Thrombophilias and Recurrent Pregnancy Loss

ABSTRACT

Thrombophilia by definition represents acquired and/or genetic conditions that predispose patients to both venous and arterial thromboembolic events. Thrombosis is the most common cause of death worldwide. On the arterial side, myocardial infarction and stroke result in significant morbidity and mortality. Venous thromboembolic events most commonly involve the deep veins of the lower extremity with potential complications of pulmonary emboli. Pregnancy is a hypercoagulable state, and thromboembolism is the leading cause of antepartum and postpartum maternal mortality. With the description by Dahlback in 1993 of a condition initially labeled activated protein C resistance, significant advances have rapidly followed. Activated protein C resistance was linked to an underlying point mutation resulting in coagulation factor V (factor V Leiden). Recent attention has focused on certain inherited thrombophilic factors that may predispose to arterial and/or venous thromboses and their possible association with pregnancy complications, including early pregnancy loss. These include a group of mostly autosomal dominant, inherited gene mutations leading to a hypercoagulable state, such as factor V Leiden G1691A, factor II or prothrombin G20210A, and hyperhomocysteinemia associated with methylenetetrahydrofolate reductase C677T mutation. In addition, deficiencies in protein S, protein C, and antithrombin can lead to a hypercoagulable state. Although some studies of recurrent pregnancy loss patients with a positive test for an inherited thrombophilia are conflicting, a case-control study of untreated recurrent miscarriage patients who were heterozygous for the factor V Leiden mutation revealed a lower success rate than the controls who had a history of idiopathic recurrent miscarriage. With the identification of genetic risk factors, there has been synergistic amplification of thrombotic risk when one has an abnormal gene (e.g., factor V Leiden) plus environmental issues (e.g., pregnancy). Current understanding indicates that a combination of risk factors, including multiple inherited thrombophilic defects associated with secondary hypercoagulable states, have a particularly strong association with adverse pregnancy outcome.

KEYWORDS

Recurrent pregnancy loss - thrombophilias - coagulation abnormalities - miscarriage - antiphospholipid antibodies

