Inherited Thrombophilia and Gestational Vascular Complications

 

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ABSTRACT

Severe obstetric complications, including preeclampsia, intrauterine growth retardation, abruptio placentae, and stillbirth, constitute a major cause of maternal and perinatal morbidity and death. The etiology of these severe obstetric complications is still unknown. However, the frequent finding of structural and thrombotic changes in placental capillaries, which lead to inadequate fetomaternal circulation and decreased placental perfusion, and the high prevalence of heritable or acquired risk factors for thrombosis found in women with these complications strongly suggest a cause-and-effect relationship. This review describes the recent findings on the association between these obstetric complications and the various thrombophilias, and recent therapeutic approaches. Aspirin, which was regarded as the drug of choice for the prevention of such obstetric complications, has proved to be ineffective in a large clinical trial. The encouraging observations on the efficacy of low-molecular-weight heparins, which are also included in the recently published guidelines of The American College of Chest Physicians, are summarized in this review. However, controlled clinical trials are still necessary to allow the development of better clinical standards.

REFERENCES

• 1 Roberts J M, Taylor R N, Musici T J. et al . Preeclampsia: an endothelial cell disorder.  Am J Obstet Gynecol . 1989;  161 1200-1204
  PubMedGoogle Scholar
• 2 Salafia C M, Pezzulo J C, Lopez-Zeno J A, Minior V K, Vintzileos A M. Placental pathologic features of preterm preeclampsia.  Am J Obstet Gynecol . 1995;  173 1079-1105
  CrossrefPubMedGoogle Scholar
• 3 Shanklin D R, Sibai B M. Ultrastructural aspects of preeclampsia.  Am J Obstet Gynecol . 1989;  161 735-741
  PubMedGoogle Scholar
• 4 Khong T Y, Pearce J M, Robertson W B. Acute atherosis in preeclampsia: maternal determination and fetal outcome in the presence of the lesion.  Am J Obstet Gynecol . 1987;  157 360-363
  PubMedGoogle Scholar
• 5 Salafia C M, Minior V K, Pezzulo J C. et al . Intrauterine growth restriction in infants of less than thirty-two weeks' gestation: associated placental pathologic features.  Am J Obstet Gynecol . 1995;  173 1049-1057
  CrossrefPubMedGoogle Scholar
• 6 Green J R. Placenta previa and abruptio placentae. In: Creasy RK, Resnik R, eds. Maternal Fetal Medicine: Principles and Practice Philadelphia: Saunders 1994: 609-610
  Google Scholar
• 7 Redman C WG, Sacks G P, Sargent I L. Preeclampsia: an excessive maternal inflammatory response to pregnancy.  Am J Obstet Gynecol . 1999;  180 499-506
  CrossrefPubMedGoogle Scholar
• 8 Dahlbäck B. Molecular genetics of venous thromboembolism.  Ann Intern Med . 1995;  27 187-192
  PubMedGoogle Scholar
• 9 Bertina R M. Genetic approach to thrombophilia.  Thromb Haemost . 2001;  86 92-103
  PubMedGoogle Scholar
• 10 Conard J, Horellou M H, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women.  Thromb Haemost . 1990;  63 319-320
  PubMedGoogle Scholar
• 11 De Stefano V, Leone G, Mastrangelo S. et al . Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S.  Thromb Haemost . 1994;  71 799-800
  PubMedGoogle Scholar
• 12 Bertina R M, Koeleman B P, Köster T. et al . Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
  CrossrefPubMedGoogle Scholar
• 13 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. 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;  88 3698-3703
  CrossrefPubMedGoogle Scholar
• 14 Frosst P, Blom H J, Milos R. et al . A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet . 1995;  10 111-113
  CrossrefPubMedGoogle Scholar
• 15 Glueck C J, Wang P, Fontaine R N. et al . Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome.  Metabolism . 1999;  48 1589-1595
  CrossrefPubMedGoogle Scholar
• 16 Glueck C J, Phillips H, Cameron D. et al . The 4G/4G polymorphism of the hypofibrinolytic PAI-1 gene: an independent risk factor for serious pregnancy complications.  Metabolism . 2000;  49 845-852
