GEBELİK VE KALITSAL TROMBOFİLİ

Gebelikte ortaya çıkan venöz tromboembolizm (VTE) maternal mortalite ve morbiditeyi arttıran en önemlifaktörlerden birisidir. Gebelikle ilişkili VTE geçiren kadınların 2/3'ünde edinsel ve %30-50'sinde kalıtsaltrombofilik risk faktörü saptanmıştır. Gebelikte kalıtsal olarak ortaya çıkan en sık kalıtsal trombofili nedenlerifaktör-V Leiden (FV-L), protrombin G20210A ve metilentetrahidrofolat redüktaz gen mutasyonlarıdır. Kalıtsaltrombofilili gebelerde VTE yanı sıra plasental vasküler zedelenme, infarktüs ve fibrinoid nekroz nedeniyleablatio plasenta, yineleyen gebelik kayıpları, intrauterin fetal ölümler, intrauterin fetal gelişmegerilikleri(İUFGG) ve preeklampsi görülmektedir.Gebelikte kalıtsal trombofili tarama testleri gebelik ya da puerperium ile ilişkili VTE, birinci, ikinci trimestirdeortaya çıkan yineleyen gebelik kaybı ve intrauterin fetal ölüm olgularında gereklidir. Ancak şiddetli preeklampsi,İUFGG, ablatio placenta gibi gebelik komplikasyonlarında da önerilebilir. Bu testler özellikle doğumdan 3 aysonra yapılmalıdır.Gebelikte ortaya çıkan akut VTE tedavisinde unfraksiyone heparin (UFH) ya da düşük molekül ağırlıklıheparinler (DMAH) kullanılmalıdır. Her iki heparin de plasentaya geçmediği için gebelikte güvenlidir. En azUFH kadar etkili olan DMAH'in biyoyararlılığı daha fazla ve yan etkileri daha azdır.Gebelikte VTE rekürrensi %1-13 arasındadır. Antitrombin eksikliği ve VTE öyküsü olan tüm kalıtsal trombofililigebeler yüksek riskte kabul edilmekte ve agressif olarak antikoagulan proflaksisi önerilmektedir. VTE öyküsüolmayan heterozigot Protein C eksikliği, homozigot FV-L ve protrombin gen mutasyonlu ve AT eksikliğidışındaki kombine trombofilili gebeler ise orta risk gurubunda olup tromboproflaksi yapılmalıdır. HeterozigotPS eksikliği, FV-L, protrombin gen mutasyonları bulunan gebeler ise düşük risk altında olup tromboproflaksiönerilmemektedir. Ancak tromboz için ek bir risk faktörü bulunan, yineleyen bebek kaybı, intrauterin fetal ölüm,şiddetli preeklampsi, İUFGG gibi komplikasyon gelişen, dört saatten uzun sürecek uçak yolculuğuna çıkacakkalıtsal trombofilili gebelerde de tromboproflaksi yapılmalıdır. Tromboproflaksi DMAH ile gebelik boyunca vedoğumdan sonraki ilk altı hafta süresince uygulanmalıdır

Anahtar Kelimeler:

Kalıtsal trombofili, gebelik, venöz tromboembolizm

Pregnancy and Hereditary Thrombophilia

Pregnancy-related venous thromboembolism (VTE) is one of the risk factors that increase maternal mortality and morbidity. Acquired and congenital thrombophilic risk factors were detected in 2/3 and 30-50% of women with VTE related pregnancy, respectively. The most common causes of pregnancy related VTE are factor-V Leiden (FV-L), prothrombin G20210A and methylenetetrahyrofolate reductase (MTHFR) gene mutations. In pregnant women with hereditary thrombophilia, both VTE and adverse pregnancy outcomes including pregnancy loss, placental abruption and intrauterine growth retardation (IUGR) can be seen. Screening tests for hereditary thrombophilia should be done in VTE related to pregnancy or puerperium , recurrent pregnancy loss in the first and second trimester and intrauterine fetal death. Additionally, these screening tests should also be recommended in pregnancy related complications such as severe preeclampsia, IUGR and placental abruption. These tests should be done especially after three months of pregnancy. Both low molecular weight heparin (LMWH) and unfractionated heparin are the choice of treatment in pregnancy-related VTE. These heparins do not penetrate placenta, so they are safe. Recurrence of VTE in pregnancy is 1-13 %. The pregnant women who have antithrombin deficiency and history of VTE with all types of congenital thrombophilia are accepted to be in high-risk group and aggressive thromboprophylaxis should be done in these subjects. Pregnant women who had no history of VTE with heterozygote protein C deficiency and homozygote FV-L and prothrombin gene mutations and combined thrombophilia excluding antithrombin deficiency are in moderate group and thromboprophylaxis should also be done. Heterozygote protein S deficiency, FV-L, prothrombin gene mutations are in low-risk for VTE, so that thromboprophylaxis should not be recommended. However, thromboprophylaxis should be performed in severe preeclampsia, recurrent pregnancy loss, intrauterine fetal death and IUGR and also air travels more than four hours. Thromboprophylaxis with LMWH should be done during the pregnancy and the first six weeks following labor thereafter.