REFERENCES

• 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh. 1965;  13 516-530
• 2 Griffin J H, Evatt B, Zimmerman T S et al.. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68 1370-1373
• 3 Comp P C, Nixon R R, Cooper D W et al.. Familial protein S deficiency is associated with recurrent thrombosis.  J Clin Invest. 1984;  74 2082-2088
• 4 Dahlback B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.  Proc Natl Acad Sci USA. 1993;  90 1004-1008
• 5 Bertina R M, Koeleman B PC, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-66
• 6 Schafer A I. The primary and secondary hypercoagulable states. In: Schafer AI Molecular Mechanisms of Hypercoagulable States. New York; Chapman and Hall 1997
• 7 Rosendaal F R. Risk factors for venous thrombosis: prevalence, risk, and interaction.  Semin Hematol. 1997;  34 171-187
• 8 Goodnight S H, Hathaway W E. Disorders of Hemostasis and Thrombosis: A Clinical Guide. 2nd ed. New York; McGraw-Hill 2001
• 9 Laros R K. Thromboembolic disease. In: Creasy RK, Resnik R Maternal-Fetal Medicine. 4th ed. Philadelphia, PA; WB Saunders 1999: 821-831
• 10 Rai R, Regan L. Thrombophilia and adverse pregnancy outcome.  Semin Reprod Med. 2000;  18 369-377
• 11 Carp H, Dolitsky M, Tur-Kaspa I, Inbal A. Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage.  Fertil Steril. 2002;  78 58-62
• 12 Lockwood C. Inherited thrombophilias in pregnant patients: detection and treatment paradigm.  Obstet Gynecol. 2002;  99 333-341
• 13 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 901-908
• 14 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;  164(5) 558-563
• 15 Krabbendam I, Francks A, Bots M L, Fijnheer R, Bruinse H W. Thrombophilias and recurrent pregnancy loss: a critical appraisal of the literature.  Eur J Obstet Gynecol Reprod Biol. 2005;  118 143-153
• 16 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism.  Clin Haematol. 1981;  10 369-390
• 17 Arkel Y S, Ku D H. Thrombophilia and pregnancy: review of the literature and some original data.  Clin Appl Thromb Hematol. 2001;  7 259-268
• 18 Regan L, Rai R. Thrombophilia and pregnancy loss.  J Reprod Immunol. 2002;  55(1-2) 163-180
• 19 Pabinger I, Brucker S, Kyrle P A et al.. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venouw thrombosis and criteria for rational patient screening.  Blood Coagul Fibrinolysis. 1992;  3 547-553
• 20 Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.  Proc Natl Acad Sci. 1994;  91 1396-1400
• 21 Preston F E, Rosendaal F R, Walker I D et al.. Increased fetal loss in women with heritable thrombophilia.  Lancet. 1996;  348 913-916
• 22 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
• 23 Rai R, Backos M, Elgaddal S, Shebak A, Regan L. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies.  Hum Reprod. 2002;  17 442-445
• 24 Meinardi J R, Middeldorp S, de Kam P J et al.. Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med. 1999;  130 736-739
• 25 Poort S R, Rosendaal F R, Reitsma P H et al.. A 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
• 26 Pihusch R, Buchholz T, Lohse P et al.. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.  Am J Reprod Immunol. 2001;  46 124-131
• 27 Mahjoub T, Mtiraoui N, Tamim H et al.. Association between adverse pregnancy outcomes and maternal factor V G1691A (Leiden) and prothrombin G20210A genotypes in women with a history of recurrent idiopathic miscarriages.  Am J Hematol. 2005;  80 12-19
• 28 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
• 29 Welch G N, Loscalzo J. Homocysteine and atherothrombosis.  N Engl J Med. 1998;  338 1042-1050
• 30 Frost P, Blom H J, Milos R et al.. MR: a candidate genetic risk factor for vascular disease: a common mutation in the methylene tetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
• 31 Jacques P, Bostom A, Williams R. Relation between folate status a common mutation in the methlenetetrahydofolate reductase and plasma homocysteine concentrations.  Circulation. 1996;  93 7-9
• 32 Van der Put N MJ, Gabreels F, Stevens E MB et al.. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural tube defects?.  Am J Hum Genet. 1998;  62 1044-1051
• 33 Welch G, Loscalzo J. Homocysteine and atherothrombosis.  N Engl J Med. 1998;  338 1042-1051
• 34 Bonnette R E, Caudill M A, Boddie A M, Hutson A D, Kauwell G P, Bailey L B. Plasma homocysteine concentrations in pregnant and non-pregnant women with controlled folate intake.  Obstet Gynecol. 1998;  92 167-170
• 35 Verhoef P, Stampfer M J, Buring J E et al.. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate.  Am J Epidemiol. 1995;  143 845-859
• 36 Nelen W L, Bulten J, Steegers E A, Blom H J, Hanselaar A G, Eskes T K. Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss.  Hum Reprod. 2000;  15 954-960
• 37 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
• 38 Tait R, Walker I D, Perry D J et al.. Prevalence of antithrombin deficiency in the healthy population.  Br J Haematol. 1994;  87 106-112
• 39 Adelberg A M, Kuller J A. Thrombophilias and recurrent miscarriage.  Obstet Gynecol Surv. 2002;  57 703-709
• 40 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency.  N Engl J Med. 1987;  317 991-996
• 41 Coumans A B, Huijgens P C, Jakobs C et al.. Haemostatic and metabolic abnormalities in women with unexplained recurrent abortion.  Hum Reprod. 1999;  14 211-214
• 42 Brandt J T, Triplett D A, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update.  Thromb Haemost. 1995;  74 1185-1190
• 43 Wilson W A, Gharavi A E. Koike Kea: International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop.  Arthritis Rheum. 1999;  42 1309-1311
• 44 Out H J, Bruinse H W, Christians C ML et al.. A prospective, controlled multicenter study of the obstetric risk Am of pregnant women with antiphospholipid antibodies.  Am J Obstet Gynecol. 1992;  167 26-32
• 45 Kutteh W H. Antiphospholipid antibodies in reproduction.  J Reprod Immunol. 1997;  35 151-171
• 46 Esplin M S. Antiphospholipid sundrome. ACOG Practice Bulletin No. 68.  Obstet Gynecol. 2005;  106 1113-1121
• 47 Rand J H. The antiphospholipid syndrome.  Annu Rev Med. 2003;  54 409-424
• 48 Rand J H, Wu X X, Guller S et al.. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion.  Am J Obstet Gynecol. 1994;  171 1566-1572
• 49 Shibata S, Harpel P C, Gharavi A, Rand J, Fillit H. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes.  Blood. 1994;  83 2532-2540
• 50 Ermel L D, Marshburn P B, Kutteh W H. Interaction of heparin with antiphospholipid antibodies (APA) from the sera of women with recurrent pregnancy loss (RPL).  Am J Reprod Immunol. 1995;  33 14-20
• 51 Franklin R D, Kutteh W H. Effects of unfractionated and low molecular weight heparin on antiphospholipid antibody binding in vitro.  Obstet Gynecol. 2003;  101 455-462
• 52 Di Simone N, Ferrazani S, Castellani R, Ce Carolis S, Mancuso S, Caruso A. Heparin and low-dose aspirin restore placental human chorionic gonadotropin secretion abolished by antiphospholipid antibody containing sera.  Hum Reprod. 1997;  12 2061-2065
• 53 Girardi G. Heparin treatment in pregnancy loss: potential therapeutic benefits beyond anticoagulation.  J Reprod Immunol. 2005;  66 45-51
• 54 Sarig G, Lanir N, Hoffman R, Brenner B. Protein C global assay in the evaluation of women with idiopathic pregnancy loss.  Thromb Haemost. 2002;  88 32-36
• 55 Rai R, Tuddenham E, Backos M et al.. Thromboelastography, whole-blood haemostasis and recurrent miscarriage.  Hum Reprod. 2003;  18 2540-2543
• 56 Porter T F, Scott J R. Evidence-based care of recurrent miscarriage.  Best Pract Res Clin Obstet Gynaecol. 2005;  19 85-101
• 57 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
• 58 Kutteh W H, Ermel L. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss lwith lower dose heparin and aspirin.  Am J Reprod Immunol. 1996;  35 402-407
• 59 Franklin R D, Kutteh W H. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population.  Hum Reprod. 2002;  17 2981-2985
• 60 Kutteh W H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.  Am J Obstet Gynecol. 1996;  174 1584-1589
• 61 Quere I, Mercier E, Bellet H, Janbon C, Mares P, Gris J C. Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia.  Fertil Steril. 2001;  75 823-825
• 62 Pattison N S, Chamley L W, Birdsall M, Zanderigo A M, Liddell H S, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial.  Am J Obstet Gynecol. 2000;  183 1008-1012
• 63 Empson M, Lassere M, Craig J C, Scott J R. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials.  Obstet Gynecol. 2002;  99 135-144
• 64 Noble L S, Kutteh W H, Lashley N, Franklin R D, Herrada J. Antiphospholipid antibodies (APA) associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with enoxaparin versus unfractionated heparin.  Fertil Steril. 2005;  83 684-690
• 65 Stephenson M D, Ballem P J, Tsang P et al.. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin.  J Obstet Gynaecol Can. 2004;  26 729-734
• 66 Silver R M, Branch D W. Immunologic Disorders. Philadelphia, PA; WB Saunders 1999
• 67 Triplett D A. Antiphospholipid protein antibodies: laboratory detection and clinical relevance.  Thromb Res. 1995;  78 1-31
• 68 Weiss E J, Bray P F, Tayback M et al.. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor of coronary thrombosis.  N Engl J Med. 1996;  334 1090-1094
• 69 Vandenbrouke J P, Koster T, Briet E et al.. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 1453-1457
• 70 Vad S, Lakos G, Kiss E, Sipka S, Csorba R, Poka R. Antiphospholipid antibodies in young women with and without oral contraceptive use.  Blood Coagul Fibrinolysis. 2003;  14 57-60