Download PDF
Thromb Haemost 2000; 84(02): 228-236
DOI: 10.1055/s-0037-1614001
Review Article
Schattauer GmbH

Antiphospholipid and Antiprotein Syndromes in Non-thrombotic, Non-autoimmune Women with Unexplained Recurrent Primary Early Foetal Loss

The Nîmes Obstetricians and Haematologists Study4 - NOHA4
Jean-Christophe Gris
1   From Laboratoire d’Hématologie, Faculté de Pharmacie, Montpellier, Nîmes, France
2   Laboratoire d’Hématologie, Centre Hospitalier Universitaire, Nîmes, France
3   E.A. M.E.N.R.T. “Dynamique des incohérences cardio-vasculaires”, Nîmes, France
,
Isabelle Quéré
3   E.A. M.E.N.R.T. “Dynamique des incohérences cardio-vasculaires”, Nîmes, France
4   Service de Médecine Interne B et Maladies Vasculaires, CHU, Montpellier, Nîmes, France
,
Marielle Sanmarco
5   Fédération AutoimmunitéThrombose, Hôpital de la Conception, CHU, Marseille, Nîmes, France
,
Brigitte Boutiere
5   Fédération AutoimmunitéThrombose, Hôpital de la Conception, CHU, Marseille, Nîmes, France
,
Eric Mercier
2   Laboratoire d’Hématologie, Centre Hospitalier Universitaire, Nîmes, France
,
Jean Amiral
6   SERBIO, Gennevilliers, Nîmes, France
,
Anne-Michèle Hubert
5   Fédération AutoimmunitéThrombose, Hôpital de la Conception, CHU, Marseille, Nîmes, France
,
Sylvie Ripart-Neveu
7   Département de Gynécologie et Obstétrique, CHU, Nîmes, France
,
Méderic Hoffet
7   Département de Gynécologie et Obstétrique, CHU, Nîmes, France
,
Marie-Laure Tailland
7   Département de Gynécologie et Obstétrique, CHU, Nîmes, France
,
Olivier Rousseau
7   Département de Gynécologie et Obstétrique, CHU, Nîmes, France
,
Françoise Monpeyroux
8   Département d’Information Médicale, CHU, Nîmes, France
,
Michel Dauzat
3   E.A. M.E.N.R.T. “Dynamique des incohérences cardio-vasculaires”, Nîmes, France
,
José Sampol
5   Fédération AutoimmunitéThrombose, Hôpital de la Conception, CHU, Marseille, Nîmes, France
,
Jean-Pierre Daures
8   Département d’Information Médicale, CHU, Nîmes, France
,
Jacques Berlan
1   From Laboratoire d’Hématologie, Faculté de Pharmacie, Montpellier, Nîmes, France
,
Pierre Marès
7   Département de Gynécologie et Obstétrique, CHU, Nîmes, France
› Author AffiliationsWe thank all the women from the French regions Languedoc-Roussillon and Provence-Alpes-Côte d’Azur who participated in the study. We acknowledge all the physicians who referred their patients to our team, and particularly H Coulondre, R Delpon de Vaux, D Dupaigne, C Ferrer, MP Le Gac, B Galan, F Jamet, P Quirot, E Ranque, J Vedel and S Wright for their contribution to the study. We are indebted to technicians Mr. Christian Sarlat, Mrs. Christine Galtier, Madeleine Gayraud, Françoise Vassas and Marie-Thérèse Dantan for their excellent assistance in laboratory analysis. We thank Margaret Manson for editorial assistance. We thank Marie-Claire Boffa for fruitful discussion and for expert editorial assistance.
Further Information

Publication History

Received 14 December 1999

Accepted after resubmission 13 March 2000

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

Various antiphospholipid and/or antiprotein antibodies have been suspected to be associated with recurrent early foetal loss in absence of any habitual aetiology. We conducted a hospital-based case control study on women with no antecedent of thromboembolic or autoimmune disease. We studied 3 groups of 518 women: patients with unexplained primary recurrent early foetal loss, patients with explained episodes and mothers with no previous obstetrical accident. Matching the 3 groups was carried out on the basis of age, number or pregnancies and time elapsed since the end of the last pregnancy. Significant biological markers were then prospectively tested.

The various antibodies were shown to be dependent on parity and on the presence of previous foetal loss: cut-off values were thus calculated using data obtained from the group of explained accidents, and adjusted for parity. Only anti-phosphatidylethanolamine IgM [odds ratio: 6.0, 95% confidence interval (2.3–15.7), p = 0.0003], anti-β2-glycoprotein I IgG [4.4, (1.6–11.7), p = 0.0035] anti-annexin V IgG antibodies [3.2 (1.2–8.1), p = 0.015] and lupus anticoagulant [3.0, (1.3–6.8), p = 0.009], were found to be independent retrospective risk factors for unexplained early foetal loss. These four markers were subsequently found to be, during the following pregnancy, associated with a significant risk of foetal loss despite a low-dose aspirin treatment.