Keywords:

Hereditary thrombophilia, pregnancy and venous thromboembolism,

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1. Zotz RB, Gerhardt A, Scharf RE. Inherited t h r om bop h i l i a a n d g e st a t i o n a l v e n o u s thromboembolism. Best Pract Res Clin Haematol 2003;16:243-59.
2. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. NEnglJ Med. 2000;342:3749.
3. Gre er IA. The spec ia l c as e of venous thromboembolism in pregnancy. Haemostasis 1998;28 (Suppl.3);57:543-52.
4. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scott Med J 1996;41:836.
5. McColl MD, Ramsey JE, Tait RC, et al. Risk factorsfor pregnancy associated venous thromboembolism. Thromb Haemost 1997;78:11838.
6. Sachs BP, Brown DA, Driscoll SG, et al. Maternal mortality in Massachusetts: trends and prevention. N EnglJ Med 1987;316:667-72.
7. Tengborn L, Bergqvist D, Matzsch T, et al. Recurrent thromboembolism in pregnancy and puerperium. Is there a need for thromboprophylaxis? Am J Obstet Gynecol 1989;160:90-4.
8. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of witholding heparin in pregnant women with a history of venous thromboembolism. Recurrens of Clot in this pregnancy study group. N Engl J Med 2000;343:1439- 44.
9. McColl M, Ellison J, Greer IA et al. Prevalence of the post-thrombotic syndrome in young women with previous venous thromboembolism. Br J Haematol 2000;108: 2724.
10. Greer IA. Prevention of venous thromboembolism in pregnancy.Best PractRes Clin Haematol 2003;16:261- 78.
11. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;40:913.
12. MakinA, Silverman SH, Lip GYH. Peripheral vascular disease and Virchow's triad for thrombogenesis. QJM 2002; 95:199210.
13. Zhou Y, Damsky CH, Fisher SJ. Pre-eclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997;99:215264.
14. Lyall F, Greer IA. The vascular endothelium in normal pregnancy and pre-eclampsia. Rev Reprod 1996;1:10716.
15. Booth N, Reith A, Bennett B. A plasminogen activator inhibitor (PAI-2) circulates in two molecular forms during pregnancy. Thromb Haemost 1998;59:77-9.
16. Clarke P,Brennand J,Conkie JAet al.Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.Thromb Haemost 1998;79:116670.
17. Grandone E, Margaglione M. Inherited thrombophilia and gestational vascular complications. Best Pract Res Clin Haematol 2003;16:321-32.
18. Vossen CY, Preston FE, Conard J, et al. Hereditary thrombophilia and fetal loss: a prospective follow-up study.JThromb Haemost 2004;1:592-6.
19. Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol 2004; 191:412- 24.
20. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulants response to activated protein C: prediction of a cofactor to activated protein C. NatlAcad Sci 1993;90:1004-8.
21. Greengard JS, Sun X, Xu X, et al. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994;343:1361-7.
22. Deitcher SR, Rodgers GM. Thrombosis and antithrombotic therapy. In: Wintrobe's Clinical Hematology, Greer JP, Foerster J, Lukens JN, et al (eds), Lippincott Williams Wilkins, 11 edition, Philadelphia 2004:1713-58.
23. De Stefano V, Chiusolo P, Paciaroni K, et al. Epidemiology of factor V Leiden: clinical implications.SeminThromb Hemost 1998;24:367-79.
24. Grandone E. Margaglione M,Colaizzo D, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, p r o t h r o m b i n G 2 0 2 1 0 A , a n d methylenetetrahydrofolate reductase C677T mutations.Am J Obstet Gynecol. 1998;170: 1324 8.
25. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1998;81:198202.
26. Brenner B, Mandel H, Lanir N et al.Activated protein C resistance can be associated with recurrent fetal loss. BritJ Haematol 1997;7:5514.
27. Dizon-Townson DS, Nelson LM, Easton K & Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996;175:9025.
28. Lindqvist PG, Swensson PJ, Marsal K,et al. Activated protein C resistance and pregnancy. Thromb Haemost 1996;81:532-7.
29. Facchinetti F, Marozio L, Grandone E, et al. Thrombophilic mutations are a main risk factor for placental abruption. Haematologica 2003;88:785-8.
30. Ridker PM, Miletich JP, Buring JE, et al. Factor VLeiden mutation as a risk factorforrecurrent pregnancy loss.Ann Intern Med 1998;128:10003.
31. Brenner B. Inherited thrombophilia and pregnancy loss.Best PractResClin Haematol 2003;16:311-20.
32. Rai R,Backos M, Elgaddal S, et al. Factor VLeiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum Reprod 2002;17:442-5.
33. Robertson L, Wu O, Greer I. Thrombophilia and adverse pregnancy outcome. Curr Opin Obstet Gynecol 2004,16:4538.
34. Verspyck E, Borg JY, Cam-Duchez V, et al. Thrombophilia and fetal growth restriction. Eur J Obstet GynecolReproduc Biol 2004;113:36-40.
