1. bookVolume 23 (2015): Issue 1 (March 2015)
Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
access type Open Access

Prothrombotic risk mutations and polymorphisms in patients with hemophilia A – a preliminary study / Polimorfismele și mutațiile cu risc protrombotic la pacienții cu hemofilie A - studiu preliminar

Journal Details
License
Format
Journal
eISSN
2284-5623
First Published
08 Aug 2013
Publication timeframe
4 times per year
Languages
English
Abstract

Introduction. In search for explanations of the clinical heterogeneity in patients with haemophilia (PwH) with the same mutation or degree of factor VIII deficiency, the coexistence of single or associated prothrombotic risk mutations has been widely evaluated. Objective. The evaluation of the frequency of prothrombotic risk mutations and polymorphisms in PwH in comparison with the general population. Method. The study was performed on 113 consecutive PwH consisting of PCR technology aiming to detect: factor V Leiden - G 1691A (FVL) and prothrombin (PT) - G 20210 A mutations, methylentetrahydrofolat - reductase (MTHFR) and plasminogen activator inhibitor type 1 (PAI-1) polymorphisms. Results. Within the whole study group, 52.21% patients have been identified with associated prothrombotic risk mutations or polymorphisms, 40.70% with one and 7.08% without any such alterations. The global frequency was characterized by the predominance of PAI-1 polymorphism present in 82.29% and MTHFR in 52.21% of patients. Heterozygous variants of PT G20210A, FV G1691A, MTHFR and PAI-1 were found in 7.96%, 9.73%, 39.82% and 53.98% cases, respectively. According to the disease severity, in 89 patients with severe hemophilia, the following frequencies of polymorphisms were found: for MTHFR 52.80%, for FV G1691A 5.61%, for PT G20210A 8.99% and for PAI-1 polymorphism 79.77%. Conclusions. The frequency of FV, PT and PAI-1 genes alterations in our group of hemophilia patients is higher than in the normal population. Nevertheless, considering their uneven distribution in different ethnic groups and geographical regions, more studies on a larger age- and sex-matched patient population are needed.

Keywords

Cuvinte cheie

1. van Dijk K, van der Bom JG, Fischer K, Grobbee DE, van den Berg HM. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature. Thromb Haemost. 2004 Aug;92(2):305-10.10.1160/TH04-02-0112Search in Google Scholar

2. Franchini M, Lippi G. Factor V Leiden and hemophilia. Thromb Res. 2010 Feb;125(2):119-23. DOI: 10.1016/j. thromres.2009.11.003Search in Google Scholar

3. Sanna V, Zarrilli F, Nardiello P, D’Argenio V, Rocino A, Coppola A, et al. Mutational spectrum of F8 gene and prothrombotic gene variants in haemophilia A patients from Southern Italy. Haemophilia. 2008 Jul;14(4):796-803. DOI: 10.1111/j.1365-2516.2008.01705.x10.1111/j.1365-2516.2008.01705.xSearch in Google Scholar

4. Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association! Haemophilia. 2004 Jul;10(4):319-26. DOI: 10.1111/j.1365-2516.2004.00906.x10.1111/j.1365-2516.2004.00906.xSearch in Google Scholar

5. Kurnik K, Kreuz W, Horneff S, Düring C, Schobess R, Bidlingmaier C, et al. Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children--results of a multicenter study. Haematologica. 2007 Jul;92(7):982-5. DOI: 10.3324/haematol.1116110.3324/haematol.11161Search in Google Scholar

6. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V - associated with resistance to activated protein C. Nature. 1994 May 5; 369(6475):64-7. DOI: 10.1038/369064a010.1038/369064a0Search in Google Scholar

7. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3`-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996 Nov 15;88(10):3698-703.10.1182/blood.V88.10.3698.bloodjournal88103698Search in Google Scholar

8. Födinger M, Hörl WH, Sunder-Plassmann G. Molecular biology of 5, 10-methylenetetrahydrofolate reductase. J Nephrol. 2000 Jan-Feb;13(1):20-33.Search in Google Scholar

9. Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common Methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998 May; 62(5):1258-60. DOI: 10.1086/30183610.1086/301836Search in Google Scholar

10. Abeer M, Hesham A. Genetic polymorphisms of Plasminogen Activator Inhibitor-1, vascular endothelial growth factor and angiotensin converting enzyme among pre-eclamptic women. Egypt J Med Lab Sci. 2010 Mar; 19(1):39-44.Search in Google Scholar

11. Nordt TK, Lohrmann J, Bode C. Regulation of PAI-1 expression by genetic polymorphisms. Impact on atherogenesis. Thromb Res. 2001 Sep;103 Suppl 1:S1-5.DOI: 10.1016/S0049-3848(01)00292-410.1016/S0049-3848(01)00292-4Search in Google Scholar