In non-thrombotic, non-auto-immune women with unexplained primary reccurent early foetal loss, subgroups of patients with positive anti-phosphatidylethanolamine IgM antibodies, or positive anti- β2-glycoprotein-I IgG antibodies, or positive anti-annexin V IgG anti-bodies or lupus anticoagulant must be particularised. This should allow therapeutic trials to be carried in well-defined patients.

Key words

Foetal loss - antiphospholipid antibodies - β2 glycoprotein I - annexin V - phosphatidylethanolamine
 

  • References

  • 1 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: b2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4.
    CrossrefPubMedGoogle Scholar
  • 2 Galli M, Comfurius P, Maassen C, Hemker HC, Baets MH, van Breda-Vriesman PJC, Barbui T, Zwall RFA, Bevers EM. Anticardiolipin antibodies directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7.
    CrossrefPubMedGoogle Scholar
  • 3 Fleck RA, Rapaport SI, Rao LVM. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512-9.
    PubMedGoogle Scholar
  • 4 Bevers AM, Galli M, Barbui T, Comfurius P, Zwall RFA. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Roubey RAS, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon b2-glycoprotein I. J Clin Invest 1992; 90: 1100-4.
    CrossrefPubMedGoogle Scholar
  • 6 Nakamura N, Kuragaki C, Shidara Y, Yamaji K, Wada Y. Antibody to annexin V has anti-phospholipid and lupus anticoagulant activity. Am J Hematol 1995; 49: 347-8.
    CrossrefPubMedGoogle Scholar
  • 7 Garcia CO, Kanbour-Shakir A, Tang H, Molina JF, Espinoza LR, Gharavi AE. Induction of experimental antiphospholipid antibody syndrome in PL/J mice following immunization with beta 2 GPI. Am J Reprod Immunol 1997; 37: 118-24.
    CrossrefPubMedGoogle Scholar
  • 8 Chamley LW, Duncalf AM, Mitchell MD, Johnson PM. Action of anticardiolipin and antibodies to b2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet 1998; 352: 1037-8.
    CrossrefPubMedGoogle Scholar
  • 9 Cabral AR, Amigo MC, Cabiedes J, Alarcon-Segovia D. The antiphospholipid/cofactor syndromes: a primary variant with antibodies to b2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays. Am J Med 1996; 101: 472-81.
    CrossrefPubMedGoogle Scholar
  • 10 Gris JC, Quéré I, Montpeyroux F, Mercier E, Ripart-Neveu S, Tailland ML, Hoffet M, Berlan J, Daurès JP, Marès P. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and non thrombotic antecedent – The Nîmes Obstetricians and Haematologists study 5 (NOHA5). Thromb Haemost 1999; 81: 891-99.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Constant G, Gouault-Heilmann M, Martinolli JL. Heparin inactivation during blood storage. Its prevention by blood collection in citric acid, theophylline, adenosine, dipyridamol – -CTAD mixture. Thromb Res 1983; 31: 365-74.
    CrossrefPubMedGoogle Scholar
  • 12 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the second international workshop for identification of lupus anticoagulants. Thromb Haemost 1995; 74: 1597-603.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Gris JC, Ripart-Neveu S, Maugard C, Tailland ML, Brun S, Courtieu C, Biron C, Hoffet M, Hédon B, Marès P. Prospective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. Thromb Haemost 1997; 77: 1096-103.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Reber G, Arvieux J, Comby E, Degenne D, de Moerloose P, Sanmarco M, Potron G. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. Thromb Haemost 1995; 73: 444-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Amiral J, Minard F, Chambrette B. Development of standardized immunoassays for identification, characterization and quantitation of antiphospholipid antibodies (APA). Biol Clin Hematol 1991; 13: 81-8.
    PubMedGoogle Scholar
  • 17 Amiral J, Larrivaz I, Cluzeau D, Adam M. Standardization of immunoassays for antiphospholipid antibodies with β2-GPI and role of other phospholipid cofactors. Haemostasis 1994; 24: 191-203.
    PubMedGoogle Scholar
  • 18 Horbach DA, van Oort E, Templeman MJ, Derksen RHWM, de Groot PG. The prevalence of a non-phospholipid-binding form of β2-glycoprotein I in human plasma. Thromb Haemostas 1998; 80: 791-7.
    PubMedGoogle Scholar
  • 19 Bezaud A, Guillin MC, Olmeda F, Quintina M, Gomez G. Prothrombin Madrid: a new familial abnormality of prothrombin. Thromb Res 1979; 16: 47-58.
    CrossrefPubMedGoogle Scholar
  • 20 Romisch J, Heimburger N. Purification and characterization of six annexins from human plasma. Biol Chem Hoppe Seyler 1990; 371: 383-8.
