Obstetric Antiphospholipid Syndrome: An Update on Pathophysiology and Management

ABSTRACT

Antiphospholipid antibodies (aPLs) are acquired antibodies directed against negatively charged phospholipids, a group of inner and outer cell membrane antigens found in mammals. Obstetric antiphospholipid antibody syndrome (APS) is diagnosed in the presence of certain clinical features in conjunction with positive laboratory findings. Although obstetric APS was originally reported in association with slow progressive thrombosis and infarction in the placenta, it is most often associated with a poor obstetric outcome. In fact, obstetric APS is one of the most commonly identified causes of recurrent pregnancy loss (RPL). Thus obstetric APS is distinguished from APS in other organ systems where the most common manifestation is thrombosis. Several pathophysiological mechanisms of action of aPLs have been described. The most common histopathological finding in early pregnancy loss has been defective endovascular decidual trophoblastic invasion. Treatment with heparin and aspirin is emerging as the therapy of choice, with ∼75% of treated women with RPL and aPLs having a successful delivery compared with <50% without treatment. This review highlights the diagnostic challenges of obstetric APS, the obstetric complications associated with APS, proposed pathophysiological mechanisms of APS during pregnancy, and the management of women during and after pregnancy.

KEYWORDS

Antiphospholipid syndrome - antiphospholipid antibodies - obstetric antiphospholipid syndrome - recurrent pregnancy loss - fetal demise - unfractionated heparin - complications of pregnancy - thrombosis

REFERENCES

• 1 De Wolf F, Carreras L O, Moerman P, Vermylen J, Van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant.  Am J Obstet Gynecol. 1982;  142 (7) 829-834
• 2 Adler R R, Ng A K, Rote N S. Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR.  Biol Reprod. 1995;  53 (4) 905-910
• 3 Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote N S. Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion.  Biol Reprod. 1997;  56 (1) 50-58
• 4 Quenby S, Mountfield S, Cartwright J E, Whitley G S, Chamley L, Vince G. Antiphospholipid antibodies prevent extravillous trophoblast differentiation.  Fertil Steril. 2005;  83 (3) 691-698
• 5 Rand J H. Molecular pathogenesis of the antiphospholipid syndrome.  Circ Res. 2002;  90 (1) 29-37
• 6 Out H J, Kooijman C D, Bruinse H W, Derksen R H. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies.  Eur J Obstet Gynecol Reprod Biol. 1991;  41 (3) 179-186
• 7 Kutteh W H, Rote N S, Silver R. Antiphospholipid antibodies and reproduction: the antiphospholipid antibody syndrome.  Am J Reprod Immunol. 1999;  41 (2) 133-152
• 8 Schust D J, Hill J A. Recurrent Pregnancy Loss. Philadelphia, PA: Lippincott Williams & Wilkins; 2002
• 9 Rand J H. The antiphospholipid syndrome.  Annu Rev Med. 2003;  54 409-424
• 10 Harris E N, Gharavi A E, Boey M L et al.. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus.  Lancet. 1983;  2 (8361) 1211-1214
• 11 Wasserman A, Neisser A, Bruck C. Eine Serodiagnostiche reaktion bei syphilis.  Dtsch Med Wochenschr. 1906;  32 745-749
• 12 Landsteiner K, Muller R, Potzl D. Studies on the complement binding reaction in syphilis.  Wien Klin Wochenschr. 1907;  20 1565
• 13 Pangborn M C, Pangborn M C. A new seriologically active phospholipid from beef heart.  Proc Soc Exp Biol Med. 1941;  48 484-486
• 14 Moore J E, Mohr C F. Biologically false positive serologic tests for syphilis; type, incidence, and cause.  J Am Med Assoc. 1952;  150 (5) 467-473
• 15 Conley C L, Hartmann R C. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus.  J Lab Clin Invest. 1952;  31 621-622
