akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2021.230akusherstvo-1072Research ArticleCLINICAL CASEКЛИНИЧЕСКИЙ СЛУЧАЙManagement of antithrombin III deficiency in pregnancy: a representative case and a literature reviewВедение беременности при дефиците антитромбина III: обзор литературы и описание клинического случаяhttps://orcid.org/0000-0002-1388-5827АкиньшинаС. В.AkinshinaS. V.

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

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

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

62 Str. Zemlyanoi Val, Moscow 109004.

svetlana_aki@mail.ruhttps://orcid.org/0000-0003-3010-345XГенинаП. К.GeninaP. K.

Генина Полина Константиновна - студент 6-го курса лечебного факультета.

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

Polina K. Genina - 6th year Student, Department of General Medicine, Sechenov University.

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

https://orcid.org/0000-0001-8404-1042БицадзеВ. О.BitsadzeV. O.

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

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

Scopus Author ID: 6506003478.

Researcher ID: F-8409-2017.

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

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

Scopus Author ID: 6506003478.

Researcher ID: F-8409-2017.

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

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

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

Scopus Author ID: 57194547147.

Researcher ID: F-8384-2017.

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

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

Scopus Author ID: 57194547147.

Researcher ID: F-8384-2017.

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

Цибизова Валентина Ивановна – кандидат медицинских наук, акушер-гинеколог НИЛ оперативной гинекологии Института перинатологии и педиатрии; врач отделения функциональной и ультразвуковой диагностики.

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

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

2 Akkuratova Str., Saint Petersburg 197341.

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

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

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

Scopus Author ID: 57222220144.

Researcher ID: M-5660-2016.

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

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

Scopus Author ID: 57222220144.

Researcher ID: M-5660-2016.

ООО «Медицинский женский центр»Россия«Medical Centre for Women» LLCRussian FederationПервый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский университет)РоссияSechenov UniversityRussian FederationНациональный медицинский исследовательский центр имени В.А. Алмазова Министерства здравоохранения Российской ФедерацииРоссияAlmazov National Medical Research Centre, Health Ministry of Russian FederationRussian Federation202109092021154441450Copyright © Akinshina S.V., Genina P.K., Bitsadze V.O., Khizroeva J.K., Tsibizova V.I., Makatsariya A.D., 20212021Акиньшина С.В., Генина П.К., Бицадзе В.О., Хизроева Д.Х., Цибизова В.И., Макацария А.Д.Akinshina S.V., Genina P.K., Bitsadze V.O., Khizroeva J.K., Tsibizova V.I., 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/1072

The work is aimed at discussing pregnancy management for the most thrombogenic genetic thrombophilia - antithrombin III (AT-III) deficiency. A detailed analysis of the literature and clinical case of pregnancy management in a patient with AT-III deficiency, pulmonary embolism and habitual history of miscarriage has been performed and presented. Patients with AT-III deficiency are at high risk for developing thrombotic and obstetric complications even despite using therapeutic doses of anticoagulants. Indications for use and modes of administration of AT-III concentrate have not been currently defined clearly. Monitoring therapy with low molecular weight heparin is largely complicated because a test for determining anti-Xa activity is AT-III-dependent. In addition to standard methods for controlling antithrombotic therapy, we used tests characterizing the dynamic blood clot parameters: thromboelastography and thrombin generation test. The peak risk resulting in both thrombotic and hemorrhagic complications in such patients occurs during period of labor and the postpartum period, when a change in the regimen of anticoagulant therapy is required with its temporary withdrawal and additional administration of AT-III concentrate.

Работа посвящена проблеме ведения беременности при наиболее тромбогенной генетической тромбофилии - дефиците антитромбина III (AT-III). Проведен детальный анализ литературы и представлен разбор собственного клинического случая ведения беременности у пациентки с дефицитом AT-III, тромбоэмболией легочной артерии и привычным невынашиванием беременности в анамнезе. Пациентки с дефицитом AT-III относятся к группе высокого риска по развитию тромботических и акушерских осложнений, даже несмотря на терапевтические дозы антикоагулянтов. Показания к применению и режимы введения концентрата AT-III в настоящее время четко не определены. Контроль терапии низкомолекулярным гепарином в значительной степени затруднен, так как тест на определение анти-Ха активности является AT-III-зависимым. Помимо стандартных методов контроля антитромботической терапии, мы использовали тесты, характеризующие динамические параметры сгустка: тромбоэластограмму, тест генерации тромбина. Наибольший риск с точки зрения как тромботических, так и геморрагических осложнений у таких больных представляет период родов и послеродовый период, когда требуется изменение режима антикоагулянтной терапии с временной ее отменой и дополнительное введение концентрата AT-III.

