Recurrent Pregnancy Loss: Etiology of Thrombophilia

ABSTRACT

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-β2-glycoprotein I antibody (aβ2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class aβ2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class aβ2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.

KEYWORD

Thrombophilia - factor V Leiden mutation - methylene tetrahydrofolate reductase - antiphospholipid antibody - abortion

REFERENCES

• 1 Sanson B J, Friederich P W, Simioni P. The risk of abortion and stillbirth in antithrombin-III, protein C-, and protein S-deficient women.  Thromb Haemost . 1996;  75 387-388
• 2 Preston F E, Rosendaal F R, Walker I D. Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
• 3 Balasch J, Reverter J C, Fabregues F. First-trimester repeated abortion is not associated with activated protein C resistance.  Hum Reprod . 1997;  12 1094-1097
• 4 Dizon-Townson D S, Kinney S, Branch D W, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage.  J Reprod Immunol . 1997;  34 217-223
• 5 Pauer H U, Neesen J, Hinney B. Factor V Leiden and its relevance in patients with recurrent abortions.  Am J Obstet Gynecol . 1998;  178 629
• 6 Gris J C, Ripart-Neveu S, Maugard C. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages.  The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost . 1997;  77 1096-1103
• 7 Kupferminc M J, Eldor A, Steinman N. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
• 8 Nelen W L, Steegers E A, Eskes T K, Blom H J. Genetic risk factor for unexplained recurrent early pregnancy loss.  Lancet . 1997;  350 861
• 9 Quere I, Bellet H, Hoffet M. A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages.  Fertil Steril . 1998;  69 152-154
• 10 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease.  Lancet . 1990;  336 177-178
• 11 McNeil H P, Simpson R J, Chesterman C N, Krilis S A. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H).  Proc Natl Acad Sci USA . 1990;  87 4120-4124
• 12 Galli M, Comfurius P, Maassen C. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma cofactor.  Lancet . 1990;  335 1544-1547
• 13 Koike T, Matsuura E. What is the ``true'' antigen for anticardiolipin antibodies?.  Lancet . 1991;  337 671-672
• 14 Matsuura E, Igarashi Y, Fujimoto M. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor.  J Immunol . 1992;  148 3885-3891
• 15 Tsutsumi A, Matsuura E, Ichikawa K. Antibodies to β2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus.  Arthritis Rheum . 1996;  39 1466-1474
• 16 McNally T, Purdy G, Mackie I J, Machin S J, Isenberg D A. The use of anti-β2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis.  Br J Haematol . 1995;  91 471-473
• 17 Ozawa N, Makino T, Matsubayashi H. β2-GPI- dependent and independent binding of anticardiolipin antibodies in patients with recurrent spontaneous abortions.  Clin Lab Anal . 1994;  8 255-259
• 18 Aoki K, Dudkiewicz A B, Matsuura E. Clinical significance of β2-glycoprotein I-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: correlation with conventional antiphospholipid antibody detection systems.  Am J Obstet Gynecol . 1995;  172 926-931
• 19 Tait R C, Walker I D, Reitsma P H. Prevalence of protein C deficiency in the healthy population.  Thromb Haemost . 1995;  73 87-93
• 20 Conard J, Horellou M H, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in ATIII, protein C or protein S.  Thromb Haemost . 1990;  63 319-320
• 21 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency.  Arterioscler Thromb Vasc Biol . 1996;  16 742-748
• 22 Bock S C, Harris J F, Balazs I, Trent J M. Assignment of the human antithrombin III structural gene to chromosome 1q23-25.  Cytogenet Cell Genet . 1985;  39 67-69
• 23 Cosgriff T M, Bishop D T, Hershgold E J. Familial antithrombin III deficiency: its natural history, genetics, diagnosis and treatment.  Medicine (Baltimore) . 1983;  62 209-220
• 24 Beresford C H. Antithrombin III deficiency.  Blood Rev . 1988;  2 239-250
• 25 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency: incidence and clinical features.  Am J Med . 1989;  34S (34S)
• 26 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency.  Gynecol Obstet Invest . 1982;  14 127-141
• 27 McColl M D, Ramsay J E, Tait R C. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost . 1997;  78 1183-1188
• 28 Jochmans K, Lissens W, Vervoort R. Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis.  Blood . 1994;  83 146-151
• 29 Yamada H, Hoshi N, Kato E H. Novel mutation (E113X) of antithrombin III gene (AT3) in a woman with gestational recurrent thrombosis.  Am J Med Genet . 2000;  91 348-350
• 30 Bertina R M, Koeleman B P, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
• 31 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
• 32 Grandone E, Margaglione M, Colaizzo D. Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia.  Thromb Haemost . 1997;  77 1052-1054
