Evaluation Of PAI-1 Polymorphisms in Central and Peripheral Thromboembolies

Year 2021, Volume: 38 Issue: 2, 167 - 171, 03.04.2021

Özge Arıcı Düz , Oktay Olmuşçelik , Ali İhsan Gemici , Özlem Saatci

Abstract

Objective
Thromboembolism is a clinical finding that occurs due to thrombus; formed in the vascular system and has various etiological factors. It can be classified as central and peripheral thromboembolism. Our objective in this study is to explore genetic risk factors in central and peripheral thromboembolism and reveal the differences.
Material and Methods
342 thromboembolism patients were retrospectively included to the study between January 2016 and December 2019. Demographic characteristics, risk factors for thromboembolism and genetic mutations in central and peripheral thromboembolism groups were overviewed. The genetic mutations evaluated in patients were Factor V Leiden G1691A, Factor V HR1299R, Factor II (Prothrombin) G20210A, MTHFR (Methylenetetrahydrofolate reductase) C677T, MTHFR A1298C, PAI 4G / 5G.
Results
Within the scope of the study, genetic analyzes of 106 patients were reached and included in the study. 72 central embolisms (69.8%), 34 (31.2%) peripheral embolism were detected. 63 of the central emboli were from arterial and 9 were from venous origin. There was no significant difference between age, gender and risk factors of central thromboembolism and peripheral thromboembolism patients (p˃0.05), but smoking was more common in central thromboembolism patients (p: 0.041). 4G / 5G polymorphism was observed more frequently in patients with central thromboembolism (p: 0.039).
Conclusion
Thromboembolism is a multifactorial disease, 4G / 5G polymorphism is a medium risk factor for thromboembolism. We conclude that 4G / 5G polymorphism is more frequent in central thromboembolism than peripheral thromboembolism and its evaluation can give more information about the thromboembolic risk analyse.

