akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347.2019.13.3.245-254akusherstvo-578Research ArticleLECTUREЛЕКЦИЯVenous thrombosis in pregnant women: genetic and epigenetic risk factorsВенозные тромбозы у беременных женщин: генетические и эпигенетические факторы рискаЭлаламиИ.ElalamyI.

Элалами Исмаил – д.м.н., профессор медицинского Университета Сорбонны, Париж, Франция; директор гематологии Центра Тромбозов, Госпиталь Тенон, Париж, Франция; профессор кафедры акушерства и гинекологии Института здоровья детей, Сеченовский Университет, Москва, Россия.

Франция, 75006 Париж, Улица медицинского факультета, д. 12; Франция, 75020 Париж, Китайская улица, д. 4; Россия, 109004 Москва, ул. Земляной Вал, д. 62.

Ismail Elalamy – MD, PhD, Professor, Medicine Sorbonne University, Paris, France; Director of Hematology Department of Thrombosis Center, Hospital Tenon, Paris, France; Professor, Department of Obstetrics and Gynecology, Institute of Children's Health, Sechenov University, Moscow, Russia.

12 Rue de l'École de Médecine, 75006 Paris, France; 4 Rue de la Chine, 75020 Paris, France; 62 St. Zemlyanoi Val, Moscow 109004, Russia.

Медицинский Университет Сорбонны; Госпиталь Тенон; ФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет)ФранцияMedicine Sorbonne University; Hospital Tenon; Sechenov UniversityFrance201920092019133245254Copyright © Elalamy I., 20192019Элалами И.Elalamy I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/578

The most common cause of thrombosis isischemic heart attack, the second one is stroke, and the third one is venous thrombosis. According to European studies, venous thrombosis accounts for about 12 % of the population’s deaths. The pathogenesis of thrombosis is well presented in the form of the Virchow’s triad; that includes damage to the vascular endothelium, hypercoagulation and stasis. A pregnant woman is deficient in fibrinolytics and excessive in procoagulants. Pregnancy can be seen as a natural example of the Virchow’s triad: the woman develops a state of hypercoagulation only because she is pregnant. Hypercoagulable state in pregnant women directly correlates with age, genetic thrombophilias, and autoimmune diseases. The formation of a blood clot may be associated with genetic factors, the so-called familial thrombophilias. This type of thrombophilia is caused by abnormalities in the genes that carry information about proteins involved in blood coagulation – proteins C and S, antithrombin III, Leiden mutation, prothrombin anomaly G 202110A. Thus, thrombosis is the result of an interaction between genetic and acquired risk factors or a combination of them. This is confirmed by the RIETE data registry. It is highly advisable to identify patients at risk and determine the strategy of managing these patients with the least dangerous consequences.

Самой частой причиной развития тромбоза является ишемический сердечный приступ, на втором месте – инсульт, на третьем – венозный тромбоз. По результатам европейских исследований, венозный тромбоз составляет в совокупности около 12 % смертей населения. Патогенез тромбоза представлен в триаде Вирхова, которая включает повреждение эндотелия сосуда, гиперкоагуляцию и стаз. У беременной женщины формируется дефицит фибринолитиков и избыток прокоагулянтов. Беременность является натуральной триадой Вирхова – женщина имеет состояние гиперкоагуляции только потому, что она является беременной. Гиперкоагуляционное состояние у беременных прямо коррелирует с возрастом, генетическими тромбофилиями, аутоиммунными заболеваниями. Возникновение тромба может быть связано и с генетическими факторами, так называемыми семейными тромбофилиями. Данный вид тромбофилии обусловлен аномалиями в генах, несущих информацию о белках, принимающих участие в свертывании крови – протеины С и S, антитромбин III, мутация Лейдена, аномалия протромбина G 202110A. Таким образом, тромбоз является результатом взаимодействия между генетическими и приобретенными факторами риска или их комбинацией. Это подтверждается данными регистра RIETE. Необходимо выявлять пациентов в группе риска и определять стратегию ведения больных с наименьшими опасными последствиями.

