Skip to main content
SpringerLink
Log in

The association between thrombophilic gene mutations and recurrent pregnancy loss

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To determine whether the Factor V (1691G/A), Factor V HR2 (4070A/G), Prothrombin (20210G/A), PAI-1 (-675 I/D, 5G/4G), ACE (intron 16 I/D), Factor VII (Gln353Arg), Factor XIII (Val34Leu), β-fibrinogen (-455G/A), Glycoprotein Ia (807C/T), tPA (intron 8 D/I) gene mutations could be risk factors for recurrent pregnancy loss (RPL).

Methods

Genotyping of thrombophilic gene mutations were carried out by amplification Refractory Mutation System-PCR (ARMS-PCR) method after DNA extraction.

Results

We found that the mutant allele frequencies of Factor V (1691G/A), Factor V HR2 (4070A/G), Prothrombin (20210G/A), PAI-1 (-675 I/D, 5G/4G), Factor XIII (Val34Leu) and β-fibrinogen (-455G/A) were more seen in the case group compared with the healthy control; However, the difference between the two group is not statistically significant (p > 0.05). Whilst the mutant allele frequencies of other studied genes were lower in the case in comparison to the fertile control women (p > 0.05).

Conclusion

Taken together, our data has shown that the prevalence of thrombophilic gene mutations was similar in women with RPL and healthy controls. Therefore, it appears that further studies on large-scale population and other genetic variants will be needed to conclusively find candidate genes for RPL unknown etiology in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Allison JL, Schust DJ. Recurrent first trimester pregnancy loss: revised definitions and novel causes. Curr Opin Endocrinol Diabetes Obes. 2009;16:446–50.

    Article  PubMed  Google Scholar 

  2. Altintas A, Pasa S, Akdeniz N, Cil T, Yurt M, Ayyildiz O, et al. Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: data from the southeast of Turkey. Ann Hematol. 2007;86:727–31.

    Article  PubMed  CAS  Google Scholar 

  3. Berthold H, Guido AH, Jorgen K, Peter H, Holger K, Abdulgabar S. Screening for multiple hereditary hypercoagulability factors using the amplification refractory mutation system. Thromb Res. 2003;111:115–20.

    Article  CAS  Google Scholar 

  4. Bloomenthal D, Dadelszen P, Liston R, Magee L, Tsang P. The effect of factor V Leiden carriage on maternal and fetal health. CMAJ. 2002;167:48–54.

    PubMed  PubMed Central  Google Scholar 

  5. Bom JG, Knijff P, Haverkate F, Bots ML, Meijer P, deJong PTVM, et al. Tissue plasminogen activator and risk of myocardial infarction. Circulation. 1997;95:2623–7.

    Article  PubMed  Google Scholar 

  6. Brandt JT. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med. 2002;126:1376–81.

    PubMed  CAS  Google Scholar 

  7. Bray PF. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol. 2000;7:284–9.

    Article  PubMed  CAS  Google Scholar 

  8. Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ. Polymorphisms in the ACE and PAI -1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod. 2003;18:2473–7.

    Article  PubMed  CAS  Google Scholar 

  9. Carp H, Salomon O, Seidman D. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod. 2002;17:1633–7.

    Article  PubMed  Google Scholar 

  10. Castoldi E, Simioni P, Kalafatis M, Lunghi B, Tormene D, Girelli D, et al. Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood. 2000;96:1443–8.

    PubMed  CAS  Google Scholar 

  11. Cleary-Goldman J, Nakhuda GS, Zimmermann RC, Sauer MV. The role of factor V Leiden mutation in recurrent pregnancy loss. J Am Med Wom Assoc. 2003;58:165–72.

    PubMed  Google Scholar 

  12. Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol. 2006;55:360–8.

    Article  PubMed  CAS  Google Scholar 

  13. Coulam CB, Wallis D, Weinstein J, DasGupta DS, Jeyendran RS. Comparison of thrombophilic gene mutations among patients experiencing recurrent miscarriage and deep vein thrombosis. Am J Reprod Immunol. 2008;60:426–31.