  CrossrefPubMedGoogle Scholar
• 17 Lockshin M D. Pregnancy loss in the antiphospholipid syndrome.  Thromb Haemost . 1999;  82 641-648
  PubMedGoogle Scholar
• 18 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder.  Thromb Haemost . 1997;  78 297-301
  PubMedGoogle Scholar
• 19 Greer I A. Epidemiology, risk factors and prophylaxis of venous thrombo-embolism in obstetrics and gynaecology.  Clin Obstet Gynaecol . 1997;  11 403-430
  PubMedGoogle Scholar
• 20 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet . 1999;  353 1258-1265
  CrossrefPubMedGoogle Scholar
• 21 Greer I A. The challenge of thrombophilia in maternal-fetal medicine.  N Engl J Med . 2000;  342 424-425
  CrossrefPubMedGoogle Scholar
• 22 Finazzi G, Barbui T. Different incidence of venous thrombosis in patients with inherited deficiencies of antithrombin III, protein C and protein S.  Thromb Haemost . 1994;  71 15-18
  PubMedGoogle Scholar
• 23 Friederich P W, Sanson B J, Simioni P. et al . Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.  Ann Intern Med . 1996;  125 955-960
  CrossrefPubMedGoogle Scholar
• 24 Clark P, Brennand J, Conkie J A. et al . Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.  Thromb Haemost . 1998;  79 1166-1170
  PubMedGoogle Scholar
• 25 Hallak M, Senderowicz J, Cassel A. et al . Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy.  Am J Obstet Gynecol . 1997;  176 889-893
  PubMedGoogle Scholar
• 26 Bokarewa M I, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy.  Br J Haematol . 1996;  92 473-478
  CrossrefPubMedGoogle Scholar
• 27 Shu H, Wramsby M, Bokarewa M, Blombäck M, Bremme K. Decrease in protein C inhibitor activity and acquired APC resistance during normal pregnancy.  J Thromb Thrombolysis . 2000;  9 277-281
  CrossrefPubMedGoogle Scholar
• 28 Martinelli I, Sacchi E, Landi G. et al . High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.  N Engl J Med . 1998;  338 1793-1797
  CrossrefPubMedGoogle Scholar
• 29 Kupferminc M J, Eldor A, Steinman N. et al . Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
  CrossrefPubMedGoogle Scholar
• 30 den Heijer M, Köster T, Blom H J. et al . Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.  N Engl J Med . 1996;  334 759-762
  Google Scholar
• 31 McColl M D, Ellison J, Reid F. et al . Prothrombin 20210 G→A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol . 2000;  107 565-569
  PubMedGoogle Scholar
• 32 Lindqvist P G, Svensson P J, Dahlbäck B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss-a possible evolutionary selection mechanism.  Thromb Haemost . 1998;  79 69-73
  PubMedGoogle Scholar
• 33 Glueck C J, Kupferminc M J, Fontaine R N. et al . Increased frequency of the hypofibrinolytic 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene in women with obstetric complications.  Obstet Gynecol . 2001;  97 44-48
  CrossrefPubMedGoogle Scholar
• 34 de Vries I J, Dekker G A, Huijgens P C. et al . Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies.  Br J Obstet Gynaecol . 1997;  104 1248-1254
  CrossrefPubMedGoogle Scholar
• 35 Goddijn-Wessel T A, Wouters M G, van de Molen F E. et al . Hyperhomocysteinemia: a risk factor for placental abruption or infarction.  Eur J Obstet Gynecol Reprod Biol . 1996;  66 23-29
  CrossrefPubMedGoogle Scholar
• 36 Vollsett S E, Bjorke-Monsen A AL, Igrens L M. Plasma total homocysteine and previous pregnancies: the Hordaland homocysteine study. Proceedings of the 2nd International Symposium on Homocysteine (Abst).  Neth J Med . 1998;  52 S54
  PubMedGoogle Scholar
• 37 Van der Molen F E, Verbrüggen B, Novakova I. et al . Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy.  Br J Obstet Gynaecol . 2000;  107 785-791
  PubMedGoogle Scholar
• 38 Pabinger I, Grafenhofer H, Kaider A. et al . Preeclampsia and fetal loss in women with a history of venous thromboembolism.  Arterioscler Thromb Vasc Biol . 2001;  21 874-879
  CrossrefPubMedGoogle Scholar
• 39 Vern T Z, Alles A J, Kowal-Vern A, Longtine J, Roberts D J. Frequency of factor V (Leiden) and prothrombin G20210A in placentas and their relationship with placental lesions.  Hum Pathol . 2000;  31 1036-1043
