Recurrent Pregnancy Loss: Etiology of Thrombophilia

Hideto Yamada; Emi H. Kato; Gen Kobashi; Yasuhiko Ebina; Shigeki Shimada; Mamoru Morikawa; Takahiro Yamada; Noriaki Sakuragi; Seiichiro Fujimoto

doi:10.1055/s-2001-14070

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2001; 27(2): 121-130
DOI: 10.1055/s-2001-14070

Recurrent Pregnancy Loss: Etiology of Thrombophilia

Hideto Yamada¹ , Emi H. Kato¹ , Gen Kobashi² , Yasuhiko Ebina¹ , Shigeki Shimada¹ , Mamoru Morikawa¹ , Takahiro Yamada¹ , Noriaki Sakuragi¹ , Seiichiro Fujimoto¹

¹Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, Japan and
²Department of Health for Senior Citizens, Hokkaido University School of Medicine, Sapporo, Japan

Abstract

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

Volltext

Referenzen

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