    Article  PubMed  CAS  Google Scholar 

  14. Dawood F, Mountford R, Farquharson R, Quenby S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR. Hum Reprod. 2007;22:2546–53.

    Article  PubMed  CAS  Google Scholar 

  15. Dossenbach-Glaninger A, Trotsenburg M, Dossenbach M, Oberkanins C, Moritz A, Krugluger W, et al. Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss. Clin Chem. 2003;49:1081–6.

    Article  PubMed  CAS  Google Scholar 

  16. Dunne FM, Doggen CJ, Heemskerk M, Rosendaal FR, Helmerhorst FM. Factor V Leiden mutation in relation to fecundity and miscarriage in women with venous thrombosis. Hum Reprod. 2005;20:802–6.

    Article  PubMed  CAS  Google Scholar 

  17. Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009;2:76–83.

    PubMed  PubMed Central  Google Scholar 

  18. Garcia-Enguidanos A, Calle ME, Valero J, Luna S, Dominguez-Rojas V. Risk factors in miscarriage: a review. Eur J Obstet Gynecol Reprod Biol. 2002;102:111–9.

    Article  PubMed  CAS  Google Scholar 

  19. Ghee CB, Burrows RF. Prothrombin G20210A mutation is not associated with recurrent miscarriages. Aust N Z J Obstet Gynaecol. 2002;42:167–9.

    Article  PubMed  Google Scholar 

  20. Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol. 2006;56:230–6.

    Article  PubMed  CAS  Google Scholar 

  21. Goodman C, Hur J, Goodman CS, Jeyendran RS, Coulam C. Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages? Am J Reprod Immunol. 2009;62:365–70.

    Article  PubMed  CAS  Google Scholar 

  22. Gumpel C, Fornasiero L, Suarez S, Santillan G, Colabianchi J. PAI- 1 4G⁄ 5G polymorphism detection and obstetric complications. Thromb Res. 2009;123:S148.

    Article  Google Scholar 

  23. Hashimoto K, Shizusawa Y, Shimoya K. The factor V Leiden mutation in Japanese couples with recurrent spontaneous abortion. Hum Reprod. 1999;14:1872–4.

    Article  PubMed  CAS  Google Scholar 

  24. Humphries SE, Cook M, Dubovitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet. 1987;1:1452–5.

    Article  PubMed  CAS  Google Scholar 

  25. Jaleh Z, Mozhdeh M, Khatereh A, Fariborz G, Zohreh T. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol. 2011;155:217–20.

    Article  Google Scholar 

  26. Jeddi-Tehrani M, Torabi R, Zarnani AH, Mohammadzadeh A, Arefi S, Zeraati H, et al. Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss. Am J Reprod Immunol. 2011;66:149–56.

    Article  PubMed  CAS  Google Scholar 

  27. Kupferminc MJ. Thrombophilia and pregnancy. Reprod Biol Endocrinol. 2003;1:111–33.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Marty S, Barro C, Chatelain B, Fimbel B, Tribout B, Reynaud J, et al. The paradoxical association between inherited factor VII deficiency and venous thrombosis. Haemophilia. 2008;14:564–70.

    Article  PubMed  CAS  Google Scholar 

  29. Meka A, Reddy BM. Recurrent spontaneous abortions: an overview of genetic and non-genetic backgrounds. Int J Hum Genet. 2006;6:109–17.

    CAS  Google Scholar 

  30. Okumus G, Kiyan E, Arseven O, Tabak L, Bayrak EK, Unaltuna NE, et al. Platelet glycoprotein ia 807c/t and 873g/a polymorphisms in patients with venous thromboembolism. Clin Appl Thromb Hemost. 2007;13:101–3.

    Article  PubMed  CAS  Google Scholar 

  31. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet. 2005;272:95–108.

    Article  PubMed  CAS  Google Scholar 

  32. Reiner AP, Siscovick DS, Rosendaal FR. Platelet glycoprotein gene polymorphisms and risk of thrombosis: facts and fancies. Rev Clin Exp Hematol. 2001;5:262–87.