• 16 Beaumont J L. Acquired hemorrhagic syndrome caused by a circulating anticoagulant; inhibition of the thromboplastic function of the blood platelets; description of a specific test. [in French].  Sang. 1954;  25 1-5
• 17 Laurell A B, Nilsson I M. Hypergammaglobulinemia, circulating anticoagulant, and biologic false positive Wassermann reaction; a study in two cases.  J Lab Clin Med. 1957;  49 (5) 694-707
• 18 Bowie E J, Thompson Jr J H, Pascuzzi C A, Owen Jr C A. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants.  J Lab Clin Med. 1963;  62 416-430
• 19 Alarcon Segovia D, Osmundson P J. Peripheral vascular syndromes associated with systemic lupus erythematosus.  Ann Intern Med. 1965;  62 907-919
• 20 Lechner K. A new type of coagulation inhibitor.  Thromb Diath Haemorrh. 1969;  21 (3) 482-499
• 21 Feinstein D I, Rapaport S I. Acquired inhibitors of blood coagulation.  Prog Hemost Thromb. 1972;  1 75-95
• 22 Nilsson I M, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant (“antithromboplastin”).  Acta Med Scand. 1975;  197 (3) 153-159
• 23 Von Felton A, Gehrig D, Martius F. Antiphospholipid antibodies as a cause of thrombocytopenia and p-pathia.  Eur J Clin Invest. 1977;  7 223
• 24 Soulier J P, Boffa M C. Avortements à répétition, thromboses et anticoagulant circulant anti-thromboplastine.  Nouv Presse Med. 1980;  9 859-864
• 25 Thiagarajan P, Shapiro S S, De Marco L. Monoclonal immunoglobulin M lambda coagulation inhibitor with phospholipid specificity. Mechanism of a lupus anticoagulant.  J Clin Invest. 1980;  66 (3) 397-405
• 26 Carreras L O, Vermylen J, Spitz B, Van Assche A. “Lupus” anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauterine death.  Br J Obstet Gynaecol. 1981;  88 (9) 890-894
• 27 Hughes G RV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant.  Br Med J (Clin Res Ed). 1983;  287 (6399) 1088-1089
• 28 Hughes G RV. The anticardiolipin syndrome.  Clin Exp Rheumatol. 1985;  3 (4) 285-286
• 29 Loizou S, McCrea J D, Rudge A C, Reynolds R, Boyle C C, Harris E N. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results.  Clin Exp Immunol. 1985;  62 (3) 738-745
• 30 Harris E N, Baguley E, Asherson R A, Hughes G RV. Clinical and serological features of the antiphospholipid syndrome (APS).  Br J Rheumatol. 1987;  26 (Suppl 2) 19
• 31 Branch D W, Rote N S, Dostal D A, Scott J R. Association of lupus anticoagulant with antibody against phosphatidylserine.  Clin Immunol Immunopathol. 1987;  42 (1) 63-75
• 32 McNeil H P, Simpson R J, Chesterman C N, Krilis S A. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H).  Proc Natl Acad Sci U S A. 1990;  87 (11) 4120-4124
• 33 Rosove M H, Tabsh K, Wasserstrum N, Howard P, Hahn B H, Kalunian K C. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies.  Obstet Gynecol. 1990;  75 (4) 630-634
• 34 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 (5) 1584-1589
• 35 Wilson W A, Gharavi A E, Koike T et al.. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop.  Arthritis Rheum. 1999;  42 (7) 1309-1311
• 36 Lockshin M D. Antiphospholipid antibody. Babies, blood clots, biology.  JAMA. 1997;  277 (19) 1549-1551
• 37 Alarcón-Segovia D, Delezé M, Oria C V et al.. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients.  Medicine (Baltimore). 1989;  68 (6) 353-365
• 38 Kutteh W H, Lyda E C, Abraham S M, Wacholtz M C. Association of anticardiolipin antibodies and pregnancy loss in women with systemic lupus erythematosus.  Fertil Steril. 1993;  60 (3) 449-455
• 39 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 (2) 295-306
• 40 Harris E N. Syndrome of the black swan.  Br J Rheumatol. 1987;  26 (5) 324-326