Keywords

PAI polymorphisms, thromboembolism, stroke, 4G / 5G polymorphism

References

• Referans1 Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd, 1993. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. Jan;24(1):35-41.
• Referans2 Attia J, Thakkinstian A, Wang Y, Lincz L, Parsons M, Sturm J, McGettigan P, Scott R, Meldrum C, Levi C., 2007. The PAI-1 4G/5G gene polymorphism and ischemic stroke: an association study and meta-analysis. J Stroke Cerebrovasc Dis. 16(4):173-9.
• Referans3 Barcellona D, Fenu L, Cauli C, Pisu G, Marongiu F., 2003. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost. 90(6):1061-4.
• Referans4 Bastard JP, Piéroni L, Hainque B., 2000. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabetes Metab Res Rev. 16(3):192-201.
• Referans5 Benchenane K, López-Atalaya JP, Fernández-Monreal M, Touzani O, Vivien D., 2004. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci. 27(3):155-60.
• Referans6 Boncoraglio GB, Bodini A, Brambilla C, Carriero MR, Ciusani E, Parati EA., 2006. An effect of the PAI-1 4G/5G polymorphism on cholesterol levels may explain conflicting associations with myocardial infarction and stroke. Cerebrovasc Dis. 22(2-3):191-5.
• Referans6 Cao Y, Chen W, Qian Y, Zeng Y, Liu W., 2014. Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population. Int J Neurosci. 124(12):874-81.
• Referans7 Casas JP, Hingorani AD, Bautista LE, Sharma P., 2004. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 61(11):1652-1661.
• Referans8 Catto AJ, Carter AM, Stickland M, Bamford JM, Davies JA, Grant PJ., 1997. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost. 77(4):730-4.
• Referans9 Chen CH, Eng HL, Chang CJ, Tsai TT, Lai ML, Chen HY, Liu CJ, Lin TM., 2003. 4G/5G promoter polymorphism of plasminogen activator inhibitor-1, lipid profiles, and ischemic stroke. J Lab Clin Med. 142(2):100-5.
• Referans10 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM., 1993. 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. 25;268(15):10739-45.
• Referans11 Endler G, Lalouschek W, Exner M, Mitterbauer G, Häring D, Mannhalter C., 2000. The 4G/4G genotype at nucleotide position -675 in the promotor region of the plasminogen activator inhibitor 1 (PAI-1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol. 110(2):469-71.
• Referans12 Eriksson P, Kallin B, van 't Hooft FM, Båvenholm P, Hamsten A., 1995. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA. 14;92(6):1851-5.
• Referans13 Gurgey A, Balta G, Boyvat A., 2003. Factor V Leiden mutation and PAI-1 gene 4G/5G genotype in thrombotic patients with Behcet's disease. Blood Coagul Fibrinolysis. 14(2):121-4.
• Referans14 Hatano S., 1976. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ. 54(5):541-53.
• Referans15 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd., 2000. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 27;160(6):809-15.
• Referans16 Incalcaterra E, Meli F, Muratori I, Corrado E, Amato C, Canino B, Ferrara F., 2014. Residual vein thrombosis and onset of post-thrombotic syndrome: influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene. Thromb Res. 133(3):371-4.
• Referans17 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG., 1996. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation. 1;94(9):2057-63.
• Referans18 Kain K, Young J, Bamford J, Bavington J, Grant PJ, Catto AJ., 2002. Determinants of plasminogen activator inhibitor-1 in South Asians with ischaemic stroke. Cerebrovasc Dis. 14(2):77-83.
• Referans19 Kupeli E, Verdi H, Simsek A, Atac FB, Eyuboglu FO., 2011. Genetic mutations in Turkish population with pulmonary embolism and deep venous thrombosis. Clin Appl Thromb Hemost. 17(6):87-94.
• Referans20 Kyrle PA, Eichinger S., 2005. Deep vein thrombosis. Lancet. 365(9465):1163-74.
• Referans21 Liguori R, Quaranta S, Di Fiore R, Elce A, Castaldo G, Amato F.,2014. A novel polymorphism in the PAI-1 gene promoter enhances gene expression. A novel pro-thrombotic risk factor? Thromb Res. 134(6):1229-33.
• Referans22 Loskutoff DJ., 1991. Regulation of PAI-1 gene expression. Fibrinolysis. 5:197-206.
• Referans23 Meltzer ME, Lisman T, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, Rosendaal FR., 2010. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood. 8;116(1):113-21.
• Referans24 Pepper MS., 2001. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol. 21(7):1104-17.
• Referans25 Ploplis VA., 2011. Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular disease. Curr Drug Targets. 12(12):1782-9.
• Referans26 Roest M, van der Schouw YT, Banga JD, Tempelman MJ, de Groot PG, Sixma JJ, Grobbee DE., 2000. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation. 101(1):67-70.
• Referans27 Roest M, Banga JD., 2003. Editorial comment-- genetic make-up for increased PAI-1 expression protects against stroke. Stroke. 34(12):2828-9.
• Referans28 Sartori MT, Vettor R, De Pergola G, De Mitrio V, Saggiorato G, Della Mea P, Patrassi GM, Lombardi AM, Fabris R, Girolami A., 2001. Role of the 4G/5G polymorphism of PaI-1 gene promoter on PaI-1 levels in obese patients: influence of fat distribution and insulin-resistance. Thromb Haemost. 86(5):1161-9.
• Referans29 Seguí R, Estellés A, Mira Y, España F, Villa P, Falcó C, Vayá A, Grancha S, Ferrando F, Aznar J., 2000. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol. 111(1):122-8.
• Referans30 Strandberg L, Lawrence D, T Ny., 1988. The organization of the human-plasminogen-activator-inhibitor-1 gene. Implications on the evolution of the serine-protease inhibitor family. Eur J Biochem. 176(3):609-16.
• Referans31 Su MT, Lin SH, Chen YC, Kuo PL., 2013. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Thromb Haemost. 109(1):8-15.
• Referans32 Tjärnlund-Wolf A, Brogren H, Lo EH, Wang X., 2012. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke. 43(10):2833-9.
• Referans33 Tsantes AE, Nikolopoulos GK, Bagos PG, Rapti E, Mantzios G, Kapsimali V, Travlou A., 2007. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost. 97(6):907-13.
• Referans34 Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas S, Kopterides P, Vaiopoulos G., 2008. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res. 122(6):736-42.
• Referans35 van Goor ML, Gómez García E, Leebeek F, Brouwers GJ, Koudstaal P, Dippel D., 2005. The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke. A case-control study. Thromb Haemost. 93(1):92-6.
• Referans36 Vergouwen MD, Frijns CJ, Roos YB, Rinkel GJ, Baas F, Vermeulen M., 2004. Plasminogen activator inhibitor-1 4G allele in the 4G/5G promoter polymorphism increases the occurrence of cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke. 35(6):1280-3.
• Referans37 Verschuur M, Jellema A, Bladbjerg EM, M Feskens EJ, Mensink RP, Møller L, Vos HL, de Maat MP., 2005. The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals. Atherosclerosis. 181(2):275-84.
• Referans38 Zidovetzki R, Chen P, Fisher M, Hofman FM, Faraci FM., 1999. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke. 30(3):651-5.