ppharmПедиатрическая фармакологияPediatric pharmacology1727-57762500-3089Издательство «ПедиатрЪ»10.15690/pf.v19i4.2444ppharm-2205Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESСовременные аспекты диагностики нарушений функции противосвертывающей системы у детей с различными полиморфизмами в генах коагуляции. Первые результатыModern Aspects of Anticoagulation System Disorders Diagnosis in Children with Different Polymorphisms in Coagulation Genes. Initial Resultshttps://orcid.org/0000-0001-8311-9506ГордееваО. Б.GordeevaOlga B.

Гордеева Ольга Борисовна, кандидат медицинских наук, заведующая отделом научных основ гемостаза НИИ педиатрии и охраны здоровья детей НКЦ №2 ФГБНУ «РНЦХ им. акад. Б.В. Петровского», доцент кафедры факультетской педиатрии педиатрического факультета ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России

eLibrary SPIN: 2562-7725

117593, Москва, Литовский бульвар, д. 1Ател./факс: +7 (495) 427-55-77

MD, PhD

eLibrary SPIN: 2562-7725

10, str. 1, Fotievoy street, 119333, Moscow

obr@yandex.ruhttps://orcid.org/0000-0001-8320-2027ВашакмадзеН. Д.VashakmadzeNato D.

Вашакмадзе Нато Джумберовна, д.м.н., профессор

eLibrary SPIN: 2906-9190

Москва

MD, PhD, Professor

eLibrary SPIN: 2906-9190

Moscow

https://orcid.org/0000-0002-9883-0445КарасеваМ. С.KarasevaMaria S.

Карасева Мария Сергеевна

eLibrary SPIN: 8370-3480

Москва

MD

eLibrary SPIN: 8370-3480

Moscow

https://orcid.org/0000-0001-9510-5515БабайкинаМ. А.BabaykinaMarina A.

Бабайкина Марина Анатольевна

eLibrary SPIN: 3557-5876

Москва

MD

eLibrary SPIN: 3557-5876

Moscow

https://orcid.org/0000-0001-6614-6115ЖурковаН. В.ZhurkovaNatalia V.

Журкова Наталья Вячеславовна, к.м.н.

eLibrary SPIN: 4768-6310

Москва

MD, PhD

eLibrary SPIN: 4768-6310

Moscow

https://orcid.org/0000-0002-6150-0880СолошенкоМ. А.SoloshenkoMargarita A.

Солошенко Маргарита Александровна, к.м.н.

eLibrary SPIN: 2954-9873

Москва

MD, PhD

eLibrary SPIN: 2954-9873

Moscow

https://orcid.org/0000-0002-3159-269XКретоваЕ. В.KretovaElena V.

Кретова Елена Владимировна

Москва

MD

Moscow

НИИ педиатрии и охраны здоровья детей НКЦ №2 ФГБНУ «РНЦХ им. акад. Б.В. Петровского»; РНИМУ им. Н.И. ПироговаРоссияPediatrics and Child Health Research Institute in Petrovsky National Research Centre of Surgery; Pirogov Russian National Research Medical UniversityRussian FederationНИИ педиатрии и охраны здоровья детей НКЦ №2 ФГБНУ «РНЦХ им. акад. Б.В. Петровского»РоссияPediatrics and Child Health Research Institute in Petrovsky National Research Centre of SurgeryRussian Federation202221102022194326335Copyright © Гордеева О.Б., Вашакмадзе Н.Д., Карасева М.С., Бабайкина М.А., Журкова Н.В., Солошенко М.А., Кретова Е.В., 20222022Гордеева О.Б., Вашакмадзе Н.Д., Карасева М.С., Бабайкина М.А., Журкова Н.В., Солошенко М.А., Кретова Е.В.Gordeeva O.B., Vashakmadze N.D., Karaseva M.S., Babaykina M.A., Zhurkova N.V., Soloshenko M.A., Kretova E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pedpharma.ru/jour/article/view/2205