• 41 American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics . ACOG Practice Bulletin No. 118: Antiphospholipid syndrome.  Obstet Gynecol. 2011;  117 (1) 192-199
• 42 Silver R M, Draper M L, Scott J R, Lyon J L, Reading J, Branch D W. Clinical consequences of antiphospholipid antibodies: an historic cohort study.  Obstet Gynecol. 1994;  83 (3) 372-377
• 43 Martin B A, Branch D W, Rodgers G M. Sensitivity of the activated partial thromboplastin time, the dilute Russell's viper venom time, and the kaolin clotting time for the detection of the lupus anticoagulant: a direct comparison using plasma dilutions.  Blood Coagul Fibrinolysis. 1996;  7 (1) 31-38
• 44 Pengo V, Tripodi A, Reber G Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis et al. Update of the guidelines for lupus anticoagulant detection.  J Thromb Haemost. 2009;  7 (10) 1737-1740
• 45 Di Simone N, Meroni P L, de Papa N et al.. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I.  Arthritis Rheum. 2000;  43 (1) 140-150
• 46 McIntyre J A. Immune recognition at the maternal-fetal interface: overview.  Am J Reprod Immunol. 1992;  28 (3–4) 127-131
• 47 Schousboe I, Rasmussen M S. Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I.  Thromb Haemost. 1995;  73 (5) 798-804
• 48 Gleicher N, el-Roeiy A, Confino E, Friberg J. Reproductive failure because of autoantibodies: unexplained infertility and pregnancy wastage.  Am J Obstet Gynecol. 1989;  160 (6) 1376-1380; discussion 1380–1385
• 49 Matzner W, Chong P, Xu G, Ching W. Characterization of antiphospholipid antibodies in women with recurrent spontaneous abortions.  J Reprod Med. 1994;  39 (1) 27-30
• 50 Gilman-Sachs A, Lubinski J, Beer A E, Brend S, Beaman K D. Patterns of anti-phospholipid antibody specificities.  J Clin Lab Immunol. 1991;  35 (2) 83-88
• 51 Branch D W, Silver R, Pierangeli S S, van Leeuwen I, Harris E N. Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome.  Obstet Gynecol. 1997;  89 (4) 549-555
• 52 Yetman D L, Kutteh W H. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies.  Fertil Steril. 1996;  66 (4) 540-546
• 53 Kutteh W H, Corey A, Jaslow C R. Antiphospholipid antibodies and recurrent pregnancy loss: Prevalence of anticardiolipin antibodies, the lupus anticoagulant, and antiphosphatidyl serine antibodies.  Lupus. 2010;  19 546
• 54 Peaceman A M, Silver R M, MacGregor S N, Socol M L. Interlaboratory variation in antiphospholipid antibody testing.  Am J Obstet Gynecol. 1992;  166 1780-1784
• 55 Carreras L O, Forastiero R R, Martinuzzo M E. Which are the best biological markers of the antiphospholipid syndrome?.  J Autoimmun. 2000;  15 (2) 163-172
• 56 Kutteh W H, Franklin R D. Assessing the variation in antiphospholipid antibody (APA) assays: comparison of results from 10 centers.  Am J Obstet Gynecol. 2004;  191 (2) 440-448
• 57 Franklin R D, Kutteh W H. Effects of unfractionated and low molecular weight heparin on antiphospholipid antibody binding in vitro.  Obstet Gynecol. 2003;  101 (3) 455-462
• 58 Franklin R D, Kutteh W H. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population.  Hum Reprod. 2002;  17 (11) 2981-2985
• 59 Eby C. Antiphospholipid syndrome review.  Clin Lab Med. 2009;  29 (2) 305-319
• 60 Rodger M A. Thrombophilia and placenta-mediated pregnancy complications: from the bench to bedside to policy.  Thromb Res. 2009;  123 (Suppl 2) S100-S104
• 61 Benedetto C, Marozio L, Tavella A M, Salton L, Grivon S, Di Giampaolo F. Coagulation disorders in pregnancy: acquired and inherited thrombophilias.  Ann N Y Acad Sci. 2010;  1205 106-117
• 62 Hatasaka H H. Recurrent miscarriage: epidemiologic factors, definitions, and incidence.  Clin Obstet Gynecol. 1994;  37 (3) 625-634
