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Gestational complications of the prothrombin G20210A mutation related to prothrombin activity

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Aim: to study the association between prothrombin activity in the blood plasma and gestational complications in women with the prothrombin G20210A mutation.

Materials and methods. A prospective clinical cohort study including 290 pregnant women aged 18 to 45 years was conducted from 2012 to 2018. Two cohorts were formed: a study group of 140 patients with the GA genotype and a control group of 150 women with the GG genotype. In the groups, the activity of prothrombin (Factor II) in the venous blood plasma was evaluated during pregnancy. The stages of cytotrophoblast invasion were taken into account when relating the prothrombin activity to gestational complications.

Results. The median prothrombin activity in the control group ranged from 108 % during the preconception period to 144 % during pregnancy (95 % CI = 130–150). In the study group with the GA genotype, the activity was significantly higher at the same periods: from 149 to 181 % (95 % CI = 142–195; p < 0.0001). With the prothrombin activity from 148.5 to 180.6 %, the pregnancy in the study group progressed normally. Higher levels of prothrombin activity were associated with early and/or severe preeclampsia (PE), and fetal growth retardation (FGR).

Conclusion. The obtained data on prothrombin activity in the blood plasma during pregnancy complications suggest that the manifestation of the GA genotype in the form of early and/or severe PE and FGR is associated with the level of plasma prothrombin activity. The threshold value of Factor II activity was calculated for patients with the G20210A mutation; based on this value it becomes possible to predict PE at the preconception stage (171.0 %; AUC – 0.86; p < 0.0001) and at a gestational age of 7–8 weeks (181.3 %; AUC – 0.84; p < 0.0001).

About the Authors

M. G. Nikolaeva
Altai State Medical University, Health Ministry of Russian Federation
Russian Federation

Mariya G. Nikolaeva – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology with the course of Professional Postgraduate Education

40 Lenin Avе., Barnaul 656038

Scopus Author ID: 57191960907

N. N. Yasafova
Altai Regional Clinical Hospital
Russian Federation

Natalia N. Yasafova – MD, Hematologist

1 Lyapidevskogo Str., Barnaul 656045

A. P. Momot
Altay Branch of National Research Center for Hematology, Health Ministry of Russian Federation
Russian Federation

Andrey P. Momot – MD, Dr Sci Med, Professor, Director

1 Lyapidevskogo Str., Barnaul 656045

Scopus Author ID: 6603848680

M. S. Zainulina
I.P. Pavlov First Saint Petersburg State Medical University, Health Ministry of Russian Federation; V.F. Snegirev Maternity Hospital № 6
Russian Federation

Marina S. Zainulina – MD, Dr Sci Med, Professor, Department of Obstetrics, Gynecology and Reproductive Medicine, I.P. Pavlov First Saint Petersburg State Medical University; Head Physician, V.F. Snegirev Maternity Hospital № 6

6/8 Lev Tolstoy Str., Saint Petersburg 197022, 

5 Mayakovskogo Str., Saint Petersburg 192014

Scopus Author ID: 37076359000

Researcher ID: B-5746-2018

K. A. Momot
Altai Regional Clinical Hospital
Russian Federation

Ksenia A. Momot – MD, Hematologist

1 Lyapidevskogo Str., Barnaul 656045

I. A. Taranenko
Altai Regional Clinical Hospital
Russian Federation

Irina A. Taranenko – MD, PhD, Hematologist

1 Lyapidevskogo Str., Barnaul 656045


1. Poort S.R., Rosendaal F.R., Reitsma P.H., Bertina R.M. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88(10):3698–703.

2. Simioni P., Tormene D., Manfrin D. et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol. 1998;103(4):1045–50. DOI: 10.1046/j.1365-2141.1998.01112.x.

3. Kyrle P.A., Mannhalter C., Béguin S. et al. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol. 1998;18(8):1287–91. DOI: 10.1161/01.atv.18.8.1287.

4. Franco R.F., Reitsma P.H. Genetic risk factors of venous thrombosis. Hum Genet. 2001;109(4):369–84. DOI: 10.1007/s004390100593.

5. Zivelin A., Rosenberg N., Faier S. et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood. 1998;92(4):1119–24.

6. Nowak-Göttl U., Junker R., Kreuz W. et al; Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood. 2001;97(4):858–62. DOI: 10.1182/blood.V97.4.858.

7. Rosendaal F.R., Doggen C.J., Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79(4):706–8. DOI: 10.1055/s-0037-1615049.

8. Emmerich J., Rosendaal F.R., 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):809–16. DOI: 10.1055/s-0037-1616136.

9. 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. DOI: 10.1378/chest.11-2300.

10. Thromboembolic disease in pregnancy and the puerperium: acute management. Green-top Guideline No. 37b. Royal College of Obstetricians and Gynaecologists, 2015. 32 s. Available at: (Accessed: 10.10.2019).

11. Butenas S., van’t Veer C., Mann K.G. “Normal” thrombin generation. Blood. 1999;94(7):2169–78.

12. Momot A.P., Nikolaeva M.G., Yasafova N.N. et al. Clinical and laboratory manifestations of the prothrombin gene mutation in women of reproductive age. J Blood Med. 2019;10:255–263. DOI: 10.2147/JBM.S212759.

13. Makatsariya A.D., Bitsadze V.O., Khizroeva D.Kh. et al. Thromboprophylaxis in pregnant women with thrombophilia and thrombosis in past medical history. [Tromboprofilaktika u beremennyh s trombofiliej i trombozami v anamneze]. Byulleten’ SO RAMN. 2013;33(6):99–109. (In Russ.).

14. Robertson L., Wu O., Langhorne P. et al. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132(2):171–96. DOI: 10.1111/j.1365-2141.2005.05847.x.

15. Gao H., Tao F.B. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb Res. 2015;135(2):339–46. DOI: 10.1016/j.thromres.2014.12.001.

16. Lin J., August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005;105(1):182–92. DOI: 10.1097/01.AOG.0000146250.85561.e9.

17. Rodger M.A., Walker M.C. et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost. 2014;12(4):469–78. DOI: 10.1111/jth.12509.

18. Strizhakov A.N., Voloschuk I.N., Timokhina E.V. et al. A clinical significance of thrombophilia in the development of apoptosis and proliferation in placental insufficiency. [Klinicheskoe znachenie trombofilii v razvitii apoptoza i proliferacii pri placentarnoj nedostatochnosti]. Voprosy ginekologii, akusherstva i perinatologii. 2010;9(4):5–12. (In Russ.).

19. Bitsadze V.O., Makatsariya A.D., Hizroeva D.H. et al. Thrombophilia as a most important link in the pathogenesis of pregnancy м complications. [Trombofiliya kak vazhnejshee zveno patogeneza oslozhnenij beremennosti]. Prakticheskaya medicina. 2012;(5):22–9. (In Russ.).

20. Nadeev A.P., Zhukova V.A., Karpov M.A. et al. Morphology of placenta in hereditary thrombophilia. [Morfologiya placenty pri nasledstvennoj trombofilii]. Arhiv patologii. 2014;76(3):33–6. (In Russ.).

21. Milovanov A.P., Kuznetsova N.B., Bushtyreva I.O. The morphology, typical combinations of polymorphic genes of hemostasis, and specific features of the pathogenesis of retrochorial hematoma in missed abortion. [Morfologiya, harakternye sochetaniya polimorfnyh genov gemostaza i osobennosti patogeneza retrohorial’noj gematomy pri nerazvivayushchejsya beremennosti]. Arhiv patologii. 2016;78(5):3–8. (In Russ.). DOI: 10.17116/patol20167853-8.

22. Karpich S. A., Shmeleva V. M., Kapustin S. I. et al. Assessment of prothrombotic phenotype by thrombin generation test in asymptomatic carriers of G1691A mutation in factor FV and/or G20210A mutation in prothrombin gene. [Ocenka protromboticheskogo feno-tipa u asimptomnyh nositelej mutacii G1691A v gene V i/ili G20210A v gene protrombina s pomoshch’yu testa generacii trombina]. Tromboz, gemostaz i reologiya. 2018;(3):11–6. (In Russ.). DOI: 10.25555/THR.2018.3.0845.

23. Tranquilli A.L. Introduction to ISSHP new classification of preeclampsia. Pregnancy Hypertens. 2013;3(2):58–9. DOI: 10.1016/j.preghy.2013.04.006.

24. The Investigation and Management of the Small–for–Gestational–Age Fetus. Green–top Guideline No. 31. Royal College of Obstetricians and Gynecologists, 2014. 34 s. Available at: (Accessed: 10.10.2019).

25. Baluda V.P., Barkagan Z.S., Kuznik B.I., Lakin K.M. Laboratory methods for hemostasis studying: monograph. Ed. E.D. Goldberg. [Laboratornye metody issledovaniya sistemy gemostaza: monografiya. Pod red. E.D. Gol’dberga]. Tomsk: Izd-vo «Krasnoe znamya», 1980. 313 s. (In Russ.).

26. Momot A.P., Molchanova I.V., Batrak T.A. et al. Reference values of hemostatic system parameters in normal pregnancy and after delivery. [Referensnye znacheniya pokazatelej sistemy gemostaza pri fiziologicheski protekayushchej beremennosti i posle rodorazresheniya]. Problemy reprodukcii. 2015;21(1):89–97. (In Russ.). DOI: 10.17116/repro20152189-97.

27. Song B., Zhang G., Zhu W., Liang Z. ROC operating point selection for classification of imbalanced data with application to computer-aided polyp detection in CT colonography. Int J Comput Assist Radiol Surg. 2014;9(1):79–89. DOI: 10.1007/s11548-013-0913-8.

28. Radzinsky V.E. Non-developing pregnancy. Methodical recommendations of MARS (Interdisciplinary Association of Specialists in Reproductive Medicine). [Nerazvivayushchayasya beremennost’. Metodicheskie rekomendacii MARS (Mezhdisciplinarnoj associacii specialistov reproduktivnoj mediciny)]. Moskva: Redakciya zhurnala StatusPraesens, 2015. 48 s. (In Russ.). Available at: (Accessed: 10.10.2019).

29. Mierla D., Szmal C., Neagos D. et al. Association of prothrombin (A20210G) and factor V Leiden (A506G) with recurrent pregnancy loss. Maedica (Buchar). 2012;7(3):222–6.

30. Kornyushina E.A., Zainulina M.S. Abnormalities of coagulation system, methods of their correction and pregnancy outcomes in patients with thrombophilia and miscarriage. [Narusheniya sistemy gemostaza, metody ih korrekcii i iskhody beremennosti u bol’nyh s nevynashivaniem i trombofiliej]. Zhurnal akusherstva i zhenskih boleznej. 2008;57(4):89–95. (In Russ.).

31. Said J.M., Higgins J.R., Moses E.K. et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol. 2010;115(1):5–13. DOI: 10.1097/AOG.0b013e3181c68907.

32. Soria J.M., Almasy L., Souto J.C. et al. Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood. 2000;95(9):2780–5.

For citation:

Nikolaeva M.G., Yasafova N.N., Momot A.P., Zainulina M.S., Momot K.A., Taranenko I.A. Gestational complications of the prothrombin G20210A mutation related to prothrombin activity. Obstetrics, Gynecology and Reproduction. 2020;14(2):192-202. (In Russ.)

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