• 33 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
• 34 Dizon-Townson D S, Kinney S, Branch D W, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage.  J Reprod Immunol . 1997;  34 217-223
• 35 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
• 36 Kobashi G, Yamada H, Asano T. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan.  Semin Thromb Hemost . 1999;  25 487-489
• 37 Kodaira H, Ishida F, Shimodaira S. Resistance to activated protein C and Arg 506 Gln factor V mutation are uncommon in eastern Asian populations.  Acta Haematol . 1997;  98 22-25
• 38 Kluft C, Dooijewaard G, Emeis J J. Role of the contact system in fibrinolysis.  Semin Thromb Hemost . 1987;  13 50-68
• 39 Mannhalter C, Fischer M, Hopmeier P, Deutsch E. Factor XII activity and antigen concentration in patients suffering from recurrent thrombosis.  Fibrinolysis . 1987;  1 259-263
• 40 McPherson R A. Thromboembolism in Hageman trait.  Am J Clin Pathol . 1977;  68 420-423
• 41 Dyerberg J, Stoffersen E. Recurrent thrombosis in a patient with factor XII deficiency.  Acta Haematol . 1980;  63 278-282
• 42 Lämmle B, Wuillemin W A, Huber I. Thromboembolism and bleeding tendency in congenital factor XII deficiency-a study on 74 subjects from 14 Swiss families.  Thromb Haemost . 1991;  65 117-121
• 43 Halbmayer W M, Mannhalter C, Feichtinger C, Rubi K, Fischer M. The prevalence of factor XII deficiency in 103 orally anticoagulated outpatients suffering from recurrent venous and/or arterial thromboembolism.  Thromb Haemost . 1992;  68 285-290
• 44 Winter M, Gallimore M, Jones D W. Should factor XII assays be included in thrombophilia screening?.  Lancet . 1995;  346 52
• 45 Mangal A K, Naiman S C. Hageman factor deficiency and oral contraceptives.  Lancet . 1980;  1 774
• 46 Goodnough L T, Saito H, Ratnoff O D. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases.  Medicine (Baltimore) . 1983;  62 248-255
• 47 Lodi S, Isa L, Pollini E, Bravo A F, Scalvini A. Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction.  Scand J Haematol . 1984;  33 80-82
• 48 Penny W J, Colvin B T, Brooks N. Myocardial infarction with normal coronary arteries and factor XII deficiency.  Br Heart J . 1985;  53 230-234
• 49 Hellstern P, Kohler M, Schmengler K, Doenecke P, Wenzel E. Arterial and venous thrombosis and normal response to streptokinase treatment in a young patient with severe Hageman factor deficiency.  Acta Haematol . 1983;  69 123-126
• 50 Schved J F, Gris J C, Neveu S, Dupaigne D, Mares P. Factor XII congenital deficiency and early spontaneous abortion.  Fertil Steril . 1989;  52 335-336
• 51 Braulke I, Pruggmayer M, Melloh P. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters?.  Fertil Steril . 1993;  59 98-101
• 52 Cool D E, MacGillivray R T. Characterization of the human blood coagulation factor XII gene.  Intron/exon gene organization and analysis of the 5'-flanking region. J Biol Chem . 1987;  262 13662-13673
• 53 Miyazawa K, Wang Y, Minoshima S, Shimizu N, Kitamura N. Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene-phylogenetic and functional relationship with blood coagulation factor XII, urokinase, and tissue-type plasminogen activator.  Eur J Biochem . 1998;  258 355-361
• 54 Shimomura T, Miyazawa K, Komiyama Y. Activation of hepatocyte growth factor by two homologous proteases, blood-coagulation factor XIIa and hepatocyte growth factor activator.  Eur J Biochem . 1995;  229 257-261
• 55 Uehara Y, Minowa O, Mori C. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/ scatter factor.  Nature . 1995;  373 702-705
• 56 Schmidt C, Bladt F, Goedecke S. Scatter factor/hepatocyte growth factor is essential for liver development.  Nature . 1995;  373 699-702
• 57 Yamada H, Kato E H, Ebina Y. Factor XII deficiency in women with recurrent miscarriage.  Gynecol Obstet Invest . 2000;  49 80-83
• 58 Sohda S, Arinami T, Hamada H. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia.  Med Genet . 1997;  34 525-526
• 59 Frosst P, Blom H J, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet . 1995;  10 111-113
• 60 McCully K S. Homocysteine and vascular disease.  Nat Med . 1996;  2 386-289
• 61 Kobashi G, Yamada H, Asano T. Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and preeclampsia in Japanese women.  Am J Med Genet . 2000;  93 122-125
• 62 Ray J G, Laskin C A. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review.  Placenta . 1999;  20 519-529
• 63 Morita H, Taguchi J, Kurihara H. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease.  Circulation . 1997;  95 2032-2036
• 64 Tsutsumi A, Matsuura E, Ichikawa K. IgA class anti-β2-glycoprotein I in patients with systemic lupus erythematosus.  J Rheumatol . 1998;  25 74-78
• 65 Yamada H, Tsutsumi A, Ichikawa K, Kato E H, Koike T, Fujimoto S. IgA class anti-β2-glycoprotein I in women with unexplained recurrent spontaneous abortion.  Arthritis Rheum . 1999;  42 2727-2728