Обоснование. Патология системы гемостаза является актуальной и малоизученной проблемой в педиатрии. Одной из основных причин нарушений в системе коагуляции с развитием тромботических событий выступает нарушение в различных звеньях системы гемостаза. К сосудистым катастрофам чаще всего приводит дефицит факторов противосвертывающей системы. Принято считать, что тромбозы — частое явление у взрослых пациентов, и не уделяется должного внимания изучению нарушений в системе первичных физиологических антикоагулянтов у детей. Чаще развивается приобретенный дефицит белков-антикоагулянтов на фоне различных патологических состояний, особенно после перенесенных инфекционных заболеваний. Все эти заболевания (тромбофилии, тромботические эпизоды, сердечно-сосудистая патология, болезни нервной системы, генетические заболевания) могут встречаться по отдельности и в сочетании друг с другом, причем клиническая картина коагуляционных нарушений может быть сходной. Цель исследования — оценить изменения в системе физиологических антикоагулянтов у детей с различной патологией, имеющих полиморфные варианты некоторых генов коагуляции и перенесших новую коронавирусную инфекцию. Методы. В исследование были включены 33 ребенка, перенесших новую коронавирусную инфекцию тяжелого течения в семейных кластерах и имеющих тяжелую хроническую патологию, потенциально ассоциированную с нарушениями в системе коагуляции (с поражением нервной системы, гипертрофической кардиомиопатией, наследственными моногенными синдромами, с синдромом гематомезенхимальной дисплазии). Всем детям было проведено комплексное обследование, включавшее клинический осмотр, лабораторную и инструментальную диагностику). Результаты. Предварительные результаты исследования свидетельствуют о достаточной частоте встречаемости полиморфных вариантов генов коагуляции (у трети детей с различными заболеваниями в исследовании), у части детей определено снижение активности гликопротеинов противосвертывающей системы (от 6 до 36%), что подтверждает концепцию актуальности исследования дефицита факторов противосвертывающей системы и необходимость дальнейшего динамического наблюдения за пациентами, а также выявления предикторов тромбофилии у детей в выбранных целевых группах. Исследование для выявления нарушений противосвертывающей системы и мутаций в генах коагуляции позволит предсказать риск развития тромботических нарушений. Заключение. Полученные в работе результаты подтвердили значимую роль проводимого исследования для комплексной оценки нарушений функционирования системы гемостаза у детей, что позволит оптимизировать подход к диагностике и персонализировать стратегию ведения пациентов с различной хронической патологией и нарушениями в системе естественных антикоагулянтов. В настоящий момент исследование продолжается.

Background. Hemostatic system pathology is topical and poorly studied issue in pediatrics. One of the main causes of coagulation pathway disorders associated with thrombotic events is abnormality in various parts of the hemostatic system. Vascular accidents are commonly caused by anticoagulation system factors deficiency. Conventionally, thrombosis is a common event in adult patients, and there is no adequate attention to disorders of primary physiological anticoagulants system in children. More often acquired anticoagulant proteins deficiency develops in presence of various pathological conditions, especially after the past infectious diseases. All these diseases (thrombophilia, trombotic events, cardiovascular pathology, nervous system diseases, genetic diseases) can occur separately and in association with each other, plus clinical picture of coagulation events may be similar. Objective. The aim of the study is to evaluate changes in the physiological anticoagulants system in children with different pathologies who have polymorphic variants in coagulation genes and who had new coronavirus infection. Methods. The study included 33 children who had severe coronavirus infection in family clusters and had severe chronic pathology potentially associated with disorders of the coagulation system (nervous system damage, hypertrophic cardiomyopathy, hereditary monogenic syndromes, hemato-mesenchymal dysplasia syndrome). All children underwent complete examination including clinical examination, laboratory, and instrumental diagnostics. Results. Preliminary study results indicate significant incidence of polymorphic variants in coagulation genes (one third of children with various diseases from the study). Some children had decreased activity of anticoagulation system glycoproteins (from 6% to 36%) that confirmed the topicality of the examination of anticoagulation system factors deficiency and the need for further dynamic follow-up, as well as revealing of trombophilia predictors in children in selected target groups. Study on revealing anticoagulation system disorders and mutations in coagulation genes will predict the risk of thrombotic disorders. Conclusion. The obtained results have confirmed the significant role of the ongoing study for comprehensive assessment of hemostatic system disorders in children. That will allow us to optimize the approach to diagnosis and personalize the management strategy for patients with different chronic pathologies and disorders of the natural anticoagulants system. The study is currently ongoing.

