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PAI-1, Thrombophilia and Pregnancy: Research Review

A short overview of the role of plasminogen activator inhibitor type 1 (PAI-1) in thrombophilia and fertility - and the science behind it.

April 2, 2022 Pregmune Team

While pregnant, a person’s risk for blood clots in their veins (venous thromboembolism) increases 5- to 6-fold. If they have hereditary thrombophilia, that risk can increase more than 30-fold. Additionally, thrombophilia increases the chance of blood clots in the placenta, which can increase the likelihood of pregnancy loss.

Plasminogen activator inhibitor type 1 (PAI-1) is a protein that inhibits a process that prevents blood clots. In other words, less PAI-1 equals better protection against thrombosis. The high risk 4G allele increases levels of PAI-1 and by doing so can increase a person’s risk for blood clot and miscarriage. This test determines if the patient carries the higher risk 4G allele.


The main function of plasminogen activator inhibitor type 1 (PAI-1) is to decrease fibrinolysis (process that prevents blood clot formation), which leads to fibrin accumulation and vascular thrombosis1. An elevated plasma PAI-1 concentration has been identified as a risk factor for the development of myocardial infarction2.

Further, during implantation and placentation, PAI-1 inhibits the extra cellular matrix (ECM) degradation and remodeling of the endometrium, which inhibits the invasion of trophoblast3-4.
This suggests that PAI-1 expression may be a contributing factor in the etiology of recurrent pregnancy loss.
Indeed, the resulting shallow implantation may be associated with PAI-1 polymorphism and pregnancy losses or pre-eclampsia.

PAI-1 gene polymorphism has been shown to modulate the expression of PAI-1. Individuals homozygous for 4G (4G/4G) have the highest plasma PAI-1 level, heterozygous individuals (4G/5G) display an intermediate level while 5G homozygous individuals (5G/5G) have the lowest PAI-1 level5-6.

Published clinical data

Many published studies comparing PAI-1 genotype between fertile controls and women experiencing recurrent pregnancy losses (RPL) and/or recurrent implantation failure (RIF) showed an increased incidence of the PAI-1 4G/4G allele in infertile patients. Indeed, PAI-1 4G/4G is associated with increased risks of RIF (+350%), RPL (+120%) and RIF with RPL (+170%)9.

The presence of one allele 4G (heterozygous patient) was shown to increase a patient risk for miscarriage by 46%7 while being homozygous (4G/4G) increases a patient risk for a miscarriage by 89%-100%7-8

Coagulation and fibrinolytic cascades are key component in the process leading to pre-eclampsia. Therefore, increased PAI-1 levels may promote spiral arterial or intervillous thrombosis that reduces placental perfusion and may trigger pre-eclampsia11. Indeed, in a review including 58 meta-analysis, PAI-1 4G/5G polymorphism was shown to be a significant contributor to the pathogenesis of PE12.

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About Pregmune: We’re an innovative reproductive health technology company, built on a solid foundation of data gained from decades of experience and thousands of successful pregnancies. Our team of fertility specialists and scientists are using artificial intelligence to decipher the complexity of the immune system and help patients grow the families of their dreams.

Our first product, IRMA, provides patients and their doctors with a personalized report and evidence-based treatment plan that addresses immunological sources of unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure.


  1. Kuhli C, Luchtenberg M, Scharrer I, Hattenbach LO. Massive subhyaloidal hemorrhage associated with severe PAI-1 deficiency. Graefes Arch Clin Exp Ophthalmol. 2005;243(10):963-966.
  2. Sartori MT, Danesin C, Saggiorato G, Tormene D, Simioni P, Spiezia L, Patrassi GM, Girolami A. The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia. Clin Appl Thromb Hemost. 2003 Oct;9(4):299-307.
  3. Floridon C, Nielsen O, Holund B, et al. Does plasminogen activator inhibitor-1 (PAI-1) control trophoblast invasion? A study of 1558 Reproductive Sciences 24(11) fetal and maternal tissue in intrauterine, tubal and molar pregnancies. Placenta. 2000;21(8):754-762.
  4. Ye Y, Vattai A, Zhang X, Zhu J, Thaler CJ, Mahner S, Jeschke U, von Schönfeldt V. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases. Int J Mol Sci. 2017 Jul 29;18(8).
  5. Festa A, D’Agostino R Jr, Rich SS, Jenny NS, Tracy RP, Haffner SM. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Circulation. 2003;107(19):2422-2427.
  6. Grubic N, Stegnar M, Peternel P, Kaider A, Binder BR. A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res. 1996 Dec 15;84(6):431-43.
  7. Seguí R, Estellés A, Mira Y, España F, Villa P, Falcó C, Vayá A, Grancha S, Ferrando F, Aznar J. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol. 2000 Oct;111(1):122-8.
  8.  Huang Z, Tang W, Liang Z, Chen Q, Li M, Li Y, Lao S, Pan H, Huang L, Huang M,  Hu X, Zhao J. Plasminogen Activator Inhibitor-1 Polymorphism Confers a Genetic Contribution to the Risk of Recurrent Spontaneous Abortion: An Updated Meta-Analysis. Reprod Sci. 2017 Nov;24(11):1551-1560.
  9. Li X, Liu Y, Zhang R, Tan J, Chen L, Liu Y. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit. 2015 Apr 11;21: 1051-6.
    29- Salazar Garcia MD, Sung N, Mullenix TM, Dambaeva S, Beaman K, Gilman-Sachs A, Kwak-Kim J. Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles. Am J Reprod Immunol. 2016 Jul;76(1):70-81.
  10. Williams PJ, Broughton Pipkin F (2011) The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 25: 405–17.
  11.  Belo L, Santos-Silva A, Rumley A, Lowe G, Pereira-Leite L, et al. (2002) Elevated tissue plasminogen activator as a potential marker of endothelial dysfunction in pre-eclampsia: correlation with proteinuria. BJOG 109: 1250–5.
  12.  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 Jun;51(6):720-730.