    CrossrefPubMedGoogle Scholar
  • 21 Berard M, Boffa MC, Karmochkine M, Aillaud MF, Juhan-Vague I, Frances C, Cacoub P, Piette JC, Harle JR. Plasma reactivity to hexagonal II phase phosphatidylethanolamine is more frequently associated with lupus anticoagulant than with anti-phosphatidylethanolamine antibodies. J Lab Clin Med 1993; 122: 601-5.
    PubMedGoogle Scholar
  • 22 Molo MW, Kelly M, Balos R, Mullaney K, Radwanska E. Incidence of fetal loss in patients after detection of fetal heart activity with early transvaginal ultrasound. J Reprod Med 1993; 38: 804-6.
    PubMedGoogle Scholar
  • 23 Makikallio K, Tekay A, Jouppila P. Yolk sac and umbilicoplacental hemodynamics during early human embryonic development. Ultrasound Obstet Gynecol 1999; 14: 175-9.
    CrossrefPubMedGoogle Scholar
  • 24 Ogasawara M, Sasa H, Katano K, Aoyama T, Aoki K, Suzumori K. Recurrent abortion and moderate or strong antiphospholipid antibody production. Int J Gynaecol Obstet 1998; 62: 183-8.
    CrossrefPubMedGoogle Scholar
  • 25 Rai R, Cohne H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriages associated with phospholipid antibodies. Br Med J 1997; 314: 253-7.
    CrossrefPubMedGoogle Scholar
  • 26 Sugi T, Katsunuma J, Izumi SI, McIntyre J, Makino T. Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil Steril 1999; 71: 1060-5.
    CrossrefPubMedGoogle Scholar
  • 27 Karmochkine M, Berard M, Piette JC, Cacoub P, Aillaud MF, Harle JR, Godeau P, Boffa MC, Harle JR. Antiphosphatidylethanolamine antibodies in systemic lupus erythematosus. Lupus 1993; 02: 420.
    PubMedGoogle Scholar
  • 28 Vlachoyiannopoulos PG, Beigdeber G, Dueymes M, Youinou P, Hunt JE, Krilis SA, Moutsopoulos HM. Antibodies to phosphatidylethanolamine in antiphospholipid syndrome and systemic lupus erythematosus: their correlation with anticardiolipin antibodies and beta 2 glycoprotein-I plasma levels. Autoimmunity 1993; 16: 245-9.
    CrossrefPubMedGoogle Scholar
  • 29 Sugi T, McIntyre JA. Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen-PE complex. Blood 1995; 86: 3083-9.
    PubMedGoogle Scholar
  • 30 Boffa MC, Berard M, Sigi T, McIntyre JA. Antiphosphatidylethanolamine antibodies as the only antiphospholipid antibodies detected by ELISA. II. Kininogen reactivity. J Rheumatol 1996; 23: 1375-9.
    PubMedGoogle Scholar
  • 31 Horie S, Ishii H, Hara H, Kazama M. Enhancement of thrombin-thrombomodulin-catalysed protein C activation by phosphatidylethanolamine containing unsaturated fatty acids: possible physiological significance of phosphatidylethanolamine in anticoagulant activity of thrombomodulin. Biochem J 1994; 301: 683-91.
    CrossrefPubMedGoogle Scholar
  • 32 Neuenschwander PF, Bianco-Fisher E, Rezaie AR, Morrissey JH. Phosphatidylethanolamine augments factor VIIa-tissue factor activity: enhancement of sensivity to phosphatidylserine. Biochemistry 1995; 34: 13988-93.
    CrossrefPubMedGoogle Scholar
  • 33 Aoki K, Dudkiewicz AB, Matsuura E, Novotny M, Kaberlein G, Gleicher N. Clinical significance of β2-glycoprotein-dependent anticardiolipin antibodies in the reproductive autoimmune failure syndrome: correlation with conventional antiphospholipid antibody detection systems. J Obstet Gynecol 1995; 172: 926-31.
    CrossrefPubMedGoogle Scholar
  • 34 Katano K, Aoki A, Sasa H, Ogasawara M, Matsuura E, Yagami Y. Beta 2-glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women. Hum Reprod 1996; 11: 509-12.
    CrossrefPubMedGoogle Scholar
  • 35 Matsuda J, Gotoh M, Saitoh N, Gohchi K, Tsukamoto M, Yamamoto T. Anti-annexin antibody in the sera of patients with habitual fetal loss or preeclampsia. Thromb Res 1994; 75: 105-6.
    CrossrefPubMedGoogle Scholar
  • 36 Kaburaki J, Kuwana M, Yamamoto M, Kawai S, Ikeda Y. Clinical significance of anti-annexin V antibodies in patients with systemic lupus erythematosus. Am J Hematol 1997; 54: 209-13.
    CrossrefPubMedGoogle Scholar
  • 37 Schild H, Rtzschke O, Kalbacher H, Rammensee HG. Limit of T cell tolerance to self proteins by peptide presentation. Science 1990; 247: 1587-9.
    CrossrefPubMedGoogle Scholar
  • 38 Rand JH, Wu XX, Andree HAM, Lockwood CJ, Guller S, Scher J, Harpel PC. Pregnancy loss in the antiphospholipid-antibody syndrome – a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-60.
    CrossrefPubMedGoogle Scholar
  • 39 Wang X, Campos B, Kaetzel MA, Dedman JR. Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol 1999; 180: 1008-16.
    CrossrefPubMedGoogle Scholar