гемостаздетидефицитпротивосвертывающая системаантитромбин IIIполиморфизмыhemostasischildrendeficiencyanticoagulation systemantitrombin IIIpolymorphismsИсточник финансирования не указан.Not specified.ReferencesMichiels C. Endothelial cell functions. J Cell Physiol. 2003;196(3):430–443. doi: https://doi.org/10.1002/jcp.10333Michiels C. Endothelial cell functions. J Cell Physiol. 2003;196(3):430–443. doi: https://doi.org/10.1002/jcp.10333Kenet G, Cohen O, Bajorat T, Nowak-Gottl U. Insights into neonatal thrombosis. Thromb Res. 2019;181(Suppl 1):S33–S36. doi: https://doi.org/10.1016/S0049-3848(19)30364-0Kenet G, Cohen O, Bajorat T, Nowak-Gottl U. Insights into neonatal thrombosis. Thromb Res. 2019;181(Suppl 1):S33–S36. doi: https://doi.org/10.1016/S0049-3848(19)30364-0Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002;109(1):116– 123. doi: https://doi.org/10.1542/peds.109.1.116Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002;109(1):116– 123. doi: https://doi.org/10.1542/peds.109.1.116Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics. 1995;96(5 Pt 1):939–943.Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics. 1995;96(5 Pt 1):939–943.Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 1997;76(3):F163–F167. doi: https://doi.org/10.1136/fn.76.3.f163Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 1997;76(3):F163–F167. doi: https://doi.org/10.1136/fn.76.3.f163Tuckuviene R, Christensen AL, Helgestad J, et al. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr. 2011;159(4):663–669. doi: https://doi.org/10.1016/j.jpeds.2011.03.052Tuckuviene R, Christensen AL, Helgestad J, et al. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr. 2011;159(4):663–669. doi: https://doi.org/10.1016/j.jpeds.2011.03.052Edstrom CS, Christensen RD. Evaluation and treatment of thrombosis in the neonatal intensive care unit. Clin Perinatol. 2000;27(3):623–641. doi: https://doi.org/10.1016/s0095-5108(05)70042-7Edstrom CS, Christensen RD. Evaluation and treatment of thrombosis in the neonatal intensive care unit. Clin Perinatol. 2000;27(3):623–641. doi: https://doi.org/10.1016/s0095-5108(05)70042-7Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118(13):1373–1382. doi: https://doi.org/10.1161/CIRCULATIONAHA.108.789008Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118(13):1373–1382. doi: https://doi.org/10.1161/CIRCULATIONAHA.108.789008Hwang JH, Chung ML, Lim YJ. Incidence and risk factors of subclinical umbilical catheter-related thrombosis in neonates. Thromb Res. 2020;194:21–25. doi: https://doi.org/10.1016/j.thromres.2020.05.034Hwang JH, Chung ML, Lim YJ. Incidence and risk factors of subclinical umbilical catheter-related thrombosis in neonates. Thromb Res. 2020;194:21–25. doi: https://doi.org/10.1016/j.thromres.2020.05.034Cabannes M, Bouissou A, Favrais G, et al. Systematic ultrasound examinations in neonates admitted to NICU: evolution of portal vein thrombosis. J Perinatol. 2018;38(10):1359–1364. doi: https://doi.org/10.1038/s41372-018-0132-9Cabannes M, Bouissou A, Favrais G, et al. Systematic ultrasound examinations in neonates admitted to NICU: evolution of portal vein thrombosis. J Perinatol. 2018;38(10):1359–1364. doi: https://doi.org/10.1038/s41372-018-0132-9Dubbink-Verheij GH, Visser R, Roest AA, et al. Thrombosis after umbilical venous catheterisation: prospective study with serial ultrasound. Arch Dis Child Fetal Neonatal Ed. 2020;105(3):299– 303. doi: https://doi.org/10.1136/archdischild-2018-316762Dubbink-Verheij GH, Visser R, Roest AA, et al. Thrombosis after umbilical venous catheterisation: prospective study with serial ultrasound. Arch Dis Child Fetal Neonatal Ed. 2020;105(3):299– 303. doi: https://doi.org/10.1136/archdischild-2018-316762Ramenghi LA, Cardiello V, Rossi A. Neonatal cerebral sinovenous thrombosis. Handb Clin Neurol. 2019;162:267–280. doi: https://doi.org/10.1016/B978-0-444-64029-1.00012-6Ramenghi LA, Cardiello V, Rossi A. Neonatal cerebral sinovenous thrombosis. Handb Clin Neurol. 