.3825.Gruber A., Marzec U.M., Buetehorn U., Hanson S., Perzborn E. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood. 2008;112(11):3825. https://doi.org/10.1182/blood.V112.11.3825.3825.Lu G., DeGuzman F.R., Hollenbach S.J. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–51. https://doi.org/10.1038/nm.3102.Lu G., DeGuzman F.R., Hollenbach S.J. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–51. https://doi.org/10.1038/nm.3102.Mark C., Kitt M.M., Vandana M. et al. A phase 2 randomized, doubleblind, placebo-controlled trial demonstrating reversal of rivaroxabaninduced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors. Blood. 2013;122(21):3636. https://doi.org/10.1182/BLOOD.V122.21.3636.3636.Mark C., Kitt M.M., Vandana M. et al. A phase 2 randomized, doubleblind, placebo-controlled trial demonstrating reversal of rivaroxabaninduced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors. Blood. 2013;122(21):3636. https://doi.org/10.1182/BLOOD.V122.21.3636.3636.Connolly S.J., Crowther M., Eikelboom J.W. et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326–35. https://doi.org/10.1056/NEJMoa1814051.Connolly S.J., Crowther M., Eikelboom J.W. et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326–35. https://doi.org/10.1056/NEJMoa1814051.Laulicht B., Bakhru S., Lee C. et al. Small molecule antidote for anticoagulants. Circulation. 2012;126(Suppl 1):11395.Laulicht B., Bakhru S., Lee C. et al. Small molecule antidote for anticoagulants. Circulation. 2012;126(Suppl 1):11395.HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927– 36. https://doi.org/10.1016/S0140-6736(20)30848-5.HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927– 36. https://doi.org/10.1016/S0140-6736(20)30848-5.Hemphill J.C., Greenberg S.M., Anderson C.S. et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032–60. https://doi.org/10.1161/STR.0000000000000069.Hemphill J.C., Greenberg S.M., Anderson C.S. et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032–60. https://doi.org/10.1161/STR.0000000000000069.Lansberg M.G., O'Donnell M.J., Khatri P. et al. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e601S–e636S. https://doi.org/10.1378/chest.11-2302.Lansberg M.G., O'Donnell M.J., Khatri P. et al. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e601S–e636S. https://doi.org/10.1378/chest.11-2302.Pennlert J., Overholser R., Asplund K. et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017;48(2):314–20. https://doi.org/10.1161/STROKEAHA.116.014643.Pennlert J., Overholser R., Asplund K. et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017;48(2):314–20. https://doi.org/10.1161/STROKEAHA.116.014643.Nielsen P.B., Larsen T.B., Skjoth F., Lip G.Y. Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial hemorrhage in patients with atrial fibrillation. JAMA Intern Med. 2017;177(4):563–70. https://doi.org/10.1001/jamainternmed.2016.9369.Nielsen P.B., Larsen T.B., Skjoth F., Lip G.Y. Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial hemorrhage in patients with atrial fibrillation. JAMA Intern Med. 2017;177(4):563–70. https://doi.org/10.1001/jamainternmed.2016.9369.Gralnek I.M., Dumonceau J.-M., Kuipers E.J. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015;47(10):a1–a46. https://doi.org/10.1055/s-0034-1393172.Gralnek I.M., Dumonceau J.-M., Kuipers E.J. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015;47(10):a1–a46. https://doi.org/10.1055/s-0034-1393172.Majeed A., Wallvik N., Eriksson J. et al. Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding. Thromb Haemost. 2017;117(3):491–9. https://doi.org/10.1160/TH16-07-0498.Majeed A., Wallvik N., Eriksson J. et al. Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding. Thromb Haemost. 2017;117(3):491–9. https://doi.org/10.1160/TH16-07-0498.

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