Download PDF
Semin Thromb Hemost 2022; 48(05): 607-624
DOI: 10.1055/s-0041-1742082
Review Article

The Role of Plasminogen Activator Inhibitor Type 1 (PAI-1) in Placenta-Mediated Pregnancy Complications: A Systematic Review

Ida Agersnap
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Peter H. Nissen
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department for Clinical Medicine, Aarhus University, Aarhus, Denmark
,
Anne-Mette Hvas
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department for Clinical Medicine, Aarhus University, Aarhus, Denmark
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Plasminogen activator inhibitor type 1 (PAI-1) is a main inhibitor of fibrinolysis. The PAI-1 gene (SERPINE1) harbors genetic variants with the potential of modifying plasma levels of PAI-1. A delicate balance exists between the coagulation and fibrinolytic system, and changes in PAI-1 have been suggested to compromise establishment of a successful pregnancy. Therefore, this systematic review investigated the association between genetic variants and/or plasma levels of PAI-1 and placenta-mediated pregnancy complications. An extensive literature search was conducted in PubMed, Embase, and Web of Science on the 29th of April 2021. All studies underwent quality rating according to The Study Quality Assessment Tools checklist provided by National Heart, Lung and Blood Institute. A total of 71 studies were included, among which 60 studies investigated PAI-1 genotypes and 11 studies measured PAI-1 plasma levels. In 32 out of 59 studies, no association was found between the PAI-1 4G/5G polymorphism (rs1799768) and placenta-mediated pregnancy complications, which was stated as no significant difference in the genotype distribution comparing women with and without placenta-mediated pregnancy complications or no significantly increased odds of placenta-mediated pregnancy complications carrying the 4G/4G or 4G/5G genotype. Eight out of 11 studies reported significantly higher PAI-1 plasma levels in preeclamptic women than in women without preeclampsia. In conclusion, no clear evidence indicates that PAI-1 polymorphisms are associated with placenta-mediated pregnancy complications, and the possible association between high PAI-1 plasma levels and preeclampsia needs further investigations. Thus, investigation of PAI-1 genotypes and PAI-1 plasma levels does not currently seem to have a place in daily clinical practice managing placenta-mediated pregnancy complications.

Keywords

placenta-mediated pregnancy complications - plasminogen activator inhibitor type 1 - low-molecular weight heparin - PAI-1 - pregnancy

Supplementary Material



Publication History

Article published online:
12 January 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Ye Y, Vattai A, Zhang X. et al. Role of plasminogen activator inhibitor type 1 in pathologies of female reproductive diseases. Int J Mol Sci 2017; 18 (08) E1651
    CrossrefPubMedGoogle Scholar
  • 2 Pannekoek H, Veerman H, Lambers H. et al. Endothelial plasminogen activator inhibitor (PAI): a new member of the Serpin gene family. EMBO J 1986; 5 (10) 2539-2544
    CrossrefPubMedGoogle Scholar
  • 3 Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D. Brief report: complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 1992; 327 (24) 1729-1733
    CrossrefPubMedGoogle Scholar
  • 4 D'Elia AV, Fabbro D, Driul L, Barillari G, Marchesoni D, Damante G. Plasminogen activator inhibitor-1 gene polymorphisms in pre-eclampsia. Semin Thromb Hemost 2011; 37 (02) 97-105
