Thrombophilia in complicated pregnancies

Abstract

Objective: To investigate the incidence and etiology of pregnancy complications associated with thrombophilic factors. Methods: Fifty-four patients with complicated pregnancy and 40 healthy pregnant subjects were included the study. Factor V Leiden (FVL) mutation, protein S, protein C, anti-thrombin deficiency levels were investigated. Results: Of the 54 patients with complicated pregnancy, 29 had preeclampsia, 18 had intra uterine growth retardation, and 7 had intrauterine fetal loss. The most common defect was FVL mutation. FVL mutations in patient group and the control group were 27.2% and 10%, respectively, which were statistically significant. The protein S, protein C, and anti-thrombin deficiencies were found higher in the patient group compared to control (p>0.05 for each). Conclusion: FVL mutation was found higher in patient group compared to the control group, Protein C deficiency and anti-thrombin deficiency were related to preeclampsia but not other pregnancy complications. Clinicians should take into account the thrombophilia in complicated pregnancy, especially preeclampsia. J Clin Exp Invest 2013; 4 (4): 497-502

Keywords

• Factor V Leiden, protein C, protein S, anti-thrombin, complicated pregnancy

Komplikasyonlu gebeliklerde trombofili

Öz

Amaç: Gebelik komplikasyonlarında trombofilik faktörlerin görülme sıklığını ve etiyolojideki yerinin araştırılması. Yöntemler: Komplikasyonlu gebeliği olan 54 hasta ve sağlıklı 40 gebe olgu çalışma kapsamına dahil edildi. Faktör V Leiden (FVL) mutasyonu, protein S, protein C, anti-trombin eksiklikleri araştırıldı. Bulgular: Komplike gebeliği olan 54 hastanın 29\'unda preeklampsi, 18\'inde intrauterin büyüme geriliği ve 7 olguda ise intrauterin fetal kayıp saptandı. En sık gözlenen bozukluk FVL mutasyonu idi. FVL mutasyonu hasta ve kontrol gruplarında sırasıyla %27,2 ve %10 olup istatistiksel olarak anlamlı idi. Protein S, protein C, anti-trombin eksiklikleri hasta grubunda kontrol grubuna göre daha yüksek oranda gözlense de anlamlılık saptanmadı (p>0,05). Sonuç: FVL mutasyonu hasta grubunda kontrol grubuna göre yüksek bulundu. Protein C ve anti-trombin eksiklikleri diğer gebelik komplikasyonlarından ziyade preeklampsi ile ilişkili bulunmuştur. Klinisyenler başta preeklampsi olmak üzere komplike gebeliklerde trombofiliyi göz önünde bulundurmalıdırlar.

Anahtar Kelimeler

• Faktör V Leiden, protein C, protein S, anti-trombin, komplike gebelik

References

1. De Sefano V, Finazzi G, Mannucci PM. Inherited throm- bophilia: Patogenesis, Clinical syndromes and man- agement. Blood 1996;87:3531-3444.
2. Girling J, de Swiet M. Inherited thrombofilia and pregnan- cy. Curr Opin Obstet Gynecol 1998;10:135-144.
3. Griffin J, Evatt B, Zimmerman T, et al. Deficiency of pro- tein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-1373.
4. Dahlback B, Carlsson M, Svensson PJ. Familial throm- bophilia due to a previously unrecognised mechanism characterized by poor anticoagulant response to activat- ed Protein C: Prediction of a cofactor to activated Protein C. Proc Natl Acad Sci USA 1993; 90:1004-1008.
5. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic diseases: a clinical perspec- tive. Ann Intern Med 1997;127:895-903.
6. Griffin JH, Evatt B, Wideman C, et al. Anticoagulant pro- tein C pathway defective in majority thrombophilic pa- tients. Blood 1993;82:1989-1993.
7. Higgins JR, Walshe JJ, Darling MR, Norris L, Bonnar J. Hemostasis in the uteroplacental and peripheral circu- lations in normotensive and pre-eclamptic pregnancies. Am J Obstet Gynecol 1998;179:520-526.
8. McLintock C, Horth RA, Dekker G. Inherited trrombo- philias: Implications for pregnancy associated venous thromboembolism nd obstetric complications. Curr Probl Obstet Gynecol Fertil 2001;24:109-152.

