Prevalence of PAI-1 (F2, F5, FGB) gene polymorphisms in women with obesity: impact on pregnancy outcomes

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The coexistence of obesity and thrombophilic gene polymorphisms (PAI-1, F5, F2, FGB) in pregnant women significantly increases the risk of obstetric complications. Metabolic disturbances in obesity (hyperinsulinemia, elevated levels of proinflammatory cytokines) potentiate the expression of these genes, leading to pronounced hemostatic disorders such as hypercoagulation, hypofibrinolysis, and impaired placentation. Clinically, this manifests as higher rates of preeclampsia, fetal growth restriction, gestational diabetes, and venous thromboembolism. The impact of individual polymorphisms (particularly F2 and FGB) remains controversial and largely depends on the patient’s ethnic background and combinations with other genetic variants. For instance, PAI-1 4G/5G shows a consistent association with adverse outcomes in some populations, whereas isolated F5 Leiden polymorphism rarely correlates with placental complications without synergistic effects from PAI-1 or obesity. Addressing this issue requires personalized strategies. Anticoagulant therapy (low-molecular-weight heparins) is effective mainly in cases of high combined thrombotic risk, but additional control of metabolic disorders (weight reduction, correction of insulin resistance) is essential to manage placental insufficiency. Future research priorities include the development of ethnicity-adapted algorithms integrating combinatorial genetic profiles and biomarker changes.

Full Text

Restricted Access

About the authors

Madina M. Mukhtarova

Dagestan State Medical University

Author for correspondence.
Email: arabakor@gmail.com
ORCID iD: 0009-0008-7153-0080
SPIN-code: 4980-5340
Russian Federation, 1 Lenin sq, Makhachkala, Republic of Dagestan, 367000

Zukhra A. Abusueva

Dagestan State Medical University

Email: zuhraabusueva@mail.ru
ORCID iD: 0000-0002-7729-1606
SPIN-code: 2434-9228

MD, Dr. Sci. (Medicine)

Russian Federation, 1 Lenin sq, Makhachkala, Republic of Dagestan, 367000

Natella A. Stefanyan

Dagestan State Medical University

Email: nstefanyan@inbox.ru
ORCID iD: 0000-0002-6418-5599
SPIN-code: 4124-1850

Associate Professor

Russian Federation, 1 Lenin sq, Makhachkala, Republic of Dagestan, 367000

Svetlana A. Alieva

Dagestan State Medical University

Email: svetlanaaidemirovna@mail.ru
ORCID iD: 0009-0005-8384-2952
SPIN-code: 3099-7711

MD, Cand. Sci. (Medicine), Associate Professor

Russian Federation, 1 Lenin sq, Makhachkala, Republic of Dagestan, 367000

Salidat M. Mamayeva

Dagestan State Medical University

Email: mamaeva.salidat@mail.ru
ORCID iD: 0000-0002-8884-0420
SPIN-code: 9357-0321