35. Poort SR, Rosendaal FR, Reitsma PH,et al. A common genetic variations in the 3' untranslated region of prothrombin gene is associated with elevated plasma prothrombin levels and an inrease in venous thrombosis.Blood 1996;88:3698-3703.
36. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999;82:610-9.
37. Martinelli I, DeStafano V, Taioli E, et al. Inherited thrombophilias and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002;87:7915.
38. Camilleri RS,Peebles D, Portmann C, et al. 455G/Afibrinogen gene polymorphism, factor V Leiden, prothrombin G20210A mutation and MTHFR C677T, and placental vascular complications. Blood Coagul Fibrinolysis 2004,15:13947.
39. Vefring H, Lie RT,Odegard R, et al. Maternal and fetal variants of genetic thrombophilias and the risk of preeclampsia. Epidemiology 2004;15: 31722.
40. Martinelli I, Taioli E, Cetin I et al. Mutations in coagulation factors in women with unexplained late fetal loss. NEnglJ Med 2000; 43: 10158.
41. Martinelli P, Grandone E, Colaizzo D et al. Familial thrombophilia and the occurrence of fetal growth restriction. Hematologica 2001;86: 42831.
42. Kupferminc MJ, Peri H, Zwang E et al. High prevalence ofthe prothrombin genemutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 2000;11:9637.
43. De Maat MPM, Jansen MWJC, Hile ETM, et al. Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost 2004;2:158893.
44. Cl a r k e R, Da l y L, Rob i n son K, e t a l . Hyperhomocysteinemia: an independent risk factor for vascular disease. NEnglJ Med 1991;324:1149-55.
45. Welch GN. Homocysteine and atherothrombosis. N EnglJ Med 1998;338:1042-50.
46. Wilson ML, Goodwin TM, Pan Vl,et al. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003; 58: 3966.
47. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049- 57.
48. Lentz SR, Piegors DJ, Fernandez JA, et al. Effect of hyperhomocysteinemia on protein C activation and activity.Blood 2002;100:2108-12.
49. Makris M. Hyperhomocysteinemia and thrombosis. ClinLab Haematol 2000;22:133-43.
50. McColl MD, Ellison J, Reid F, et al. Prothrombin20210GA, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 2000;107:5679.
51. Kupferminc MJ. Thrombophilia and pregnancy. ReprodBiol Endocrinol 2003, 1:111.
52. Walker ID. Thrombophilia in pregnancy. J Clin Pathol 2000;53:57380.
53. Toglia MR, Weg JG. Venous thromboembloism during pregnancy. NEnglJ Med 1996; 335:108-14.
54. De Stefano V, Leone G, Mastrangelo S,, et al. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1994; 72:352-8.
55. Gebhardt GS, Hall DR. Inherited and acquired thrombophilias and poor pregnancy outcome: should we be treating with heparin? Curr Opin Obstet Gynecol 2003,15:5016.
56. Younis J, Samueloff A. Gestational vascular complications. Best Pract Res Clin Haematol 2003;16:135-51.
57. Kupferminc MG, Fait G, Many A et al. Severe preeclampsia and high frequency of genetic thrombophilic muta tions. Obste t Gynecol 2000;96:145149.
58. Dekker GA, de Vries JIP, Doelitzsch PM et al. Underlying disorders associated with severe earlyonset preeclampsia. Am J Obstet Gynecol1995; 173: 10421048.
59. Dulitzki M, Pauzner R, Langevitz P et al. Lowmolecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:3803.
60. Lepercq J, Conard J, Borel-Derlon A et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001;108:113440.
61. Sanson BJ, Lensing AWA, Prins MH et al. Safety of low-molecular weight heparin in pregnancy: a systemic review.Thromb Haemost 1999;81:66872.
62. Schafer AI, Levine MN, Konkle BA, et al. Thrombotic disorders: diagnosis and treatment. Hematology (Am Soc Hematol Educ Program). 2003;520-39.
63. Bowles L, Cohen H. Inherited thrombophilias and anticoagulation in pregnancy. Best Pract Res Clin Haematol 2003;17:471-89.
64. Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 2005;93:63- 9.
65. Macchi L, Sarfati R, Guicheteau M, et al. Thromboembolic prophylaxis with danaparoid (Orgaran) in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal's disease. Clin Appl Thromb Hemost 2000;6:187-9.
66. Lindhoff-Last E, Bauersachs R. Heparin-induced thrombocytopenia-alternative anticoagulation in pregnancy and lactation. Semin Thromb Hemost 2002;28:439-46.
67. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Investigation and management of heritable thrombophilia.BrJ Haematol 2001;114:51228.
68. Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications-Yes. JThromb Haemost 2003;1:2070-2.
69. Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with the antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol 2002;99:13544.
70. Richards EM, Makris M, Preston FE. The successful use of protein C concentrate during pregnancy in a patient with type 1 protein C deficiency, previous thrombosis and recurrent fetal loss. Br J Haematol 1997;98:6601.