• 63 Branch D W, Carson S A. The American College of Obstetricians and Gynecologists. Management of Recurrent Early Pregnancy Loss. Washington, DC: The American College of Obstetricians and Gynecologists; 2001. ACOG Practice Bulletin No. 24
• 64 Jaslow C R, Carney J L, Kutteh W H. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses.  Fertil Steril. 2010;  93 (4) 1234-1243
• 65 Allison J L, Schust D J. Recurrent first trimester pregnancy loss: revised definitions and novel causes.  Curr Opin Endocrinol Diabetes Obes. 2009;  16 (6) 446-450
• 66 Vinatier D, Dufour P, Cosson M, Houpeau J L. Antiphospholipid syndrome and recurrent miscarriages.  Eur J Obstet Gynecol Reprod Biol. 2001;  96 (1) 37-50
• 67 Chauleur C, Galanaud J P, Alonso S et al.. Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies.  J Thromb Haemost. 2010;  8 (4) 699-706
• 68 Vora S, Shetty S, Ghosh K. Thrombophilic dimension of recurrent fetal loss in Indian patients.  Blood Coagul Fibrinolysis. 2008;  19 (6) 581-584
• 69 Oron G, Ben-Haroush A, Goldfarb R, Molad Y, Hod M, Bar J. Contribution of the addition of anti-β2-glycoprotein to the classification of antiphospholipid syndrome in predicting adverse pregnancy outcome.  J Matern Fetal Neonatal Med. 2011;  24 (4) 606-609
• 70 Abrahams V M. Mechanisms of antiphospholipid antibody-associated pregnancy complications.  Thromb Res. 2009;  124 (5) 521-525
• 71 Ziakas P D, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis.  Obstet Gynecol. 2010;  115 (6) 1256-1262
• 72 Hoppe B, Burmester G R, Dörner T. Heparin or aspirin or both in the treatment of recurrent abortions in women with antiphospholipid antibody (syndrome).  Curr Opin Rheumatol. 2011;  23 (3) 299-304
• 73 Backos M, Rai R, Baxter N, Chilcott I T, Cohen H, Regan L. Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin.  Br J Obstet Gynaecol. 1999;  106 (2) 102-107
• 74 Branch D W, Khamashta M A. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies.  Obstet Gynecol. 2003;  101 (6) 1333-1344
• 75 Robertson L, Wu O, Langhorne P Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study et al. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 (2) 171-196
• 76 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.  Eur J Obstet Gynecol Reprod Biol. 2002;  101 (1) 6-14
• 77 Ruffatti A, Tonello M, Cavazzana A, Bagatella P, Pengo V. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy.  Thromb Res. 2009;  123 (3) 482-487
• 78 Werner E F, Lockwood C J. Thrombophilias and stillbirth.  Clin Obstet Gynecol. 2010;  53 (3) 617-627
• 79 Nodler J, Moolamalla S R, Ledger E M, Nuwayhid B S, Mulla Z D. Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset.  BMC Pregnancy Childbirth. 2009;  9 11-18
• 80 do Prado A, Piovesan D, Staub H, Horta B L. Association of anticardiolipin antibodies with pre-eclampsia: a systematic review and meta-analysis.  Obstet Gynecol. 2010;  116 1433-1443
• 81 Heilmann L, Schorsch M, Hahn T, Fareed J. Antiphospholipid syndrome and pre-eclampsia.  Semin Thromb Hemost. 2011;  37 (2) 141-145
• 82 Branch D W, Silver R M, Blackwell J L, Reading J C, Scott J R. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience.  Obstet Gynecol. 1992;  80 (4) 614-620
• 83 Cowchock F S, Reece E A, Balaban D, Branch D W, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment.  Am J Obstet Gynecol. 1992;  166 (5) 1318-1323
• 84 Laskin C A, Bombardier C, Hannah M E et al.. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.  N Engl J Med. 1997;  337 (3) 148-153
• 85 Kutteh W H, Ermel L D. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin.  Am J Reprod Immunol. 1996;  35 (4) 402-407
• 86 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 (1) 135-144