  CrossrefPubMedGoogle Scholar
• 40 Dekker G A, de Vries I P J, Doelitzsch P M. et al . Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol . 1995;  173 1042-1048
  CrossrefPubMedGoogle Scholar
• 41 Dizon-Townson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia.  Am J Obstet Gynecol . 1996;  175 902-905
  CrossrefPubMedGoogle Scholar
• 42 Grandone E, Margaglione M, Colaizzo D. et al . Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia.  Thromb Haemost. 1997;  77 1052-1054
  PubMedGoogle Scholar
• 43 Nagy B, Toth T, Rigo Jr J. et al . Detection of factor V Leiden in severe pre-eclamptic Hungarian women.  Clin Genet . 1998;  53 478-481
  CrossrefPubMedGoogle Scholar
• 44 Rajkovic A, Catlano P M, Malinow M R. Elevated homocysteine levels with preeclampsia.  Obstet Gynecol . 1997;  90 168-171
  CrossrefPubMedGoogle Scholar
• 45 Sohda S, Arinami T, Hamada H M. et al . Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia.  J Med Genet . 1997;  34 525-526
  PubMedGoogle Scholar
• 46 Kupferminc M J, Fait G, Many A. et al . Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol . 2000;  96 45-49
  CrossrefPubMedGoogle Scholar
• 47 Rigo Jr J, Nagy B, Fintor L. et al . Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase.  Hypertens Pregnancy . 2000;  19 163-172
  CrossrefPubMedGoogle Scholar
• 48 Mello G, Parretti E, Martini E. et al . Usefulness of screening for congenital or acquired hemostatic abnormalities in women with previous complicated pregnancies.  Haemostasis . 1999;  29 197-203
  CrossrefPubMedGoogle Scholar
• 49 Lindoff C, Ingemarsson I, Martinsson G. et al . Preeclampsia is associated with reduced response to activated protein C.  Am J Obstet Gynecol . 1997;  176 457-460
  PubMedGoogle Scholar
• 50 O'Shaughnessy K M, Fu B, Ferraro F. et al . Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an east Anglian preeclampsia cohort.  Hypertension . 1999;  33 1338-1341
  PubMedGoogle Scholar
• 51 Powers R W, Minich L A, Lykins D L. et al . Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia.  J Soc Gynecol Invest . 1999;  6 74-79
  CrossrefPubMedGoogle Scholar
• 52 Krauss T, Augustin H G, Osmers R. et al . Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome.  Obstet Gynecol . 1998;  92 457-460
  CrossrefPubMedGoogle Scholar
• 53 Lindqvist P G, Svensson P J, Marsaal K. et al . Activated protein C resistance (FV:Q506) and pregnancy.  Thromb Haemost . 1999;  81 532-537
  PubMedGoogle Scholar
• 54 Kupferminc M J, Fait G, Many A. et al . Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol. . 2000;  96 45-49
  CrossrefPubMedGoogle Scholar
• 55 Infante-Rievard C, David M, Gauthier R, Rivard G E. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study.  N Engl J Med . 1991;  325 1063-1066
  PubMedGoogle Scholar
• 56 Lima F, Khamashta M A, Buchanan N M. et al . A study of sixty pregnancies in patients with the antiphospholipid syndrome.  Clin Exp Rheumatol . 1996;  14 131-136
  PubMedGoogle Scholar
• 57 Dizon-Townson D S, Meline L, Nelson L M, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction.  Am J Obstet Gynecol . 1997;  177 402-405
  CrossrefPubMedGoogle Scholar
• 58 Grandone E, Margaglione M, Colaizzo D. et al . Factor V Leiden is associated with repeated and recurrent unexplained fetal losses.  Thromb Haemost . 1997;  77 822-824
  PubMedGoogle Scholar
• 59 Brenner B, Mandel H, Lanir N. et al . Activated protein C resistance can be associated with recurrent fetal loss.  Br J Haematol . 1997;  97 551-554
  CrossrefPubMedGoogle Scholar
• 60 Brenner B, Sarig G, Weiner Z. et al . Thrombophilic polymorphisms are common in women with fetal loss without apparent cause.  Thromb Haemost . 1999;  82 6-9
  PubMedGoogle Scholar
• 61 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis J S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.  Thromb Haemost . 2000;  83 693-697
  PubMedGoogle Scholar
• 62 Preston F E, Rosendaal F R, Walker I D. et al . Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
  CrossrefPubMedGoogle Scholar