дефицит антитромбина IIIбеременностьнизкомолекулярный гепаринконцентрат антитромбина IIIривароксабанantithrombin III deficiencypregnancylow molecular weight heparinantithrombin III concentraterivaroxabanReferencesDi Minno M.N., Ambrosino P., Ageno W. et al. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res. 2015;135(5):923-32. https://doi.org/10.1016/j.thromres.2015.03.010.Di Minno M.N., Ambrosino P., Ageno W. et al. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res. 2015;135(5):923-32. https://doi.org/10.1016/j.thromres.2015.03.010.Vossen C.Y., Conard J., Fontcuberta J. et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost. 2005;3(3):459-64. https://doi.org/10.1111/j.1538-7836.2005.01197.x.Vossen C.Y., Conard J., Fontcuberta J. et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost. 2005;3(3):459-64. https://doi.org/10.1111/j.1538-7836.2005.01197.x.Lim W., Eikelboom J.W., Ginsberg J.S. Inherited thrombophilia and pregnancy associated venous thromboembolism. BMJ. 2007;334(7607):1318-21. https://doi.org/10.1136/bmj.39205.484572.55.Lim W., Eikelboom J.W., Ginsberg J.S. Inherited thrombophilia and pregnancy associated venous thromboembolism. BMJ. 2007;334(7607):1318-21. https://doi.org/10.1136/bmj.39205.484572.55.Wickstrom K., Edelstam G., Lowbeer C.H. et al. Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest. 2004;64(1):31-40. https://doi.org/10.1080/00365510410003859.Wickstrom K., Edelstam G., Lowbeer C.H. et al. Reference intervals for plasma levels of fibronectin, von Willebrand factor, free protein S and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest. 2004;64(1):31-40. https://doi.org/10.1080/00365510410003859.James A.H., Bates S.M., Bauer K.A. et al. Management of hereditary antithrombin deficiency in pregnancy. Thromb Res. 2017;157:41-5. https://doi.org/10.1016/j.thromres.2017.05.017.James A.H., Bates S.M., Bauer K.A. et al. Management of hereditary antithrombin deficiency in pregnancy. Thromb Res. 2017;157:41-5. https://doi.org/10.1016/j.thromres.2017.05.017.Franchi F., Biguzzi E., Martinelli I. et al. Normal reference ranges of antithrombin, protein C and protein S: effect of sex, age and hormonal status. Thromb Res. 2013;132(2):e152-7. https://doi.org/10.1016/j.thromres.2013.07.003.Franchi F., Biguzzi E., Martinelli I. et al. Normal reference ranges of antithrombin, protein C and protein S: effect of sex, age and hormonal status. Thromb Res. 2013;132(2):e152-7. https://doi.org/10.1016/j.thromres.2013.07.003.Folkeringa N., Brouwer J.L., Korteweg F.J. et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol. 2007;136(4):656-61. https://doi.org/10.1111/j.1365-2141.2006.06480.x.Folkeringa N., Brouwer J.L., Korteweg F.J. et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol. 2007;136(4):656-61. https://doi.org/10.1111/j.1365-2141.2006.06480.x.Mahmoodi B.K., Brouwer J.L., Ten Kate M.K. et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost. 2010;8(6):1193-200. https://doi.org/10.1111/j.1538-7836.2010.03840.x.Mahmoodi B.K., Brouwer J.L., Ten Kate M.K. et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost. 2010;8(6):1193-200. https://doi.org/10.1111/j.1538-7836.2010.03840.x.Sabadell J., Casellas M., Alijotas-Reig J. et al. Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):47-51. https://doi.org/10.1016/j.ejogrb.2009.12.004.Sabadell J., Casellas M., Alijotas-Reig J. et al. Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):47-51. https://doi.org/10.1016/j.ejogrb.2009.12.004.James A.H., Jamison M.G., Brancazio L.R., Myers E.R. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311-5. https://doi.org/10.1016/j.ajog.2005.11.008.James A.H., Jamison M.G., Brancazio L.R., Myers E.R. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311-5. https://doi.org/10.1016/j.ajog.2005.11.008.James A.H., Konkle B.A., Bauer K.A. Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;5:233-41. https://doi.org/10.2147/IJWH.S43190.James A.H., Konkle B.A., Bauer K.A. Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;5:233-41. https://doi.org/10.2147/IJWH.S43190.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.Bates S.M., Greer I.A., Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S. https://doi.org/10.1378/chest.11-2300.Bates S.M., Greer I.A., Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S. https://doi.org/10.1378/chest.11-2300.