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Bosma PJ, van den Berg EA, Kooistra T, Siemieniak DR, Slightom JL. Human plasminogen activator inhibitor-1 gene. Promoter and structural gene nucleotide sequences. J Biol Chem 1988; 263 (19) 9129-9141
    CrossrefPubMedGoogle Scholar
  • 6 Morange PE, Saut N, Alessi MC. et al. Association of plasminogen activator inhibitor (PAI)-1 (SERPINE1) SNPs with myocardial infarction, plasma PAI-1, and metabolic parameters: the HIFMECH study. Arterioscler Thromb Vasc Biol 2007; 27 (10) 2250-2257
    CrossrefPubMedGoogle Scholar
  • 7 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268 (15) 10739-10745
    CrossrefPubMedGoogle Scholar
  • 8 Eriksson P, Kallin B, van 't Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995; 92 (06) 1851-1855
    CrossrefPubMedGoogle Scholar
  • 9 Ye S, Green FR, Scarabin PY. et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude CasTemoins de I'nfarctus du Mycocarde. Thromb Haemost 1995; 74 (03) 837-841
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29 (02) 125-130
    Google Scholar
  • 11 Cerneca F, Ricci G, Simeone R, Malisano M, Alberico S, Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73 (01) 31-36
    CrossrefPubMedGoogle Scholar
  • 12 Kruithof EK, Tran-Thang C, Gudinchet A. et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987; 69 (02) 460-466
    CrossrefPubMedGoogle Scholar
  • 13 Brenner B, Kupferminc MJ. Inherited thrombophilia and poor pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2003; 17 (03) 427-439
    CrossrefPubMedGoogle Scholar
  • 14 Rodger MA, Paidas M. Do thrombophilias cause placenta-mediated pregnancy complications?. Semin Thromb Hemost 2007; 33 (06) 597-603
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Kofinas A, Kofinas G, Sutija V. The role of second trimester ultrasound in the diagnosis of placental hypoechoic lesions leading to poor pregnancy outcome. J Matern Fetal Neonatal Med 2007; 20 (12) 859-866
    CrossrefPubMedGoogle Scholar
  • 16 Proctor LK, Whittle WL, Keating S, Viero S, Kingdom JC. Pathologic basis of echogenic cystic lesions in the human placenta: role of ultrasound-guided wire localization. Placenta 2010; 31 (12) 1111-1115
    CrossrefPubMedGoogle Scholar
  • 17 Lykke JA, Bare LA, Olsen J. et al. Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort. J Thromb Haemost 2012; 10 (07) 1320-1325
    CrossrefPubMedGoogle Scholar
  • 18 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361 (9361): 901-908
    CrossrefPubMedGoogle Scholar
  • 19 Rodger MA, Walker MC, Smith GN. et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost 2014; 12 (04) 469-478
    CrossrefPubMedGoogle Scholar
  • 20 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
    Google Scholar
  • 21 National Heart, Lung and Blood Institute. Study Quality Assessment Tools. Accessed March 15, 2021 at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
    PubMedGoogle Scholar
  • 22 De Maat MP, Jansen MW, Hille ET. et al. Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost 2004; 2 (09) 1588-1593
    CrossrefPubMedGoogle Scholar
  • 23 Elmahgoub IR, Afify RA, Abdel Aal AA, El-Sherbiny WS. Prevalence of coagulation factor XIII and plasminogen activator inhibitor-1 gene polymorphisms among Egyptian women suffering from unexplained primary recurrent miscarriage. J Reprod Immunol 2014; 103: 18-22
