MEHMET AKİF SARGIN, Emel ASAR-CANAZ, Ali GEDİKBAŞI, Hilmi TOZKIR, Yavuz CEYLAN

Preeklampside Genetik Trombofilik Belirteçler

Amaç: Preeklampsi ile trombofilinin genetik belirteçlerinden olan MTHFR polimorfizmi, Faktör V Leiden mutasyonu ve Protrombin gen mutasyonu arasındaki olası ilişkiyi incelemeyi; hafif ve ağır preeklamptik olgularda ve erken başlangıçlı preeklampside bu ilişkinin klinik kuvvetini değerlendirmeyi amaçladık. Gereç ve yöntemler: Ekim 2008 ve Mart 2010 tarihleri arasında, T.C. Sağlık Bakanlığı İstanbul Bakırköy Kadın Doğum ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi'ne başvuran ve American College of Obstetrics and Gynecology (ACOG) 2002 kriterlerine göre preeklampsi tanısı konularak tedavisi yapılan 68 gebe çalışmaya alındı. Gebeliğini komplikasyonsuz olarak miadına (37 hafta ve üzeri) ulaştırmış 70 sağlıklı gebe ile kontrol grubu oluşturuldu. Her iki gruptaki gebelerden 5 ml kan EDTA'lı tüplere alınarak genetik laboratuarına gönderildi. Çalışma prospektif kohort tipi olgu kontrol çalışması olarak gerçekleştirildi.Bulgular: Preeklamptik gebeler ile kontrol grubu gebelerde faktör V Leiden, MTHFR C677T, protrombin G20210A homozigot veya heterozigot mutasyon sıklıkları açısından anlamlı fark bulunmadı. Ağır preeklamptik gebelerle kontrol grubu karşılaştırıldığında da mutasyonlar açısından istatistiksel olarak anlamlı farklılık saptanmadı. Preeklampsinin klinik bulgularının 34 hafta ve 28 hafta altında başladığı olgular ve preeklampsiye intrauterin gelişme kısıtlılığının eşlik ettiği olgular ayrı ayrı irdelendiğinde de belirtilen mutasyonlar açısından farklılık saptanmadı. Sağlıklı gebelerde en az bir mutasyona sahip olma oranı % 64 olarak hesaplandı ve en sık mutasyonun MTHFR 677 heterozigot polimorfizmi olduğu gösterildi. Sonuçlar: Ağır preeklamptik gebelerde, gebelik komplikasyonlarının normal popülasyona göre sık rastlanmasına, maternal ve fetal morbidite ve mortalitenin yüksek olmasına karşın; trombofilik genetik belirteçler sağlıklı gebelerden anlamlı farklılık göstermemektedir. Preeklampsi ve trombofili arasındaki ilişki henüz net olarak kanıtlanmamış olduğundan, bu genetik belirteç- lerin rutin tarama testi olarak kullanılması ve buna dayalı prognoz değerlendirmesi yapılması sağlıklı görünmemektedir.

Genetic Thrombophilias and Preeclampsia

Objective: We aimed to investigate the relationship between preeclampsia and inherited thrombophilias such as MTHFR gene mutations, factor V Leiden mutations and prothrombin gene mutation; and to assess the significance of the relationship at mild, severe and early-onset preeclampsia. Material and methods: 68 preeclamptic pregnants diagnosed between October 2008 and March 2010 according to the American College of Obstetrics and Gynecology (ACOG) guideline 2002, and 70 healty pregnant women who carried her pregnancy beyond term (37 weeks and after) without any complications and applied to Bakirkoy Maternity and Children Hospital were taken into study and control groups. 5 ml venous blood were taken from each women in both groups and genetic evaluation is done at laboratory. Results: AFactor V Leiden, MTHFR C677T, and prothrombin homozygous or heterozygous mutations were not statistically different between preeclamptics and healty pregnants. Comparisons for the mutations between severe preeclampsia and control cases were not statistically different. Cases with early-onset preeclampsia that occured before 34 weeks and 28 weeks, and the preeclamptic cases complicated by IUGR, were also assessed separately and mutations were not statistically different between study and control cases. The ratio of having at least one mutation in healty patiens were 64 percent, and the most common mutation was MTHFR heterozygous polymorphism. Conclusion: Although pregnancy complications, maternal and fetal morbidity and mortaliy was higher in severe preeclampsia; presence of thrombophilic gene mutations was not statistically different from healty pregnants. Because the association between preeclampsia and thrombophilia is unproven yet, using such genetic markers as routine screening for thrombophilia or prognostic tools is not recommended.