    Article  PubMed  CAS  Google Scholar 

  33. Ridker PM, Baker MT, Hennekens CH, Stampfer MJ, Vaughn DE. Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator (TPA) and risks of myocardial infarction among middle-aged men. Arterioscler Thromb Vasc Biol. 1997;17:1687–90.

    PubMed  CAS  Google Scholar 

  34. Rousseau F, Rehel R, Rouillard P, DeGranpre P, Khandjian EW. High throughput and economical mutation detection and RFLP analysis using a minimethod for DNA preparation from whole blood and acrylamide gel electrophoresis. Hum Mutat. 1994;4:51–4.

    Article  PubMed  CAS  Google Scholar 

  35. Sehirali S, Inal MM, Yildirim Y, Balim Z, Kosova B, Karamizrak T, et al. Prothrombin G20210A mutation in cases with recurrent miscarriage: a study of the Mediterranean population. Arch Gynecol Obstet. 2005;273:170–3.

    Article  PubMed  CAS  Google Scholar 

  36. Seremak-Mrozikiewicz A, Drews K, Kurzawińska G, Barlik M, Mrozikiewicz PM. The connection between Arg353Gln polymorphism of coagulation factor VII and recurrent miscarriages. Ginekol Pol. 2009;80:8–13.

    PubMed  Google Scholar 

  37. Steeds R, Adams M, Smith P, Channer K, Samani NJ. Distribution of tissue plasminogen activator insertion/deletion polymorphism in myocardial infarction and control subjects. Thromb Haemost. 1998;79:980–4.

    PubMed  CAS  Google Scholar 

  38. Subrt I, Ulcova-Gallova Z, Cerna M, Hejnalova M, Slovanova J, Bibkova K, et al. Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women. Am J Reprod Immunol. 2013. doi:10.1111/aji.12099.

    PubMed  Google Scholar 

  39. Walker ID. Thrombophilia in pregnancy. J Clin Pathol. 2000;53:573–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Yenicesu I, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C, et al. A prospective case–control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss. Am J Reprod Immunol. 2010;63:126–36.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Authors would like to express our sincerest appreciation to Dr. Siavash Dastmalchi, Dr. Morteza Ghojazadeh and Meysam Dolati for their great help in this project.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Faculty of Science, Azarbaijan Shahid Madani University, Tabriz, Iran

    Ahmad Poursadegh Zonouzi & Nader Chaparzadeh

  2. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Ahmad Poursadegh Zonouzi

  3. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Saeid Ghorbian

  4. Department of Obstetrics and Gynecology and Women’s Reproductive Health Research Center, Tabriz University of Medical Science, Tabriz, Iran

    Mahzad Mehrzad Sadaghiani, Laya Farzadi & Alieh Ghasemzadeh

  5. Department of Medical Genetic, Faculty of Medicine, Tabriz University of Medical Science, Azadi Street, Tabriz, PO Box: 5165638465, Iran

    Taiebeh Kafshdooz

  6. Faculty of Medicine, University of Liverpool, Liverpool, UK

    Masoud Sakhinia

  7. Department of Medical Genetic, Faculty of Medicine, Tabriz Genetic Analysis Centre (TGAC), Tuberculosis and Lung Diseases Research Centre, Azadi Street, Tabriz, PO Box: 5165638465, Iran

    Ebrahim Sakhinia

Authors
  1. Ahmad Poursadegh Zonouzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nader Chaparzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saeid Ghorbian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahzad Mehrzad Sadaghiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laya Farzadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alieh Ghasemzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Taiebeh Kafshdooz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masoud Sakhinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ebrahim Sakhinia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ebrahim Sakhinia.

Additional information

Capsule It seems that our selected thrombophilic gene mutations is not significantly associated with recurrent pregnancy losses in North western Iranian women.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Poursadegh Zonouzi, A., Chaparzadeh, N., Ghorbian, S. et al. The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 30, 1353–1359 (2013). https://doi.org/10.1007/s10815-013-0071-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-013-0071-5

Keywords

Search

Navigation