12. Falk G, Almquist A, Nordenhem A, Svensson H, Wiman B. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis. 1995 May;9(3):170-4. DOI: 10.1016/S0268-9499(95)80007-710.1016/S0268-9499(95)80007-7Search in Google Scholar

13. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. DOI: 10.1038/ng0595-11110.1038/ng0595-1117647779Search in Google Scholar

14. Xenophontos SL, Hadjivassiliou M, Ayrton N, Karagrigoriou A, Pantzaris M, Nicolaides AN, et al. Spectrum and prevalence of prothrombotic single nucleotide polymorphism profiles in the Greek Cypriot population. Int Angiol. 2002 Dec;21(4):322-9.Search in Google Scholar

15. Saour JN, Shoukri MM, Mammo LA. The Saudi Thrombosis and Familial Thrombophilia Registry. Design, rational, and preliminary results. Saudi Med J. 2009 Oct; 30(10):1286-90.Search in Google Scholar

16. Hussein AS. High prevalence of three prothrombotic polymorphisms among Palestinians: factor V G1691A, factor II G20210A and methylenetetrahydrofolate reductase C677T. J Thromb Thrombolysis. 2012 Oct;34(3):383-7. DOI: 10.1007/s11239-012-0731-910.1007/s11239-012-0731-9Search in Google Scholar

17. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995 Oct;346(8983):1133-4. DOI: 10.1016/S0140-6736(95)91803-510.1016/S0140-6736(95)91803-5Search in Google Scholar

18. Lucotte G, Mercier G. Population genetics of factor V Leiden in Europe. Blood Cells Mol Dis. 2001 Mar- Apr;27(2):362-7. DOI: 10.1006/bcmd.2001.038810.1006/bcmd.2001.038811259157Search in Google Scholar

19. Roosendaal FR, Doggen C, Zivelin A, Arruda V, Aiach M. Geographic distribution of the 20210G to A prothrombin variant. Thromb Haemost. 1998 Apr;79(4):706-8.10.1055/s-0037-1615049Search in Google Scholar

20. Alfirevic Z, Simundic A, Nikolac N, Sobocan N, Alfirevic I, Stefanovic M, et al. Frequency of factor II G20210A, factor V Leiden, MTHFR C677T and PAI-1 5G/4G polymorphism in patients with venous thromboembolism: Croatian case control study. Biochemia Medica. 2010 Mar;20(2):229-35. DOI: 10.11613/ BM.2010.02810.11613/BM.2010.028Search in Google Scholar

21. Kvasnička T, Hájková J, Bobčíková P, Cverhová V, Malíková I, Ulrych J, et al. The Frequencies of Six Important Thrombophilic Mutations in a Population of the Czech Republic. Physiol Res. 2014 Jan;63(2):245-53.10.33549/physiolres.93261824397802Search in Google Scholar

22. Pepe G, Camacho Vanegas O, Giusti B, Brunelli T, Marcucci R, Attanasio M, et al. Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-Methylenetetrahydrofolate reductase. Am J Hum Genet. 1998 Sep;63(3):917-20. DOI: 10.1086/30201510.1086/30201513774039718345Search in Google Scholar

23. Hessner MJ, Luhm RA, Pearson SL, Endean DJ, Friedman KD, Montgomery RR. Prevalence of Prothrombin G20210A, Factor V G1691A (Leiden), and MethylenetetrahydrofolateReductase (MTHFR) C677T in Seven Different Populations Determined by Multiplex Allele-specific PCR. Thromb Haemost. 1999 May;81(5):733-8.10.1055/s-0037-1614563Search in Google Scholar

24. Escuriola Ettingshausen C, Halimeh S, Kurnik K, Schobess R, Wermes C, Junker R, et al. Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost. 2001 Feb;85(2):218-20.10.1055/s-0037-1615679Search in Google Scholar

25. Nowak-Göttl U, Escuriola C, Kurnik K, Schobess R, Horneff S, Kosch A, et al. Haemophilia and thrombophilia. What do we learn about combined inheritance of both genetic variations? Hämostaseologie. 2003 Feb;23(1):36-40.10.1055/s-0037-1619560Search in Google Scholar

26. Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S et al. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr. 1999 Sep;129(9):1656-61.10.1093/jn/129.9.165610460200Search in Google Scholar

27. Bavikatty NR, Killeen AA, Akel N, Normolle D, Schmaier AH. Association of the prothrombin G20210A mutation with factor V Leiden in a midwestern American population. Am J Clin Pathol. 2000 Aug; 114(2):272-5. DOI: 10.1309/LQKG-F0D4-C6FFFNEH Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo