PAI-1, Thrombophilia and Pregnancy: Research Review

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.

Physiology

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 trophoblast^3-4.
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 level^5-6.

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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References

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.