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Semin Thromb Hemost 2005; 31(1): 97-103
DOI: 10.1055/s-2005-863811
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Thrombophilia Related Issues in Women and Children

Ron Hoffman1 , 2 , Benjamin Brenner2
  • 1Head of Inpatient Hematology Unit, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Bruce Rappaport Faculty of Medicine Haifa, Israel
  • 2Thrombosis & Hemostasis Unit, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Bruce Rappaport Faculty of Medicine Haifa, Israel
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Publication History

Publication Date:
11 February 2005 (online)

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ABSTRACT

Women experience increased thrombotic risk at pregnancy and puerperium as well as during hormonal therapy with oral contraceptives or hormone replacement therapy. Physiological and anatomical changes in pregnancy contribute to the hypercoagulable situation. Women with thrombophilia have an increased risk for venous and arterial thromboembolism as well as for gestational vascular complications including fetal loss, pre-eclampsia, placental abruption, and fetal growth restriction. Children are at increased thrombotic risk, particularly at the neonatal period, and may express thrombosis often in association with thrombophilia. This article will focuses on the clinical association, pathogenesis, and treatment of thrombophilia-related issues in women and children.

KEYWORDS

Pregnancy - thrombophilia - gestational complications - thrombosis - hormonal therapy

REFERENCES

  • 1 Salafia C M, Minior V K, Pezzullo J C, Popek E J, Rosenkrantz T S, Vintzileos A M. 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
  • 2 Salafia C M, Pezzullo J C, Lopez-Zeno J A, Simmens S, Minior V K, Vintzileos A M. Placental pathologic features of preterm preeclampsia.  Am J Obstet Gynecol. 1995;  173 1097-1105
    CrossrefPubMedGoogle Scholar
  • 3 Lyall F, Greer I A. Pre-eclampsia: a multifaceted vascular disorder of pregnancy.  J Hypertens. 1994;  12 1339-1345
    PubMedGoogle Scholar
  • 4 Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia.  JAMA. 1991;  266 237-241
    CrossrefPubMedGoogle Scholar
  • 5 Dekker G A, de Vries J I, Doelitzsch P M et al.. Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol. 1995;  173 1042-1048
    CrossrefPubMedGoogle Scholar
  • 6 van Pampus M G, Dekker G A, Wolf H, Huijgens P C. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.  Am J Obstet Gynecol. 1999;  180 1146-1150
    CrossrefPubMedGoogle Scholar
  • 7 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
  • 8 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
  • 9 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M. Preeclampsia is associated with a reduced response to activated protein C.  Am J Obstet Gynecol. 1997;  176 457-460
    PubMedGoogle Scholar
  • 10 Rajkovic A, Catalano P M, Malinow M R. Elevated homocysteine levels with preeclampsia.  Obstet Gynecol. 1997;  90 168-171
    CrossrefPubMedGoogle Scholar
  • 11 Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia.  J Med Genet. 1997;  34 525-526
    PubMedGoogle Scholar
  • 12 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
  • 13 Kupferminc M J, Fait G, Many A, Gordon D, Eldor A, Lessing J B. Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol. 2000;  96 45-49
    CrossrefPubMedGoogle Scholar
  • 14 Nagy B, Toth T, Rigo Jr J, Karadi I, Romics L, Papp Z. Detection of factor V Leiden mutation in severe pre-eclamptic Hungarian women.  Clin Genet. 1998;  53 478-481
    CrossrefPubMedGoogle Scholar
  • 15 El-Khairy L, Vollset S E, Refsum H, Ueland P M. Plasma total cysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study.  Am J Clin Nutr. 2003;  77 467-472
    PubMedGoogle Scholar
  • 16 Martinelli P, Grandone E, Colaizzo D et al.. Familial thrombophilia and the occurrence of fetal growth restriction.  Haematologica. 2001;  86 428-431
    PubMedGoogle Scholar
  • 17 Clark P, Walker I D, Greer I. Acquired activated protein-C resistance in pregnancy and association with increased thrombin generation and fetal weight.  Lancet. 1999;  353 292-293
    PubMedGoogle Scholar
  • 18 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;  79 963-967
    CrossrefPubMedGoogle Scholar
  • 19 Infante-Rivard C, Rivard G E, Yotov W V et al.. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.  N Engl J Med. 2002;  347 19-25
    CrossrefPubMedGoogle Scholar
  • 20 Infante-Rivard C, Rivard G E, Gauthier R, Theoret Y. Unexpected relationship between plasma homocysteine and intrauterine growth restriction.  Clin Chem. 2003;  49 1476-1482