    CrossrefPubMedGoogle Scholar
  • 24 Gerhardt A, Goecke TW, Beckmann MW. et al. The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia. J Thromb Haemost 2005; 3 (04) 686-691
    CrossrefPubMedGoogle Scholar
  • 25 Glueck CJ, Kupferminc MJ, Fontaine RN, Wang P, Weksler BB, Eldor A. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001; 97 (01) 44-48
    PubMedGoogle Scholar
  • 26 Infante-Rivard C, Rivard GE, Guiguet M, Gauthier R. Thrombophilic polymorphisms and intrauterine growth restriction. Epidemiology 2005; 16 (03) 281-287
    CrossrefPubMedGoogle Scholar
  • 27 Jeon YJ, Kim YR, Lee BE. et al. Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women. Thromb Haemost 2013; 110 (04) 742-750
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Krause M, Sonntag B, Klamroth R. et al. Lipoprotein (a) and other prothrombotic risk factors in Caucasian women with unexplained recurrent miscarriage. Results of a multicentre case-control study. Thromb Haemost 2005; 93 (05) 867-871
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Magdoud K, Herbepin VG, Touraine R, Almawi WY, Mahjoub T. Plasminogen activator inhibitor 1 4G/5G and -844G/A variants in idiopathic recurrent pregnancy loss. Am J Reprod Immunol 2013; 70 (03) 246-252
    CrossrefPubMedGoogle Scholar
  • 30 Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 2013; 288 (05) 1171-1177
    CrossrefPubMedGoogle Scholar
  • 31 Perés Wingeyer S, Aranda F, Udry S, Latino J, de Larrañaga G. Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. Med Clin (Barc) 2019; 152 (07) 249-254
    PubMedGoogle Scholar
  • 32 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 (05) 881-886
    CrossrefPubMedGoogle Scholar
  • 33 Silver RM, Saade GR, Thorsten V. et al. Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 2016; 215 (04) 468.e1-468.e17
    CrossrefPubMedGoogle Scholar
  • 34 Cui L, Shu C, Liu Z. et al. Serum protein marker panel for predicting preeclampsia. Pregnancy Hypertens 2018; 14: 279-285
    CrossrefPubMedGoogle Scholar
  • 35 Elzein HO, Muddathir AR, Rida M, Rayis DA, Elhassan EM, Adam I. Fibrinolysis parameters in Sudanese women with severe preeclampsia. Hypertens Pregnancy 2016; 35 (04) 559-564
    CrossrefPubMedGoogle Scholar
  • 36 Schjetlein R, Abdelnoor M, Haugen G, Husby H, Sandset PM, Wisløff F. Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia. Acta Obstet Gynecol Scand 1999; 78 (03) 191-197
    CrossrefPubMedGoogle Scholar
  • 37 Aarabi M, Memariani T, Arefi S. et al. Polymorphisms of plasminogen activator inhibitor-1, angiotensin converting enzyme and coagulation factor XIII genes in patients with recurrent spontaneous abortion. J Matern Fetal Neonatal Med 2011; 24 (03) 545-548
    CrossrefPubMedGoogle Scholar
  • 38 Al Sallout RJ, Sharif FA. Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the Gaza Strip. Med Princ Pract 2010; 19 (02) 99-104
    CrossrefPubMedGoogle Scholar
  • 39 Alptekin H, Alptekin N, Selimoğlu R, Cengiz T, Bariş S. Inherited thrombophilia and thromboprophylaxis: a retrospective analysis of pregnancy outcomes in 106 patients. Clin Exp Obstet Gynecol 2017; 44: 749-754
    CrossrefPubMedGoogle Scholar
  • 40 Barlik M, Seremak-Mrozikiewicz A, Drews K. et al. Correlation between factor VII and PAI-1 genetic variants and recurrent miscarriage. Ginekol Pol 2016; 87 (07) 504-509
    CrossrefPubMedGoogle Scholar
  • 41 Barlik M, Wolski H, Drews K, Pieńkowski W, Klejewski A, Seremak-Mrozikiewicz A. The contribution of Hind III C>G PAI-1 gene polymorphism in etiology of recurrent miscarriages. Ginekol Pol 2015; 86 (04) 274-279
    CrossrefPubMedGoogle Scholar
  • 42 Bertinato JF, Morelli VM, Wataru GG. et al. Polymorphisms in thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor type 1 in women with primary recurrent pregnancy loss. Blood 2013; 122 (21) 4795
    CrossrefPubMedGoogle Scholar
  • 43 Bubalo P, Buterin I, Šalek Z, Ðogić V, Zupančić-Šalek S. Association of plasminogen activator inhibitor-1 gene polymorphisms and methylene tetrahydrofolate reductase polymorphisms with spontaneous miscarriages. Acta Haematol 2017; 138 (02) 111-115
    CrossrefPubMedGoogle Scholar
  • 44 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 (11) 2473-2477
    CrossrefPubMedGoogle Scholar
  • 45 Dalmáz CA, Santos KG, Botton MR, Tedoldi CL, Roisenberg I. Relationship between polymorphisms in thrombophilic genes and preeclampsia in a Brazilian population. Blood Cells Mol Dis 2006; 37 (02) 107-110
    CrossrefPubMedGoogle Scholar
  • 46 Djurovic J, Stojkovic O, Todorovic J. et al. Genetics of suspected thrombophilia in Serbian females with infertility, including three cases, homozygous for FII 20210A or FV 1691A mutations. Hum Fertil (Camb) 2017; 20 (02) 132-139
    CrossrefPubMedGoogle Scholar
  • 47 Fabbro D, D'Elia AV, Spizzo R. et al. Association between plasminogen activator inhibitor 1 gene polymorphisms and preeclampsia. Gynecol Obstet Invest 2003; 56 (01) 17-22
    CrossrefPubMedGoogle Scholar
  • 48 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 (01) 70-81
    CrossrefPubMedGoogle Scholar
  • 49 Häkli T, Romppanen EL, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S. Plasminogen activator inhibitor-1 polymorphism in women with pre-eclampsia. Genet Test 2003; 7 (03) 265-268
    CrossrefPubMedGoogle Scholar
  • 50 Idali F, Zareii S, Mohammad-Zadeh A. et al. Plasminogen activator inhibitor 1 and methylenetetrahydrofolate reductase gene mutations in Iranian women with polycystic ovary syndrome. Am J Reprod Immunol 2012; 68 (05) 400-407
    CrossrefPubMedGoogle Scholar
  • 51 Jeddi-Tehrani M, Torabi R, Zarnani AH. 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 (02) 149-156
    CrossrefPubMedGoogle Scholar
  • 52 Joksic I, Mikovic Z, Filimonovic D. et al. Combined presence of coagulation factor XIII V34L and plasminogen activator inhibitor 1 4G/5G gene polymorphisms significantly contribute to recurrent pregnancy loss in Serbian population. J Med Biochem 2020; 39 (02) 199-207
    PubMedGoogle Scholar
  • 53 Jusić A, Balić D, Avdić A, Pođanin M, Balić A. The association of factor V G1961A (factor V Leiden), prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women. Med Glas (Zenica) 2018; 15 (02) 158-163
    PubMedGoogle Scholar
  • 54 Kamal M, El-Khayat W. Do serum angiopoietin-1, angiopoietin-2, and their receptor Tie-2 and 4G/5G variant of PAI-1 gene have a role in the pathogenesis of preeclampsia?. J Investig Med 2011; 59 (07) 1147-1150
    CrossrefPubMedGoogle Scholar
  • 55 Khosravi F, Zarei S, Ahmadvand N. et al. Association between plasminogen activator inhibitor 1 gene mutation and different subgroups of recurrent miscarriage and implantation failure. J Assist Reprod Genet 2014; 31 (01) 121-124
    CrossrefPubMedGoogle Scholar
  • 56 Kim JJ, Choi YM, Lee SK. et al. The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study. Am J Reprod Immunol 2014; 72 (06) 571-576
    CrossrefPubMedGoogle Scholar