• 63 Sanson B J, Friederich P W, Simioni P. et al . The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.  Thromb Haemost . 1996;  75 387-388
  PubMedGoogle Scholar
• 64 Ridker P M, Miletich J P, Buring J E. et al . Factor V Leiden mutation as a risk factor for recurrent pregnancy loss.  Ann Intern Med . 1998;  128 1000-1003
  PubMedGoogle Scholar
• 65 Deitcher S R, Park V M, Kutteh W H. Prothrombin 20210 GA mutation analysis in Caucasian women with early first trimester recurrent pregnancy loss (Abst).  Blood . 1998;  92(Suppl 1) 118b
  PubMedGoogle Scholar
• 66 Durnwald C P, Flora R, Agamanolis D. et al . Hereditary thrombophilia as a cause of fetal loss.  Obstet Gynecol . 2000;  95 S11-S12
  PubMedGoogle Scholar
• 67 Yamada H, Kato E H, Ebina Y. et al . Factor XII deficiency in women with recurrent miscarriage.  Gynecol Obstet Invest . 2000;  49 80-83
  CrossrefPubMedGoogle Scholar
• 68 Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae.  Am J Obstet Gynecol . 1998;  179 1565-1567
  CrossrefPubMedGoogle Scholar
• 69 Kupferminc M J, Peri H, Zwang E. et al . High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss.  Acta Obstet Gynecol Scand . 2000;  11 963-967
  PubMedGoogle Scholar
• 70 Arias F, Romero R, Joist H, Kraus F T. 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
  CrossrefPubMedGoogle Scholar
• 71 Kupferminc M J, Many A, Rosner S. et al . Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.  Am J Obstet Gynecol . 2000;  182(1 Part 2) Abst
  PubMedGoogle Scholar
• 72 Mousa H A, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?.  Hum Reprod . 2000;  15 1830-1833
  CrossrefPubMedGoogle Scholar
• 73 Caritis S, Sibai B, Hauth J. et al . Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  N Engl J Med . 1998;  338 701-705
  CrossrefPubMedGoogle Scholar
• 74 Kutteh W H, Ermel L D. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin.  Am J Reprod Immunol . 1996;  35 402-407
  CrossrefPubMedGoogle Scholar
• 75 Harenberg J, Schneider D, Heilmann L, Wolf H. Lack of anti-factor Xa activity in umbilical cord vein samples after subcutaneous administration of heparin or low molecular mass heparin in pregnant women.  Haemostasis . 1993;  23 314-320
  PubMedGoogle Scholar
• 76 Ginsberg J S, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest . 1998;  114(5 Suppl) 524S-530S
  PubMedGoogle Scholar
• 77 Gris J C, Neveu S, Tailand M L. et al . Use of low-molecular-weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity.  Thromb Haemost . 1995;  73 362-367
  PubMedGoogle Scholar
• 78 Brenner B. Inherited thrombophilia and pregnancy loss.  Thromb Haemost . 1999;  82 634-640
  PubMedGoogle Scholar
• 79 Younis J S, Ohel G, Brenner B. et al . The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.  Br J Obstet Gynaecol . 2000;  107 415-419
  PubMedGoogle Scholar
• 80 Bar J, Cohen-Sacher B, Hod M. et al . Low-molecular-weight heparin for thrombophilia in pregnant women.  Int J Gynaecol Obstet . 2000;  69 209-213
  CrossrefPubMedGoogle Scholar
• 81 Rai R, Cohen H, Dave M, Regan L: Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J .  1997;  314 253-254
  CrossrefPubMedGoogle Scholar
• 82 Kupferminc M J, Fait G, Many A. et al . Low molecular weight heparin for the prevention of obstetric complications in women with thrombophilias.  Hypertens Pregnancy . 2001;  20 35-44
  CrossrefPubMedGoogle Scholar
• 83 Riyazi N, Leeda M, de Vries I J. et al . Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study.  Eur J Obstet Gynecol Reprod Biol . 1998;  80 49-54
  CrossrefPubMedGoogle Scholar
• 84 Leeda M, Riyazi N, de Vries I J. et al . Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction.  Am J Obstet Gynecol . 1998;  179 135-139
  CrossrefPubMedGoogle Scholar
• 85 Ginsberg J S, Greer I A, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest . 2001;  119(Suppl) 122S-131S
  CrossrefPubMedGoogle Scholar
• 86 Branch D W, Peaceman A M, Druzin M. et al . A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy.  Am J Obstet Gynecol . 2000;  182 122-127
  CrossrefPubMedGoogle Scholar