    PubMedGoogle Scholar
  • 21 van der Molen E F, Verbruggen B, Novakova I, Eskes T K, Monnens L A, Blom H J. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy.  BJOG. 2000;  107 785-791
    CrossrefPubMedGoogle Scholar
  • 22 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
  • 23 Facchinetti F, Marozio L, Grandone E, Pizzi C, Volpe A, Benedetto C. Thrombophilic mutations are a main risk factor for placental abruption.  Haematologica. 2003;  88 785-788
    PubMedGoogle Scholar
  • 24 Prochazka M, Happach C, Marsal K, Dahlbäck B, Lindqvist P G. Factor V Leiden in pregnancies complicated by placental abruption.  BJOG. 2003;  110 462-466
    PubMedGoogle Scholar
  • 25 Cook C L, Pridham D D. Recurrent pregnancy loss.  Curr Opin Obstet Gynecol. 1995;  7 357-366
    PubMedGoogle Scholar
  • 26 Triplett D A, Harris E N. Antiphospholipid antibodies and reproduction.  Am J Reprod Immunol. 1989;  21 123-131
    PubMedGoogle Scholar
  • 27 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
  • 28 Wramsby M L, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation.  Fertil Steril. 2000;  74 987-991
    CrossrefPubMedGoogle Scholar
  • 29 Dossenbach-Glaninger A, van Trotsenburg M, Krugluger W et al.. Elevated coagulation factor VIII and the risk for recurrent early pregnancy loss.  Thromb Haemost. 2004;  91 694-699
    PubMedGoogle Scholar
  • 30 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 901-908
    CrossrefPubMedGoogle Scholar
  • 31 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
  • 32 Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms in women with fetal loss without apparent cause.  Thromb Haemost. 1999;  82 6-9
    PubMedGoogle Scholar
  • 33 Sarig G, Younis J S, Hoffman R, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage.  Fertil Steril. 2002;  77 342-347
    CrossrefPubMedGoogle Scholar
  • 34 Hundsdoerfer P, Vetter B, Stover B et al.. Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss.  Thromb Haemost. 2003;  90 628-635
    PubMedGoogle Scholar
  • 35 Hohlagschwandtner M, Unfried G, Heinze G, Huber J C, Nagele F, Tempfer C. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage.  Fertil Steril. 2003;  79 1141-1148
    CrossrefPubMedGoogle Scholar
  • 36 Kovalevsky G, Gracia C R, Berlin J A, Sammel M D, Barnhart K T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis.  Arch Intern Med. 2004;  8 558-563
    PubMedGoogle Scholar
  • 37 Martinelli I, Taioli E, Cetin I et al.. Mutations in coagulation factors in women with unexplained late fetal loss.  N Engl J Med. 2000;  343 1015-1018
    CrossrefPubMedGoogle Scholar
  • 38 de Vries J I, Dekker G A, Huijgens P C, Jakobs C, Blomberg B M, van Geijn H P. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies.  Br J Obstet Gynaecol. 1997;  104 1248-1254
    CrossrefPubMedGoogle Scholar
  • 39 Nelen W L, Blom H J, Steegers E A, den Heijer M, Eskes T K. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.  Fertil Steril. 2000;  74 1196-1199
    CrossrefPubMedGoogle Scholar
  • 40 Gris J C, Perneger T V, Quere I et al.. Antiphospholipid antiprotein antibodies, hemostasis-related autoantibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for early pregnancy loss: a matched case-control study.  Blood. 2003;  102 3504-3513
    CrossrefPubMedGoogle Scholar
  • 41 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
  • 42 Rutherford S, Montoro M, McGhee W, Strong T. Thromboembolic disease associated with pregnancy: an 11 year review.  Am Obstet Gynecol. 1991;  164 286
    PubMedGoogle Scholar
  • 43 Kjellberg U, Andersson N E, Rosen S, Tengborn L, Hellgren M. APC resistance and other haemostatic variables during pregnancy and puerperium.  Thromb Haemost. 1999;  81 527-531
    PubMedGoogle Scholar
  • 44 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
    CrossrefPubMedGoogle Scholar
  • 45 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
  • 46 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
  • 47 Hallak M, Senderowicz J, Cassel A, Shapira C, Aghai E. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy.  Am J Obstet Gynecol. 1997;  176 889-893
    PubMedGoogle Scholar
  • 48 Gerhardt A, Scharf R E, Beckmann M W et al.. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med. 2000;  342 374-380
    CrossrefPubMedGoogle Scholar
  • 49 Gerhardt A, Zotz R B, Struve S, Scharf R E. Homozygous and combined heterozygous factor V G1691A and Prothrombin G20210A mutations as predictors of venous thrombosis during pregnancy.  Thromb Haemost. 2001;  (suppl) 724