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.Tiede A., Tait R.C., Shaffer D.W. et al. Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost. 2008;99(3):616-22. https://doi.org/10.1160/TH07-08-0489.Tiede A., Tait R.C., Shaffer D.W. et al. Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost. 2008;99(3):616-22. https://doi.org/10.1160/TH07-08-0489.Rheaume M., Weber F., Durand M., Mahone M. Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet Gynecol. 2016;127(4):649-56. https://doi.org/10.1097/AOG.0000000000001347.Rheaume M., Weber F., Durand M., Mahone M. Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet Gynecol. 2016;127(4):649-56. https://doi.org/10.1097/AOG.0000000000001347.Pascual C., Munoz C., Huerta A.R. et al. A new case of successful outcome of pregnancy in a carrier of homozygous type II (L99F) antithrombin deficiency. Blood Coagul Fibrinolysis. 2014;25(1):74-6. https://doi.org/10.1097/MBC.0b013e3283646620.Pascual C., Munoz C., Huerta A.R. et al. A new case of successful outcome of pregnancy in a carrier of homozygous type II (L99F) antithrombin deficiency. Blood Coagul Fibrinolysis. 2014;25(1):74-6. https://doi.org/10.1097/MBC.0b013e3283646620.Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. Royal College of Obstetricians and Gynaecologists, 2015. 40 p. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf.Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. Royal College of Obstetricians and Gynaecologists, 2015. 40 p. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf.ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy. Obstet Gynecol. 2018;132(1):e18-e34. https://doi.org/10.1097/AOG.0000000000002703.ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy. Obstet Gynecol. 2018;132(1):e18-e34. https://doi.org/10.1097/AOG.0000000000002703.ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy. Obstet Gynecol. 2018;132(1):e1-e17. https://doi.org/10.1097/AOG.0000000000002706.ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy. Obstet Gynecol. 2018;132(1):e1-e17. https://doi.org/10.1097/AOG.0000000000002706.Bates S.M., Rajasekhar A., Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 201827;2(22):3317-59. https://doi.org/10.1182/bloodadvances.2018024802.Bates S.M., Rajasekhar A., Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 201827;2(22):3317-59. https://doi.org/10.1182/bloodadvances.2018024802.Rogenhofer N., Bohlmann M.K., Beuter-Winkler P. et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol. 2014;93(3):385-92. https://doi.org/10.1007/s00277-013-1892-0.Rogenhofer N., Bohlmann M.K., Beuter-Winkler P. et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol. 2014;93(3):385-92. https://doi.org/10.1007/s00277-013-1892-0.Refaei M., Xing L., Lim W. et al. Management of venous thromboembolism in patients with hereditary antithrombin deficiency and pregnancy: case report and review of the literature. Case Rep Hematol. 2017;2017:9261351. https://doi.org/10.1155/2017/9261351.Refaei M., Xing L., Lim W. et al. Management of venous thromboembolism in patients with hereditary antithrombin deficiency and pregnancy: case report and review of the literature. Case Rep Hematol. 2017;2017:9261351. https://doi.org/10.1155/2017/9261351.Skelley J.W., White C.W., Thomason A.R. The use of direct oral anticoagulants in inherited thrombophilia. J Thromb Thrombolysis. 2017;43(1):24-30. https://doi.org/10.1007/s11239-016-1428-2.Skelley J.W., White C.W., Thomason A.R. The use of direct oral anticoagulants in inherited thrombophilia. J Thromb Thrombolysis. 2017;43(1):24-30. https://doi.org/10.1007/s11239-016-1428-2.Serrao A., Lucani B., Mansour D. et al. Direct oral anticoagulants in patients affected by major congenital thrombophilia. Mediterr J Hematol Infect Dis. 2019;11(1):e2019044. https://doi.org/10.4084/MJHID.2019.044.Serrao A., Lucani B., Mansour D. et al. Direct oral anticoagulants in patients affected by major congenital thrombophilia. Mediterr J Hematol Infect Dis. 2019;11(1):e2019044. https://doi.org/10.4084/MJHID.2019.044.

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