9. Mousa HA, Alfirec Z. Do placental lesions reflect thrombo- philia state in women with adverse pregnancy outcome? Hum Reprod 2000;15:1830-1833.
10. De Stefano V, Chiusolo P, Paciaroni K, et al. Epidemi- ology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367-379.
11. Deren Ö, Baykal C, Al A, et al. Nedeni açıklanamayan gebelik komplikasyonlarında trombofilik hastalıkların rolü. Jinekoloji ve Obstetrik Bülteni 2000;9:18-22.
12. Özbek U, Tangün Y. Frequency of factor V Leiden (Arg- 506Gln) in Turkey. Br J Haematol 1997;97:504-505.
13. Yokuş O, Balçık ÖŞ, Albayrak M, et al. Thrombophilic risk factors in women with recurrent abortion. J Clin Exp Invest 2010;1:168-172.
14. Dizon-Townson DS, Nelson LM, Easton K, et al. The fac- tor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996 ;175:902-905.
15. Nagy B, Toth T, Rigo J Jr, et al. Detection of factor V leiden mutation in severe pre-eclamptic Hungarian Women. Clin Genet 1998;53:478-481.
16. Lin J, August P. Genetic thrombophilias and preeclamp- sia: a meta-analysis. Obstet Gynecol 2005;105:182-192.
17. Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden gen- otype: a meta-analysis. Thromb Haemost 2004;91:700- 711.
18. Livingston JC, Barton JR, Park V, et al. Maternal and fetal inherited thrombophilias are not related to the de- velopment of severe preeclampsia. Am J obstet Gynecol 2001;185:153-157.
19. Paternoster DM, Stella A, Simioni P, et al. Activated pro- tein C resistance in normal and pre-eclamptic pregnan- cies. Gynecol Obstet Invest 2002;54:145-149.
20. Osmanagaoglu MA, Topcuoglu K, Ozeren M, et al. Co- agulation inhibitors in preeclamptic pregnant women. Arch Gynecol Obstet 2005;271:227-230.
21. Sayin M, Varol FG, Sayin NC. Evaluation of natural coagulation inhibitor levels in various hypertensive states of pregnancy. Eur J Obstet Gynecol Reprod Biol 2005;123:183-187
22. Faught W, Garner PJ, Jones G, et al. Changes in protein C protein S levels in normal pregnancy. Am J Obstet Gy- necol 1995;172:147-150.
23. Dekker GA, de Vries JI, Doelitzsch PM, et al. Underlying disorders associated with severe early-onset preeclam- sia. Am J Obstet Gynecol 1995;173:1042-1048.
24. Kupferminc MJ, Fait G, Many A, et al. Severe pre- eclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000;96:45-49.
25. Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital anti- thrombin 3 deficiency: Review of 404 cases. Thromb Haemost 1987;58:1094-1099.
26. Gebhard GS, Hall DR. Inherited and acquired throm- bophilias and poor pregnancy outcome: should we be treating with heparin? Curr Opin Obstet Gynecol 2003;15:501-506.
27. Mc Cowan LM, Craigie S, Taylor RS, et al. Inherited Thrombophilias are not increased in ‘idiopathic’ small for gestational age pregnancies. Am J Obstet Gynechol 2003;188:81-985.
28. Howley HE, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrom- bin gene variant and intrauterine growth restriction. Am J Obstet Gynecol. 2005;192:694-708.
29. Kupferminc M, Eldor A, Steinman N, et al. Increase fre- quency of genetic thrombophilia in women with compli- cations of pregnancy. N Engl J Med 1999;340:9-13.
30. de Vries JIP, Dekker GA, Huijgens PC, et al. Hyperho- mocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997;104:1248- 1254.
31. Alonso A, Soto I, Urgelles MF, et al. Acquired and in- herited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002;187:1337-1342.
32. Sarig G, Younis JS, Hoffman R, et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002;77:342-347.
33. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348: 913-916.
34. Alfirevic Z, Roberts D, Martlew V. How strong is the as- sociation between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol 2002;101:6-14.
35. Many A, Elad R, Yaron Y, et al. Third trimester unex- plained intrauterine fetal death is associated with inher- ited thrombophilia. Obstet Gynecol 2002;99:684-687.
36. Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet 2003;361:901- 908.
37. Gonen R, Lavi N, Attias D, et al. Absence of associa- tion of inherited thrombophilia with unexplained third trimester intrauterine fetal death. Am J Obstet Gynecol 2005;192: 742-746.