MD, Cand. Sci. (Medicine), Associate Professor

Russian Federation, 1 Lenin sq, Makhachkala, Republic of Dagestan, 367000

References

  1. Samfireag M, Potre C, Potre O, et al. Assessment of the particularities of thrombophilia in the management of pregnant women in the western part of romania. Medicina (Kaunas). 2023;59(5):851. doi: 10.3390/medicina59050851
  2. Giouleka S, Tsakiridis I, Koutsouki G, et al. Obesity in pregnancy: a comprehensive review of influential guidelines. Obstet Gynecol Surv. 2023;78(1):50–68. doi: 10.1097/OGX.0000000000001091
  3. Agersnap I, Nissen PH, Hvas AM. The role of plasminogen activator inhibitor type 1 (PAI-1) in placenta-mediated pregnancy complications: a systematic review. Semin Thromb Hemost. 2022;48(5):607–624. doi: 10.1055/s-0041-1742082
  4. Maghsudlu M, Noroozi Z, Zokaei E, Motevaseli E. Systematic review and meta-analysis of association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss: an update. Thromb J. 2024;22(1):44. doi: 10.1186/s12959-024-00612-9
  5. El-Khawaga OY, ElSaid AM, Ahmed H, et al. Association between PAI-1 gene - 657 4G/5G polymorphism and preeclampsia in Egyptian women: a case-control study. BMC Pregnancy Childbirth. 2025;25(1):610. doi: 10.1186/s12884-025-07737-3
  6. Udenze IC, Arikawe AP, Makwe CC. Early pregnancy plasminogen activator inhibitor-1 levels in Nigerian women and its relationship with preeclampsia. Niger J Clin Pract. 2017;20(5):517–522. doi: 10.4103/1119-3077.183256
  7. Altwayan R, Tombuloglu H, Alhamid G, et al. Comprehensive review of thrombophilia: pathophysiology, prevalence, risk factors, and molecular diagnosis. Transfus Clin Biol. 2025;32(2):228–244. doi: 10.1016/j.tracli.2025.03.004
  8. Wysocka U, Sałacińska K, Pinkier I, et al. To test or not to test: routine thrombophilia diagnostic screening of women with reproductive failures. J Clin Med. 2023;12(24):7527. doi: 10.3390/jcm12247527
  9. Reddy RRN, Mutreja D, Moorchung N, Mukhopadhyay I. Recurrent pregnancy loss: can factor V Leiden mutations be a cause. Obstet Gynecol Sci. 2019;62(3):179–182. doi: 10.5468/ogs.2019.62.3.179
  10. Schwedler C, Heymann G, Bukreeva L, Hoppe B. Association of genetic polymorphisms of fibrinogen, factor XIII a-subunit and α2-antiplasmin with fibrinogen levels in pregnant women. Life (Basel). 2021;11(12):1340. doi: 10.3390/life11121340
  11. Ahmed NA, Adam I, Elzaki SEG, et al. Factor-V Leiden G1691A and prothrombin G20210A polymorphisms in Sudanese women with preeclampsia, a case-control study. BMC Med Genet. 2019;20(1):2. doi: 10.1186/s12881-018-0737-z
  12. Salazar Garcia MD, Sung N, Mullenix TM, et al. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with reproductive failure: metabolic, hormonal, and immune profiles. Am J Reprod Immunol. 2016;76(1):70–81. doi: 10.1111/aji.12516
  13. Komsa-Penkova R, Danailova A, Krumova S, et al. Altered thermal behavior of blood plasma proteome related to inflammatory cytokines in early pregnancy loss. Int J Mol Sci. 2022;23(15):8764. doi: 10.3390/ijms23158764
  14. Swanepoel AC, van Reenen M, de Lange-Loots Z, Pieters M. Association of the metabolic syndrome with PAI 1act and clot lysis time over a 10-year follow up in an African population. Nutr Metab Cardiovasc Dis. 2023;33(3):592–601. doi: 10.1016/j.numecd.2022.12.011
  15. Fernandes KS, Sandrim VC. 4G/5G polymorphism modulates PAI-1 circulating levels in obese women. Mol Cell Biochem. 2012;364(1-2):299–301. doi: 10.1007/s11010-012-1230-1
  16. Zhai J, Li Z, Zhou Y, Yang X. The role of plasminogen activator inhibitor-1 in gynecological and obstetrical diseases: An update review. J Reprod Immunol. 2022;150:103490. doi: 10.1016/j.jri.2022.103490
  17. Giannakou K, Evangelou E, Papatheodorou SI. Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies. Ultrasound Obstet Gynecol. 2018;51(6):720–730. doi: 10.1002/uog.18959
  18. Said JM, Tsui R, Borg AJ, et al. The PAI-1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women. J Thromb Haemost. 2012;10(5):881–886. doi: 10.1111/j.1538-7836.2012.04700.x
  19. Tangjittipokin W, Thanatummatis B, Wardati F, et al. The genetic polymorphisms and levels of adipokines and adipocytokines that influence the risk of developing gestational diabetes mellitus in Thai pregnant women. Gene. 2023;860:147228. doi: 10.1016/j.gene.2023.147228
  20. Martins Kattah F, Janjusevic M, Figueiredo N, et al. HOMA-IR as a predictor of PAI-1 levels in women with severe obesity. Biomedicines. 2024;12(6):1222. doi: 10.3390/biomedicines12061222
  21. Sokol Karadjole V, D'Amato A, Milošević M, et al. Impact of thrombophilic polymorphisms in antenatal women on perinatal health: a single-center prospective study. J Pers Med. 2024;14(4):433. doi: 10.3390/jpm14040433
  22. Golub AV, Popova LV, Shelest EA, et al. Assessment of the influence of inherited thrombophilia combined with elevated body mass index on the risk of developing venous thromboembolism. Modern Technologies in Medicine. 2016;8(4):285–287. EDN: XVCEXB
  23. Sayal HB, Beksac MS. The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study. BMC Pregnancy Childbirth. 2024;24(1):719. doi: 10.1186/s12884-024-06926-w
  24. Advisory board conclusion following the discussion "Controversial issues of low molecular weight heparins use in obstetrics". Obstetrics, Gynecology and Reproduction. 2021;15(4):461–469. doi: 10.17749/2313-7347/ob.gyn.rep.2021.244 EDN: YOYODB
  25. Wang J, Wang C, Chen N, et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: a meta-analysis. Thromb Res. 2014;134(6):1241–1248. doi: 10.1016/j.thromres.2014.09.035
  26. Chen J, Zhai C, Wang Z, et al. The susceptibility of SERPINE1 rs1799889 SNP in diabetic vascular complications: a meta-analysis of fifty-one case-control studies. BMC Endocr Disord. 2021;21(1):195. doi: 10.1186/s12902-021-00837-z
  27. Perevezentsev OA. Association of genetic variants of hemostasis system genes with gestational thrombophilia in women. Ann Med Health Sci Res. 2024;(5):1–3.
  28. Vashukova ES, Glotov AS, Kanaeva MD. Analysis haemostatic system gene polymorphism in pregnant women without complications from Russia and Ukrain. Ecological Genetics. 2011;9(1):70–80. doi: 10.17816/ecogen9170-80 EDN: NUDXDH
  29. Levine JA, Oleaga C, Eren M, et al. Role of PAI-1 in hepatic steatosis and dyslipidemia. Sci Rep. 2021;11(1):430. doi: 10.1038/s41598-020-79948-x
  30. Hoppe B, Schwedler C, Edelmann A, et al. Fibrinogen, factor XIII and α2-antiplasmin genotypes are associated with inflammatory activity and anti-citrullinated protein antibodies. Thromb Res. 2020;191:90–96. doi: 10.1016/j.thromres.2020.04.043
  31. Chen H, Nie S, Lu M. Association between plasminogen activator inhibitor-1 gene polymorphisms and recurrent pregnancy loss: a systematic review and meta-analysis. Am J Reprod Immunol. 2015;73(4):292–300. doi: 10.1111/aji.12321
  32. Huffman JE, Nicholas J, Hahn J, et al. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. Blood. 2024;144(21):2248–2265. doi: 10.1182/blood.2023022596
  33. Al Rahbi N, Al Salmi I, Hannawi S, et al. Higher fibrinogen levels among patient with end-stage kidney disease post initiation of peritoneal dialysis: cardiovascular risk attenuation. J Nephrol Renal Ther. 2021;7:043. doi: 10.24966/NRT-7313/100043
  34. Batiha GE, Al-Kuraishy HM, Al-Maiahy TJ, et al. Plasminogen activator inhibitor 1 and gestational diabetes: the causal relationship. Diabetol Metab Syndr. 2022;14(1):127. doi: 10.1186/s13098-022-00900-2
  35. Aracic N, Roje D, Jakus IA, et al. The impact of inherited thrombophilia types and low molecular weight heparin treatment on pregnancy complications in women with previous adverse outcome. Yonsei Med J. 2016;57(5):1230–1235. doi: 10.3349/ymj.2016.57.5.1230
  36. Mission JF, Marshall NE, Caughey AB. Pregnancy risks associated with obesity. Obstet Gynecol Clin North Am. 2015;42(2):335–353. doi: 10.1016/j.ogc.2015.01.008
  37. Murvai VR, Radu CM, Galiș R, et al. The relationship between thrombophilia and modifications in first-trimester prenatal screening markers. Medicina (Kaunas). 2025;61(2):318. doi: 10.3390/medicina61020318
  38. Matusevich EM, Yuryev S.Yu, Nikolaeva MG, Frankevich VE. The role of pathological hemostasis in formation of perinatal complications of the novel coronavirus infection. Akusherstvo i Ginekologiya. 2024;(6):46–55. doi: 10.18565/aig.2024.5 EDN: NYKKDX
  39. Radjabov MO, Radjabova GM, Isakhanova MM, et al. The prevalence of mutations in the genes of hereditary thrombophilia FII G20210AG>A and FV G41721A G>A in ethnic populations of Dagestan. Ecological Medicine. 2019:2(3):27–36. doi: 10.34662/2587-6988.2019.2.3.27-36 EDN: XATUTS

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 86335 от 11.12.2023 г.  
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ЭЛ № ФС 77 - 80633 от 15.03.2021 г.