2019;162:267–280. doi: https://doi.org/10.1016/B978-0-444-64029-1.00012-6Ferrari F, Vagnarelli F, Gargano G, et al. Early intracardiac thrombosis in preterm infants and thrombolysis with recombinant tissue type plasminogen activator. Arch Dis Child Fetal Neonatal Ed. 2001;85(1):F66–F69. doi: https://doi.org/10.1136/fn.85.1.f66Ferrari F, Vagnarelli F, Gargano G, et al. Early intracardiac thrombosis in preterm infants and thrombolysis with recombinant tissue type plasminogen activator. Arch Dis Child Fetal Neonatal Ed. 2001;85(1):F66–F69. doi: https://doi.org/10.1136/fn.85.1.f66Ouellette AC, Darling EK, Sivapathasundaram B, et al. Incidence, Risk Factors, and Outcomes of Neonatal Renal Vein Thrombosis in Ontario: Population-Based Cohort Study. Kidney360. 2020;1(7):640–647. doi: https://doi.org/10.34067/KID.0000912019Ouellette AC, Darling EK, Sivapathasundaram B, et al. Incidence, Risk Factors, and Outcomes of Neonatal Renal Vein Thrombosis in Ontario: Population-Based Cohort Study. Kidney360. 2020;1(7):640–647. doi: https://doi.org/10.34067/KID.0000912019Rizzi M, Goldenberg N, Bonduel M, et al. Catheter-Related Arterial Thrombosis in Neonates and Children: A Systematic Review. Thromb Haemost. 2018;118(6):1058–1066. doi: https://doi.org/10.1055/s-0038-1642635Rizzi M, Goldenberg N, Bonduel M, et al. Catheter-Related Arterial Thrombosis in Neonates and Children: A Systematic Review. Thromb Haemost. 2018;118(6):1058–1066. doi: https://doi.org/10.1055/s-0038-1642635Байрашевская А.В., Кытько О.В. Неонатальные тромбозы: причины, патогенез, особенности терапии // Российский вестник перинатологии и педиатрии. — 2021. — Т. 66. — № 2. — С. 21–28. — doi: https://doi.org/10.21508/1027–4065–2021–66–2–21–28Bairashevskaya AV, Kytko OV. Neonatal thrombosis: causes, pathogenesis, treatment features. Rossiyskiy Vestnik Perinatologii i Pediatrii = Russian Bulletin of Perinatology and Pediatrics. 2021;66(2):21–28. (In Russ). doi: https://doi.org/10.21508/1027–4065–2021–66–2–21–28Govaert P, Ramenghi L, Taal R, et al. Diagnosis of perinatal stroke II: mechanisms and clinical phenotypes. Acta Paediatr. 2009;98(11):1720–1726. doi: https://doi.org/10.1111/j.1651-2227.2009.01462.xGovaert P, Ramenghi L, Taal R, et al. Diagnosis of perinatal stroke II: mechanisms and clinical phenotypes. Acta Paediatr. 2009;98(11):1720–1726. doi: https://doi.org/10.1111/j.1651-2227.2009.01462.xSimchen MJ, Goldstein G, Lubetsky A, et al. Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke. 2009;40(1):65– 70. doi: https://doi.org/10.1161/STROKEAHA.108.527283Simchen MJ, Goldstein G, Lubetsky A, et al. Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke. Stroke. 2009;40(1):65– 70. doi: https://doi.org/10.1161/STROKEAHA.108.527283Kenet G, Lütkhoff LK, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838–1847. doi: https://doi.org/10.1161/CIRCULATIONAHA.109.913673Kenet G, Lütkhoff LK, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838–1847. doi: https://doi.org/10.1161/CIRCULATIONAHA.109.913673Torres VM, Saddi VA. Systematic review: hereditary thrombophilia associated to pediatric strokes and cerebral palsy. J Pediatr (Rio J). 2015;91(1):22–29. doi: https://doi.org/10.1016/j.jped.2014.08.004Torres VM, Saddi VA. Systematic review: hereditary thrombophilia associated to pediatric strokes and cerebral palsy. J Pediatr (Rio J). 2015;91(1):22–29. doi: https://doi.org/10.1016/j.jped.2014.08.004Online Mendelian Inheritance in Man (OMIM). In: National Library of Medicine. 15 Sep 2022. Available online: https://www.ncbi.nlm.nih.gov/omim. Accessed on September 16, 2022.Online Mendelian Inheritance in Man (OMIM). In: National Library of Medicine. 15 Sep 2022. Available online: https://www.ncbi.nlm.nih.gov/omim. Accessed on September 16, 2022.Coen Herak D, Lenicek Krleza J, Radic Antolic M, et al. Association of Polymorphisms in Coagulation Factor Genes and Enzymes of Homocysteine Metabolism With Arterial Ischemic Stroke in Children. Clin Appl Throm Hemost. 