Thrombophilia Related Issues in Women and Children

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
• 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
• 3 Lyall F, Greer I A. Pre-eclampsia: a multifaceted vascular disorder of pregnancy.  J Hypertens. 1994;  12 1339-1345
• 4 Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia.  JAMA. 1991;  266 237-241
• 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
• 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
• 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
• 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
• 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
• 10 Rajkovic A, Catalano P M, Malinow M R. Elevated homocysteine levels with preeclampsia.  Obstet Gynecol. 1997;  90 168-171
• 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
• 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
• 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
• 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
• 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
• 16 Martinelli P, Grandone E, Colaizzo D et al.. Familial thrombophilia and the occurrence of fetal growth restriction.  Haematologica. 2001;  86 428-431
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 25 Cook C L, Pridham D D. Recurrent pregnancy loss.  Curr Opin Obstet Gynecol. 1995;  7 357-366
• 26 Triplett D A, Harris E N. Antiphospholipid antibodies and reproduction.  Am J Reprod Immunol. 1989;  21 123-131
• 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
• 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
• 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
• 30 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 901-908
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 42 Rutherford S, Montoro M, McGhee W, Strong T. Thromboembolic disease associated with pregnancy: an 11 year review.  Am Obstet Gynecol. 1991;  164 286
• 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
• 44 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 60 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Venous thromboembolism and oral contraceptives.  Lancet. 1999;  354 1469-1470
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 68 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry.  Pediatrics. 1995;  96 939-943
• 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
• 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
• 71 Ginsberg J S, Greer I A, Hirsh J. Use of antithrombin agents during pregnancy.  Chest. 2001;  119 1225-1315
• 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
• 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
• 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
• 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