    PubMedGoogle Scholar
  • 50 Grandone E, Margaglione M, Colaizzo D et al.. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.  Am J Obstet Gynecol. 1998;  179 1324-1328
    CrossrefPubMedGoogle Scholar
  • 51 Martinelli I, De Stefano V, Taioli E et al.. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium.  Thromb Haemost. 2002;  87 791-795
    PubMedGoogle Scholar
  • 52 Samama M M, Rached R A, Horellou M H et al.. Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone.  Br J Haematol. 2003;  123 327-334
    CrossrefPubMedGoogle Scholar
  • 53 World health Organization . Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.  Lancet. 1995;  346 1575-1582
    PubMedGoogle Scholar
  • 54 Jick H, Jick S S, Gurewich V, Myers M W, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components.  Lancet. 1995;  346 1589-1593
    CrossrefPubMedGoogle Scholar
  • 55 Kemmeren J M, Algra A, Grobbee D E. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.  BMJ. 2001;  323 131-134
    CrossrefPubMedGoogle Scholar
  • 56 Farmer R D, Lawrenson R A, Thompson C R, Kennedy J G, Hambleton I R. Population-based study of risk of venous thromboembolism associated with various oral contraceptives.  Lancet. 1997;  349 83-88
    CrossrefPubMedGoogle Scholar
  • 57 Vandenbroucke J P, Koster T, Briet E, Reitsma P H, Bertina R M. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 1453-1457
    CrossrefPubMedGoogle Scholar
  • 58 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood. 1995;  85 1504-1508
    PubMedGoogle Scholar
  • 59 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.  Arterioscler Thromb Vasc Biol. 1999;  19 700-703
    CrossrefPubMedGoogle Scholar
  • 60 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Venous thromboembolism and oral contraceptives.  Lancet. 1999;  354 1469-1470
    PubMedGoogle Scholar
  • 61 Daly E, Vessey M P, Hawkins M M, Carson J L, Gough P. Risk of venous thromboembolism in users of hormone replacement therapy.  Lancet. 1996;  348 977-980
    CrossrefPubMedGoogle Scholar
  • 62 Grodstein F, Stampfer M J, Goldhaber S Z et al.. Prospective study of exogenous hormones and risk of pulmonary embolism in women.  Lancet. 1996;  348 983-987
    CrossrefPubMedGoogle Scholar
  • 63 Post M S, Rosing J, Van Der Mooren M J et al.. Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women.  Br J Haematol. 2002;  119 1017-1023
    CrossrefPubMedGoogle Scholar
  • 64 Herrington D M, Vittinghoff E, Howard T D et al.. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease.  Arterioscler Thromb Vasc Biol. 2002;  22 1012-1017
    CrossrefPubMedGoogle Scholar
  • 65 Koh K K, Horne III M K, Cannon III R O. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women.  Thromb Haemost. 1999;  82 626-633
    PubMedGoogle Scholar
  • 66 Psaty B M, Smith N L, Lemaitre R N et al.. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women.  JAMA. 2001;  285 906-913
    CrossrefPubMedGoogle Scholar
  • 67 Lemaitre R N, Heckbert S R, Psaty B M, Smith N L, Kaplan R C. Hormone replacement therapy and associated risk of stroke in postmenopausal women.  Arch Intern Med. 2002;  162 1954-1960
    PubMedGoogle Scholar
  • 68 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry.  Pediatrics. 1995;  96 939-943
    PubMedGoogle Scholar
  • 69 van Ommen C H, Heijboer H, Büller H R, Hirasing R A, Heijmans H S. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands.  J Pediatr. 2001;  139 676-681
    CrossrefPubMedGoogle Scholar
  • 70 Mudd S H, Skovby F, Levy H L et al.. The natural history of homocystinuria due to cystathionine beta-synthase deficiency.  Am J Hum Genet. 1985;  37 1-31
    PubMedGoogle Scholar
  • 71 Ginsberg J S, Greer I A, Hirsh J. Use of antithrombin agents during pregnancy.  Chest. 2001;  119 1225-1315
    PubMedGoogle Scholar
  • 72 Sanson B J, Lensing A W, Prins M H et al.. Safety of low-molecular-weight heparin in pregnancy: a systematic review.  Thromb Haemost. 1999;  81 668-672
    PubMedGoogle Scholar
  • 73 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
  • 74 Brenner B, Hoffman R, Carp H et al.. Enoxaparin treatment improves the gestational outcome of pregnant women with thrombophilia and recurrent pregnancy loss.  The LIVE-ENOX Study  Blood. 2002;  104 16
    PubMedGoogle Scholar
  • 75 Rosendaal F R, Vessey M, Rubmley A et al.. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis.  Br J Haematol. 2002;  116 851-854
    CrossrefPubMedGoogle Scholar

B. BrennerM.D. 

Department of Hematology and Bone Marrow Transplantation

Rambam Medical Center, Haifa 31096, Israel

Email: b_brenner@rambam.health.gov.il