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1. Walters WA, Ford JB, Sullivan EA & King JF. Maternal deaths in Australia. Medical Journal of Australia 2002;176: 413–414.
2. The National Institute for Clinical Excellence, The Scottish Executive Health Department, The Department of Health, Social Services and Public Safety, Northern Ireland, Why Mothers Die 1997– 1999: the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG Press, 2001
3. Creag MD, Malia RG, Cooper SM, et al. Screening for lupus anticoagulant and anticardiolipin antibodies in women with fetal loss. Clin Pathol 1991;44(1):45-7
4. Preston FE, Rosendaal FR, Walker ID, et al. EPCOT study: increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913-6.
5. Arias F, Romero R, Joist H, Kraus FT: Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta.J Matern Fetal Med 1998;7: 277-286.
6. Many A, Schreiber L, Rosner S, Lessing LB, Eldor A, Kupferminc MJ: Patholojic features of the placenta in women with severe pregnancy complications and thrombophilia. Obstet Gynecol 2001;98:1041-1044.
7. Gris JC, Quere I, Monpeyroux F, et al. Casecontrol study of the frequency of thrombophilic disorders in couples withlate fetal loss and no thrombotic antecedent. Thromb Haemost 1999;81:891-9.
8. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB: Increased fruquency of the genetic thrombophilia in women with complications of pregnancy. N Eng J Med 1999; 340:9-13
9. Courtney Reynolds, William C. Mabie, Baha M. Sibai. Hypertensive States of Pregnancy. Alan H. DeCherney, Lauren Nathan.Current Obstetric and Gynecology Diagnosis and Treatment. Ninth Edition. Lange/ McGraw Publishing.2003;19: 338-339
10. Greer IA. Thrombophilia: implications for pregnancy outcome. Thrombosis Research 2003; 109: 73-81.
11. Kupferminc MJ. Thrombophilia and pregnancy. Reproductive Biology and Endocrinology 2003;1:111.
12.Verspyck E, Borg JY, Le Cam-Duchez V, Goffinet F, Degre’ S, Fournet P, Marpeau L. Thrombophilia and fetal growth restriction. European Journal of Obstetrics and Gynecology and Reproductive Biology 2004;113:36-40.
13. Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. European Journal of Obstetrics and Gynecology and Reproductive Biology 2002;101:6-14.
14. Brenner B. Thrombophilia and adverse pregnancy outcome. Obstet Gynecol Clin N Am 2006;33:443-456.
15. Arias F, Romero R, Joist H, Kraus FT: Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta.J Matern Fetal Med 1998;7: 277-286.
16. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Seminars in Thrombosis and Haemostasis 1998; 24:367-79
17. Deren Ö, Baykal C, Al A, Önderoğlu L, Durukan T, Gürgey A. Nedeni açıklanamayan gebelik komplikasyonlarında trombofilik hastalıkların rolü. Jinekoloji ve Obstetrik Bülteni 2000; 9(1): 18-22.
18. Lindqvist PG, Svenson PJ, Mars K et al. Activated protein C resistance (FV:Q506) and pregnancy. Thrombosis and Haemostasis 1999; 81: 532–537.
19. Livingston JC, Barton JR, Park V et al. Maternal and fetal inherited thrombophilias are not related to the development of severe pre-eclampsia. American Journal of Obstetrics and Gynecology 2001; 185: 153–157.
20. van Pampus MG, Dekker GA,Wolf H et al. High prevalence of haemostatic abnormalities in women with a history of severe pre-eclampsia. American Journal of Obstetrics and Gynecology 1999; 180: 1146–1150.
21. Higgins JR, Kaiser T, Moses EK et al. Prothrombin G20210A mutation. Is it associated with pre-eclampsia? Gynaecological and Obstetric Investigation 2000; 50: 254–257.
22. Kupferminc MJ, Peri H, Zwang E et al. High prevalence of the prothrombin mutation in women with intrauterine growth retriction, abruptio placentae and second trimester loss. Acta Obstetricia et Gynaecologica Scandinavica 2000; 79: 963–967.
23. Sazci A, Ergul E, Kaya G, Kara I. Genotype and allele frequencies of the polymorphic methylenetetrahidrofolat reductase gene in Turkey. Cell Biochem Funct 2005;23:51-4
24. van de Put NMJ, Gabreels F, Stevens EMB, Smeitink JAM, Trijbels FJM, Eskes TKAB, van der Heuvel L, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase Gene: An additional risk factor for neural-tube defects. Am J Hum Genet 1998;62:1044-1051.
25. S. Sohda, T. Arinami, H. Hamada, N. Yamada, H. Hamaguchi. Methylenetetrahydrofolate reductase polymorphism and preeclampsia. J Med Genet 34(1997) 525-526