  • 57 Kurzawińska G, Barlik M, Drews K. et al. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population. Ginekol Pol 2016; 87 (04) 271-276
    CrossrefPubMedGoogle Scholar
  • 58 Lino FL, Traina É, Barreto JA, Moron AF, Mattar R. Thrombophilic mutations and polymorphisms, alone or in combination, and recurrent spontaneous abortion. Clin Appl Thromb Hemost 2015; 21 (04) 365-372
    CrossrefPubMedGoogle Scholar
  • 59 Ozdemir O, Yenicesu GI, Silan F. et al. Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomarkers 2012; 16 (04) 279-286
    CrossrefPubMedGoogle Scholar
  • 60 Patil R, Ghosh K, Vora S, Shetty S. Inherited and acquired thrombophilia in Indian women experiencing unexplained recurrent pregnancy loss. Blood Cells Mol Dis 2015; 55 (03) 200-205
    CrossrefPubMedGoogle Scholar
  • 61 Pegoraro RJ, Hira B, Rom L, Moodley J. Plasminogen activator inhibitor type 1 (PAI1) and platelet glycoprotein IIIa (PGIIIa) polymorphisms in Black South Africans with pre-eclampsia. Acta Obstet Gynecol Scand 2003; 82 (04) 313-317
    CrossrefPubMedGoogle Scholar
  • 62 Pietropolli A, Giuliani E, Bruno V, Patrizi L, Piccione E, Ticconi C. Plasminogen activator inhibitor-1, factor V, factor II and methylenetetrahydrofolate reductase polymorphisms in women with recurrent miscarriage. J Obstet Gynaecol 2014; 34 (03) 229-234
    CrossrefPubMedGoogle Scholar
  • 63 Sun L, Lv H, Wei W, Zhang D, Guan Y. Angiotensin-converting enzyme D/I and plasminogen activator inhibitor-1 4G/5G gene polymorphisms are associated with increased risk of spontaneous abortions in polycystic ovarian syndrome. J Endocrinol Invest 2010; 33 (02) 77-82
    CrossrefPubMedGoogle Scholar
  • 64 Torabi R, Zarei S, Zeraati H. et al. Combination of thrombophilic gene polymorphisms as a cause of increased the risk of recurrent pregnancy loss. J Reprod Infertil 2012; 13 (02) 89-94
    PubMedGoogle Scholar
  • 65 Trifonova EA, Swarovskaya MG, Ganzha OA, Voronkova OV, Gabidulina TV, Stepanov VA. The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss. J Assist Reprod Genet 2019; 36 (04) 717-726
    CrossrefPubMedGoogle Scholar
  • 66 Vora S, Shetty S, Salvi V, Satoskar P, Ghosh K. Thrombophilia and unexplained pregnancy loss in Indian patients. Natl Med J India 2008; 21 (03) 116-119
    PubMedGoogle Scholar
  • 67 Yamada N, Arinami T, Yamakawa-Kobayashi K. et al. The 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene is associated with severe preeclampsia. J Hum Genet 2000; 45 (03) 138-141
    CrossrefPubMedGoogle Scholar
  • 68 Yenicesu GI, Cetin M, Ozdemir O. 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 (02) 126-136
    CrossrefPubMedGoogle Scholar
  • 69 Abdel Gader AM, Al-Mishari AA, Awadalla SA, Buyuomi NM, Khashoggi T, Al-Hakeem M. Total and free tissue factor pathway inhibitor in pregnancy hypertension. Int J Gynaecol Obstet 2006; 95 (03) 248-253
    CrossrefPubMedGoogle Scholar
  • 70 Balcı Ekmekçi Ö, Ekmekçi H, Güngör Z. et al. Evaluation of Lp-PLA2 mass, vitronectin and PAI-1 activity levels in patients with preeclampsia. Arch Gynecol Obstet 2015; 292 (01) 53-58
    CrossrefPubMedGoogle Scholar
  • 71 Djurovic S, Clausen T, Wergeland R, Brosstad F, Berg K, Henriksen T. Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with subsequent pre-eclampsia. BJOG 2002; 109 (07) 759-764
    CrossrefPubMedGoogle Scholar
  • 72 Oladosu-Olayiwola O, Olawumi H, Babatunde A. et al. Fibrinolytic proteins of normal pregnancy and pre-eclamptic patients in North West Nigeria. Afr Health Sci 2018; 18 (03) 576-583
    CrossrefPubMedGoogle Scholar
  • 73 Schjetlein R, Haugen G, Wisløff F. Markers of intravascular coagulation and fibrinolysis in preeclampsia: association with intrauterine growth retardation. Acta Obstet Gynecol Scand 1997; 76 (06) 541-546
    CrossrefPubMedGoogle Scholar
  • 74 Swellam M, Samy N, Wahab SA, Ibrahim MS. Emerging role of endothelial and inflammatory markers in preeclampsia. Dis Markers 2009; 26 (03) 127-133
    CrossrefPubMedGoogle Scholar
  • 75 Tobinaga CM, Torloni MR, Gueuvoghlanian-Silva BY. et al. Angiogenic factors and uterine Doppler velocimetry in early- and late-onset preeclampsia. Acta Obstet Gynecol Scand 2014; 93 (05) 469-476
    CrossrefPubMedGoogle Scholar
  • 76 Bigdeli R, Younesi MR, Panahnejad E. et al. Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population. Syst Biol Reprod Med 2018; 64 (04) 274-282
    CrossrefPubMedGoogle Scholar
  • 77 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 (05) 360-368
    CrossrefPubMedGoogle Scholar
  • 78 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 (05) 426-431
    CrossrefPubMedGoogle Scholar
  • 79 Cozaru GC, Aschie M, Mitroi A, Brinzan C, Chisoi A. The genetic profile of thrombophilia in reproductive disorders. Revista De Chimie 2019; 70: 3830-3834
    CrossrefPubMedGoogle Scholar
  • 80 Dordevic V, Gvozdenov M, Pruner I. et al. The prevalence of PAI-1 4G/5G polymorphism in women with fetal loss - first data for a Serbian population. J Med Biochem 2014; 33: 203-207
    CrossrefPubMedGoogle Scholar
  • 81 Emir M, Skonieczna-Żydecka K, Valijevac A. et al. Lack of association between I/D ACE and-675 ID 4G / 5G PAI-1 polymorphisms and predicting risk of pregnancy loss (PROPALO) in Bosnian women. Proceedings of the International Conference on Medical and Biological Engineering 2017; 62: 440-444
    PubMedGoogle Scholar
  • 82 Ghosh K, Shetty S, Vora S. Plasminogen activator inhibitor-1 4G/5G gene polymorphism in women with fetal loss. Int J Gynaecol Obstet 2009; 107 (02) 159-160
    CrossrefPubMedGoogle Scholar
  • 83 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 (06) 365-370
    CrossrefPubMedGoogle Scholar
  • 84 Hefler L, Jirecek S, Heim K. et al. Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study. J Soc Gynecol Investig 2004; 11 (01) 42-44
    CrossrefPubMedGoogle Scholar
  • 85 Lenz B, Samardzija M, Drenjancevic D, Zibar D, Samardzija M, Milostic-Srb A. The investigation of hereditary and acquired thrombophilia risk factors in the development of complications in pregnancy in Croatian women. J Matern Fetal Neonatal Med 2016; 29 (02) 264-269
    CrossrefPubMedGoogle Scholar
  • 86 Loskutova TO, Demchenko TV, Kryachkova NV. Gene polymorphism of blood coagulation factors and endothelial dysfunction in early and late preeclampsia. Medical Perspectives-Medicni Perspektivi 2020; 25: 66
    CrossrefPubMedGoogle Scholar
  • 87 Morrison ER, Miedzybrodzka ZH, Campbell DM. et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002; 87 (05) 779-785
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Poursadegh Zonouzi A, Chaparzadeh N, Ghorbian S. et al. The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 2013; 30 (10) 1353-1359
    CrossrefPubMedGoogle Scholar
  • 89 Shakarami F, Akbari MT, Zare Karizi S. Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women. Iran J Reprod Med 2015; 13 (10) 627-632
    PubMedGoogle Scholar
  • 90 Subrt I, Ulcova-Gallova Z, Cerna M. et al. Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women. Am J Reprod Immunol 2013; 70 (01) 54-58
    CrossrefPubMedGoogle Scholar
  • 91 Vora S, Shetty S, Ghosh K. Thrombophilic dimension of recurrent fetal loss in Indian patients. Blood Coagul Fibrinolysis 2008; 19 (06) 581-584
    CrossrefPubMedGoogle Scholar
  • 92 Polat M, Biberoğlu EH, Güler İ, Biberoğlu ÖK. Coexistence of preeclampsia and inherited thrombophilia in Turkish pregnant women. Turk J Med Sci 2016; 46 (04) 1094-1100
    CrossrefPubMedGoogle Scholar
  • 93 Hoekstra T, Geleijnse JM, Schouten EG, Kluft C. Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk. Thromb Haemost 2004; 91 (05) 861-872
    Article in Thieme ConnectPubMedGoogle Scholar
  • 94 Kruithof EK, Gudinchet A, Bachmann F. Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb Haemost 1988; 59 (01) 7-12
    Article in Thieme ConnectPubMedGoogle Scholar
  • 95 Margaglione M, Cappucci G, d'Addedda M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18 (04) 562-567
    CrossrefPubMedGoogle Scholar
  • 96 Zhao L, Bracken MB, Dewan AT, Chen S. Association between the SERPINE1 (PAI-1) 4G/5G insertion/deletion promoter polymorphism (rs1799889) and pre-eclampsia: a systematic review and meta-analysis. Mol Hum Reprod 2013; 19 (03) 136-143
    CrossrefPubMedGoogle Scholar
  • 97 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; 21: 1051-1056
    CrossrefPubMedGoogle Scholar
  • 98 Huang Z, Tang W, Liang Z. et al. Plasminogen Activator Inhibitor-1 Polymorphism Confers a Genetic Contribution to the Risk of Recurrent Spontaneous Abortion: An Updated Meta-Analysis. Reprod Sci 2017; 24 (11) 1551-1560
    CrossrefPubMedGoogle Scholar
  • 99 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 (04) 292-300
    CrossrefPubMedGoogle Scholar
  • 100 Su MT, Lin SH, Chen YC, Kuo PL. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Thromb Haemost 2013; 109 (01) 8-15
    Article in Thieme ConnectPubMedGoogle Scholar
  • 101 American College of Obstetricians and Gynecologists' Committee on Practice Bulletins–Obstetrics. ACOG Practice Bulletin No. 197: inherited thrombophilias in pregnancy. Obstet Gynecol 2018; 132 (01) e18-e34
    CrossrefPubMedGoogle Scholar
  • 102 Royal College of Obstetricians and Gynaecologists. Green-top Guideline No. 17: The Investigation and Treatment of Couples with Recurrent First- trimester and Second-trimester Miscarriage. Accessed April 1, 2021 at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf 2011
    PubMedGoogle Scholar
  • 103 Aracic N, Roje D, Jakus IA, Bakotin M, Stefanovic V. 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 (05) 1230-1235
    CrossrefPubMedGoogle Scholar
  • 104 Estellés A, Gilabert J, Keeton M. et al. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation. Blood 1994; 84 (01) 143-150
    CrossrefPubMedGoogle Scholar
  • 105 Guller S, Ma Y, Malek A, Di Santo S, Schneider H. Differential release of plasminogen activator inhibitors (PAIs) during dual perfusion of human placenta: implications in preeclampsia. Placenta 2007; 28 (04) 278-285
    CrossrefPubMedGoogle Scholar
  • 106 Cruz-Lemini M, Vázquez JC, Ullmo J, Llurba E. Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis. Am J Obstet Gynecol 2021; S0002-9378 (20)31288-6
    PubMedGoogle Scholar
  • 107 Sillen M, Declerck PJ. Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition. Front Cardiovasc Med 2020; 7: 622473
    CrossrefPubMedGoogle Scholar