2017;23(8):1042–1051. doi: https://doi.org/10.1177/1076029616672584Coen Herak D, Lenicek Krleza J, Radic Antolic M, et al. Association of Polymorphisms in Coagulation Factor Genes and Enzymes of Homocysteine Metabolism With Arterial Ischemic Stroke in Children. Clin Appl Throm Hemost. 2017;23(8):1042–1051. doi: https://doi.org/10.1177/1076029616672584Шиффман Ф.Дж. Патофизиология крови: монография. — М.: Бином; 2017. — 448 с.Schiffman FJ. Hematologic Pathophysiology: Monography. Moscow: Binom; 2017. 448 p. (In Russ).Kim HJ, Seo JY, Lee KO, et al. Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population. Haematologica. 2014;99(3):561–569. doi: https://doi.org/10.3324/haematol.2013.092023Kim HJ, Seo JY, Lee KO, et al. Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population. Haematologica. 2014;99(3):561–569. doi: https://doi.org/10.3324/haematol.2013.092023Obeagu EI, Nwosu DC, Obeagu GU. Antithrombin III: A Review. Int J Curr Res Biol Med. 2022;7(2):20–27. doi: https://doi.org/10.22192/ijcrbm.2022.07.02.002Obeagu EI, Nwosu DC, Obeagu GU. Antithrombin III: A Review. Int J Curr Res Biol Med. 2022;7(2):20–27. doi: https://doi.org/10.22192/ijcrbm.2022.07.02.002Bauer KA. Antithrombin deficiency. In: UpToDate. November 16, 2021. Available online: https://www.uptodate.com/contents/antithrombin-deficiency?search=heparin%20antithrombin&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed on September 17, 2022.Bauer KA. Antithrombin deficiency. In: UpToDate. November 16, 2021. Available online: https://www.uptodate.com/contents/antithrombin-deficiency?search=heparin%20antithrombin&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed on September 17, 2022.Achey MA, Nag UP, Robinson VL, et al. The Developing Balance of Thrombosis and Hemorrhage in Pediatric Surgery: Clinical Implications of Age-Related Changes in Hemostasis. Clin Appl Thromb Hemost. 2020;26:1076029620929092. doi: https://doi.org/10.1177/1076029620929092Achey MA, Nag UP, Robinson VL, et al. The Developing Balance of Thrombosis and Hemorrhage in Pediatric Surgery: Clinical Implications of Age-Related Changes in Hemostasis. Clin Appl Thromb Hemost. 2020;26:1076029620929092. doi: https://doi.org/10.1177/1076029620929092Рудзевич А.Ю. Изменения гемостаза у беременных с тромбофилией, возможность профилактики осложнений беременности при приобретенной тромбофилии и антифосфолипидном синдроме // Научное обозрение. Медицинские науки. — 2019. — № 1. — С. 48–54.Rudzevich AYu. Changes in hemostasis in pregnant women with thrombophilia, possibility of prevention of complications of pregnancy in thrombophilia and antifospolipid syndrome. Scientific Review. Medical Sciences. 2019;(1):48–54. (In Russ).Navarro-Fernández J, de la Morena-Barrio ME, Padilla J, et al. Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency. Thromb Haemost. 2016;116(01):146–154. doi: https://doi.org/10.1160/TH15-11-0871Navarro-Fernández J, de la Morena-Barrio ME, Padilla J, et al. Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency. Thromb Haemost. 2016;116(01):146–154. doi: https://doi.org/10.1160/TH15-11-0871Bertina R, Koeleman B, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–67. doi: https://doi.org/10.1038/369064a0Bertina R, Koeleman B, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64–67. doi: https://doi.org/10.1038/369064a0Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic Distribution of Factor V Leiden in 4047 Men and Women: Implications for Venous Thromboembolism Screening. JAMA. 1997;277(16):1305–1307. doi: https://doi.org/10.1001/jama.1997.03540400055031Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic Distribution of Factor V Leiden in 4047 Men and Women: Implications for Venous Thromboembolism Screening. JAMA. 1997;277(16):1305–1307. doi: https://doi.org/10.1001/jama.1997.03540400055031Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508.Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508.Ibrahim-Kosta M, Suchon P, Couturaud F, et al. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation. Sci Rep. 2019;9(1):3750. doi: https://doi.org/10.1038/s41598-019-40172-xIbrahim-Kosta M, Suchon P, Couturaud F, et al. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation. Sci Rep. 2019;9(1):3750. doi: https://doi.org/10.1038/s41598-019-40172-xAbukhiran I, Jasser J, Bhagavathi S. Double-homozygosity for Factor V Leiden and Prothrombin c.*97G > A Mutation in a Young Female with Recurrent Fetal Losses and no Venous Thromboembolism. Hum Pathol (N Y). 2020;22:200425. doi: https://doi.org/10.1016/j.ehpc.2020.200425Abukhiran I, Jasser J, Bhagavathi S. Double-homozygosity for Factor V Leiden and Prothrombin c.*97G > A Mutation in a Young Female with Recurrent Fetal Losses and no Venous Thromboembolism. Hum Pathol (N Y). 2020;22:200425. doi: https://doi.org/10.1016/j.ehpc.2020.200425Emmerich J, Rosendaal FR, Cattaneo M, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in venous thromboembolism. Thromb Haemost. 2001;86(3):809– 816. doi: https://doi.org/10.1055/s-0037-1616136Emmerich J, Rosendaal FR, Cattaneo M, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in venous thromboembolism. Thromb Haemost. 2001;86(3):809– 816. doi: https://doi.org/10.1055/s-0037-1616136Momot AP, Nikolaeva MG, Yasafova NN, et al. Clinical and laboratory manifestations of the prothrombin gene mutation in women of reproductive age. J Blood Med. 2019;10:255–263. doi: https://doi.org/10.2147/JBM.S212759Momot AP, Nikolaeva MG, Yasafova NN, et al. Clinical and laboratory manifestations of the prothrombin gene mutation in women of reproductive age. J Blood Med. 2019;10:255–263. doi: https://doi.org/10.2147/JBM.S212759Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;30(43):10363–10370. doi: https://doi.org/10.1021/bi00107a001Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;30(43):10363–10370. doi: https://doi.org/10.1021/bi00107a001Giansily-Blaizot M, Rallapalli PM, Perkins SJ, et al. The EAHAD Blood Coagulation Factor VII Variant Database. Hum Mutat. 2020;41(7):1209–1219. doi: https://doi.org/10.1002/humu.24025Giansily-Blaizot M, Rallapalli PM, Perkins SJ, et al. The EAHAD Blood Coagulation Factor VII Variant Database. Hum Mutat. 2020;41(7):1209–1219. doi: https://doi.org/10.1002/humu.24025Shahbazi S, Mahdian R. Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications. Iran Biomed J. 2019;23(3):165–174. doi: https://doi.org/10.29252/.23.3.165Shahbazi S, Mahdian R. Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications. Iran Biomed J. 2019;23(3):165–174. doi: https://doi.org/10.29252/.23.3.165Hu X, Wang J, Li Y, et al. The β-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score. Sci Rep. 2017;7(1):17517. doi: https://doi.org/10.1038/s41598-017-17537-1Hu X, Wang J, Li Y, et al. The β-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score. Sci Rep. 2017;7(1):17517. doi: https://doi.org/10.1038/s41598-017-17537-1Bigdeli R, Younesi MR, Panahnejad E, et al. Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population. Syst Biol Reprod Med. 2018;64(4):274–282. doi: https://doi.org/10.1080/19396368.2018.1456576Bigdeli R, Younesi MR, Panahnejad E, et al. Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population. Syst Biol Reprod Med. 2018;64(4):274–282. doi: https://doi.org/10.1080/19396368.2018.1456576Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost. 2005;93(4):631–640. doi: https://doi.org/10.1160/TH05-01-0033Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost. 2005;93(4):631–640. doi: https://doi.org/10.1160/TH05-01-0033Li X, Liu Y, Zhan R, et al. Meta-Analysis of the Association between Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Recurrent Pregnancy. Loss Med Sci Monit. 2015;21:1051– 1056. doi: https://doi.org/10.12659/MSM.892898Li X, Liu Y, Zhan R, et al. Meta-Analysis of the Association between Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Recurrent Pregnancy. Loss Med Sci Monit. 