тромбоэмболиятромбоз глубоких вентромбоэмболия легочной артериивенозная тромбоэмболиятромбозмутация Лейденаvenous thromboembolic diseasedeep vein thrombosispulmonary embolismvenous thromboembolismthrombosisLeiden mutationReferencesScheres J.J., Lijfering W.M., Cannegieter S.C. Current and future burden of venous thrombosis: Not simply predictable. Res Pract Thromb Haemost. 2018;2(2):199–208. DOI: 10.1002/rth2.12101.Scheres J.J., Lijfering W.M., Cannegieter S.C. Current and future burden of venous thrombosis: Not simply predictable. Res Pract Thromb Haemost. 2018;2(2):199–208. DOI: 10.1002/rth2.12101.Wendelboe A.M., Raskob G.E. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118(9):1340–7. DOI: 10.1161/CIRCRESAHA.115.306841.Wendelboe A.M., Raskob G.E. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118(9):1340–7. DOI: 10.1161/CIRCRESAHA.115.306841.Bouée S., Emery C., Samson A. et al. Incidence of venous thromboembolism in France: a retrospective analysis of a national insurance claims database. Thromb J. 2016;14(1):4. DOI: 10.1186/s12959-016-0078-0.Bouée S., Emery C., Samson A. et al. Incidence of venous thromboembolism in France: a retrospective analysis of a national insurance claims database. Thromb J. 2016;14(1):4. DOI: 10.1186/s12959-016-0078-0.Burwen D.R., Wu C., Cirillo D. et al. Venous thromboembolism incidence, recurrence, and mortality based on Women's Health Initiative data and Medicare claims. Thromb Res. 2017;150:78–85. DOI: 10.1016/j.thromres.2016.11.015.Burwen D.R., Wu C., Cirillo D. et al. Venous thromboembolism incidence, recurrence, and mortality based on Women's Health Initiative data and Medicare claims. Thromb Res. 2017;150:78–85. DOI: 10.1016/j.thromres.2016.11.015.Cohen A.T., Agnelli G., Anderson F.A. et al. Venous thromboembolism (VTE) in Europe. Thromb Haemost. 2007;98(4):756–64.Cohen A.T., Agnelli G., Anderson F.A. et al. Venous thromboembolism (VTE) in Europe. Thromb Haemost. 2007;98(4):756–64.Byrnes J.R., Wolberg A.S. New findings on venous thrombogenesis. Hämostaseologie. 2017;37(1):25–35. DOI: 10.5482/HAMO-16-09-0034.Byrnes J.R., Wolberg A.S. New findings on venous thrombogenesis. Hämostaseologie. 2017;37(1):25–35. DOI: 10.5482/HAMO-16-09-0034.Di Nisio M., van Es N., Büller H.R. Deep vein thrombosis and pulmonary embolism. Lancet. 2016;388(10063):3060–73. DOI: 10.1016/S0140-6736(16)30514-1.Di Nisio M., van Es N., Büller H.R. Deep vein thrombosis and pulmonary embolism. Lancet. 2016;388(10063):3060–73. DOI: 10.1016/S0140-6736(16)30514-1.Conti E., Zezza L., Ralli E. et al. Pulmonary embolism in pregnancy. J Thromb Thrombolysis. 2014;37(3):251–70. DOI: 10.1007/s11239-013-0941-9.Conti E., Zezza L., Ralli E. et al. Pulmonary embolism in pregnancy. J Thromb Thrombolysis. 2014;37(3):251–70. DOI: 10.1007/s11239-013-0941-9.Fuchs T.A., Brill A., Wagner D.D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012;32(8):1777–83. DOI: 10.1161/ATVBAHA.111.242859.Fuchs T.A., Brill A., Wagner D.D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012;32(8):1777–83. DOI: 10.1161/ATVBAHA.111.242859.Gould T.J., Lysov Z., Liaw P.C. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;13(Suppl 1):S82–S91. DOI: 10.1111/jth.12977.Gould T.J., Lysov Z., Liaw P.C. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;13(Suppl 1):S82–S91. DOI: 10.1111/jth.12977.Giaglis S., Stoikou M., Sur Chowdhury C. et al. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front Immunol. 2016;7:565. DOI: 10.3389/fimmu.2016.00565.Giaglis S., Stoikou M., Sur Chowdhury C. et al. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front Immunol. 2016;7:565. DOI: 10.3389/fimmu.2016.00565.Takagi Y., Murata M., Kozuka T. et al. Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance. Thromb Haemost. 2016;116(6):1022–31. DOI: 10.1160/TH16-03-0223.Takagi Y., Murata M., Kozuka T. et al. Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance. Thromb Haemost. 2016;116(6):1022–31. DOI: 10.1160/TH16-03-0223.Wang T.F., Li A., Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost. 2018;2(3):429–38. DOI: 10.1002/rth2.12102.Wang T.F., Li A., Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost. 2018;2(3):429–38. DOI: 10.1002/rth2.12102.Zöller B., Hillarp A., Dahlbäck B. State-of-the-Art Review: activated protein C resistance: clinical implications. Clin Appl Thromb Hemost. 1997;3(1):25–32.Zöller B., Hillarp A., Dahlbäck B. State-of-the-Art Review: activated protein C resistance: clinical implications. Clin Appl Thromb Hemost. 1997;3(1):25–32.Naess I.A., Christiansen S.C., Romundstad P. et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5(4):692–9. DOI: 10.1111/j.1538-7836.2007.02450.x.Naess I.A., Christiansen S.C., Romundstad P. et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5(4):692–9. DOI: 10.1111/j.1538-7836.2007.02450.x.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(Suppl 2):e691S–e736S. DOI: 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(Suppl 2):e691S–e736S. DOI: 10.1378/chest.11-2300.Austin A.W, Wissmann T., von Kanel R. Stress and hemostasis: an update. Semin Thromb Hemost. 2013;39(8):902–12. DOI: 10.1055/s-0033-1357487.Austin A.W, Wissmann T., von Kanel R. Stress and hemostasis: an update. Semin Thromb Hemost. 2013;39(8):902–12. DOI: 10.1055/s-0033-1357487.Bentur O.S., Sarig G., Brenner B., Jacob G. Effects of acute stress on thrombosis. Semin Thromb Hemost. 2018;44(7):662–8. DOI: 10.1055/s-0038-1660853.Bentur O.S., Sarig G., Brenner B., Jacob G. Effects of acute stress on thrombosis. Semin Thromb Hemost. 2018;44(7):662–8. DOI: 10.1055/s-0038-1660853.Lijfering W.M., Flinterman L.E., Vandenbroucke J.P. et al. Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. Semin Thromb Hemost. 2011;37(8):885–96. DOI: 10.1055/s-0031-1297367.Lijfering W.M., Flinterman L.E., Vandenbroucke J.P. et al. Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. Semin Thromb Hemost. 2011;37(8):885–96. DOI: 10.1055/s-0031-1297367.Holst A.G., Jensen G., Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation. 2010;121(17):1896–903. DOI: 10.1161/CIRCULATIONAHA.109.921460.Holst A.G., Jensen G., Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation. 2010;121(17):1896–903. DOI: 10.1161/CIRCULATIONAHA.109.921460.Monreal M., Mahé I., Bura-Riviere A. et al. Pulmonary embolism: Epidemiology and registries. Presse Med. 2015;44(12 Pt 2):e377–e383. DOI: 10.1016/j.lpm.2015.10.006.Monreal M., Mahé I., Bura-Riviere A. et al. Pulmonary embolism: Epidemiology and registries. Presse Med. 2015;44(12 Pt 2):e377–e383. DOI: 10.1016/j.lpm.2015.10.006.Bikdeli B., Jimenez D., Hawkins M. et al. Rationale, design and methodology of the computerized registry of patients with venous thromboembolism (RIETE). Thromb Haemost. 2018;118(1):214–24. DOI: 10.1160/TH17-07-0511.Bikdeli B., Jimenez D., Hawkins M. et al. Rationale, design and methodology of the computerized registry of patients with venous thromboembolism (RIETE). Thromb Haemost. 2018;118(1):214–24. DOI: 10.1160/TH17-07-0511.Wendelboe A.M., McCumber M., Hylek E.M. et al. Global public awareness of venous thromboembolism. J Thromb Haemost. 2015;13:1365–71. DOI: 10.1111/jth.13031.Wendelboe A.M., McCumber M., Hylek E.M. et al. Global public awareness of venous thromboembolism. J Thromb Haemost. 2015;13:1365–71. DOI: 10.1111/jth.13031.

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