2015;21:1051– 1056. doi: https://doi.org/10.12659/MSM.892898Wang S. PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta-analysis. PLoS One. 2013;8(2):e56797–e56797. doi: https://doi.org/10.1371/journal.pone.0056797Wang S. PAI-1 4G/5G polymorphism contributes to cancer susceptibility: evidence from meta-analysis. PLoS One. 2013;8(2):e56797–e56797. doi: https://doi.org/10.1371/journal.pone.0056797Sillen M, Declerck PJ. Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition. Front Cardiovasc Med. 2020;7:622473. doi: https://doi.org/10.3389/fcvm.2020.622473Sillen M, Declerck PJ. Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition. Front Cardiovasc Med. 2020;7:622473. doi: https://doi.org/10.3389/fcvm.2020.622473Ozdemir O, Yenicesu GI, Silan F, et al. Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomarkers. 2012;16(4):279–286. doi: https://doi.org/10.1089/gtmb.2011.0191Ozdemir O, Yenicesu GI, Silan F, et al. Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomarkers. 2012;16(4):279–286. doi: https://doi.org/10.1089/gtmb.2011.0191Klimczak-Bitner AA, Bitner J, Hiruta K, Szemraj J. Exploring a possible association between the occurrence of the SERPINE1-675 4G/5G (rs1799889) polymorphism and the increased risk of esophageal cancer in the Caucasian population. Biochem Biophys Rep. 2021;28:101147. doi: https://doi.org/10.1016/j.bbrep.2021.101147Klimczak-Bitner AA, Bitner J, Hiruta K, Szemraj J. Exploring a possible association between the occurrence of the SERPINE1-675 4G/5G (rs1799889) polymorphism and the increased risk of esophageal cancer in the Caucasian population. Biochem Biophys Rep. 2021;28:101147. doi: https://doi.org/10.1016/j.bbrep.2021.101147Monagle P, Barnes C, Ignjatovic V, et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95(2):362–372. doi: https://doi.org/10.1160/TH05-01-0047Monagle P, Barnes C, Ignjatovic V, et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95(2):362–372. doi: https://doi.org/10.1160/TH05-01-0047Детская гематология: клинические рекомендации / под ред. А.Г. Румянцева, А.А. Масчана, Е.В. Жуковской. — М.: ГЭОТАР-Медиа; 2015. — 656 с.Detskaya gematologiya: Clinical guidelines. Rumyantsev AG, Maschan AA, Zhukovskaya EV, eds. Moscow: GEOTAR-Media; 2015. 656 p. (In Russ).van Ommen CH, Heijboer H, van den Dool EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost. 2003;1(12):2516–2522. doi: https://doi.org/10.1046/j.1538-7836.2003.00465.xvan Ommen CH, Heijboer H, van den Dool EJ, et al. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost. 2003;1(12):2516–2522. doi: https://doi.org/10.1046/j.1538-7836.2003.00465.xRevel-Vilk S, Chan A, Bauman M, Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 2003;1(5):915–921. doi: https://doi.org/10.1046/j.1538-7836.2003.00158.xRevel-Vilk S, Chan A, Bauman M, Massicotte P. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost. 2003;1(5):915–921. doi: https://doi.org/10.1046/j.1538-7836.2003.00158.xLi Y, Bezemer ID, Rowland CM, et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost. 2009;7(11):1802–1808. doi: https://doi.org/10.1111/j.1538-7836.2009.03544.xLi Y, Bezemer ID, Rowland CM, et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost. 2009;7(11):1802–1808. doi: https://doi.org/10.1111/j.1538-7836.2009.03544.xJordan FL, Nandorff A. The familial tendency in thrombo-embolic disease. Acta Med Scand. 1956;156(4):267–275. doi: https://doi.org/10.1111/j.0954-6820.1956.tb00084.xJordan FL, Nandorff A. The familial tendency in thrombo-embolic disease. Acta Med Scand. 1956;156(4):267–275. doi: https://doi.org/10.1111/j.0954-6820.1956.tb00084.xJiang J, Liu K, Zou J, et al. Associations between polymorphisms in coagulation-related genes and venous thromboembolism: A meta-analysis with trial sequential analysis. Medicine (Baltimore). 2017;96(13):e6537. doi: https://doi.org/10.1097/MD.0000000000006537Jiang J, Liu K, Zou J, et al. Associations between polymorphisms in coagulation-related genes and venous thromboembolism: A meta-analysis with trial sequential analysis. Medicine (Baltimore). 2017;96(13):e6537. doi: https://doi.org/10.1097/MD.0000000000006537

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