• 87 Lima F, Khamashta M A, Buchanan N M, Kerslake S, Hunt B J, Hughes G R. A study of sixty pregnancies in patients with the antiphospholipid syndrome.  Clin Exp Rheumatol. 1996;  14 (2) 131-136
• 88 Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy.  Obstet Gynecol. 1995;  86 (4 Pt 1) 555-559
• 89 Motta M, Lachassinne E, Boffa M C et al.. European registry of infants born to mothers with antiphospholipid syndrome: preliminary results.  Minerva Pediatr. 2010;  62 (3, Suppl 1) 25-27
• 90 Levine J S, Branch D W, Rauch J. The antiphospholipid syndrome.  N Engl J Med. 2002;  346 (10) 752-763
• 91 Tincani A, Balestrieri G, Danieli E et al.. Pregnancy complications of the antiphospholipid syndrome.  Autoimmunity. 2003;  36 (1) 27-32
• 92 Meroni P L, Riboldi P. Pathogenic mechanisms mediating antiphospholipid syndrome.  Curr Opin Rheumatol. 2001;  13 (5) 377-382
• 93 Branch D W, Dudley D J, Mitchell M D et al.. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss.  Am J Obstet Gynecol. 1990;  163 (1 Pt 1) 210-216
• 94 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies.  Proc Natl Acad Sci U S A. 2001;  88 3069-3073
• 95 Piona A, La Rosa L, Tincani A et al.. Placental thrombosis and fetal loss after passive transfer of mouse lupus monoclonal or human polyclonal anti-cardiolipin antibodies in pregnant naive BALB/c mice.  Scand J Immunol. 1995;  41 (5) 427-432
• 96 Ornoy A, Yacobi S, Matalon S T et al.. The effects of antiphospholipid antibodies obtained from women with SLE/APS and associated pregnancy loss on rat embryos and placental explants in culture.  Lupus. 2003;  12 (7) 573-578
• 97 Hanly J G, Gladman D D, Rose T H, Laskin C A, Urowitz M B. Lupus pregnancy. A prospective study of placental changes.  Arthritis Rheum. 1988;  31 (3) 358-366
• 98 Nayar R, Lage J M. Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature.  Hum Pathol. 1996;  27 (2) 201-206
• 99 Turiel M, Sarzi-Puttini P, Peretti R et al.. Thrombotic risk factors in primary antiphospholipid syndrome: a 5-year prospective study.  Stroke. 2005;  36 (7) 1490-1494
• 100 Gharavi A E, Pierangeli S S, Espinola R G, Liu X, Colden-Stanfield M, Harris E N. Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo.  Arthritis Rheum. 2002;  46 (2) 545-552
• 101 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature.  Blood. 2003;  101 (5) 1827-1832
• 102 Peaceman A M, Rehnberg K A. The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production.  Am J Obstet Gynecol. 1993;  169 (6) 1403-1406
• 103 Cariou R, Tobelem G, Soria C, Caen J. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant.  N Engl J Med. 1986;  314 (18) 1193-1194
• 104 Cosgriff T M, Martin B A. Low functional and high antigenic antithrombin III level in a patient with the lupus anticoagulant and recurrent thrombosis.  Arthritis Rheum. 1981;  24 (1) 94-96
• 105 Vogt E, Ng A K, Rote N S. A model for the antiphospholipid antibody syndrome: monoclonal antiphosphatidylserine antibody induces intrauterine growth restriction in mice.  Am J Obstet Gynecol. 1996;  174 (2) 700-707
• 106 Robertson S A, Roberts C T, van Beijering E et al.. Effect of beta2-glycoprotein I null mutation on reproductive outcome and antiphospholipid antibody-mediated pregnancy pathology in mice.  Mol Hum Reprod. 2004;  10 (6) 409-416
• 107 Yasuda S, Tsutsumi A, Chiba H et al.. beta(2)-glycoprotein I deficiency: prevalence, genetic background and effects on plasma lipoprotein metabolism and hemostasis.  Atherosclerosis. 2000;  152 (2) 337-346
• 108 Rand J H, Wu X X, Quinn A S, Taatjes D J. The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis.  Lupus. 2010;  19 (4) 460-469
• 109 Rand J H, Wu X X, Andree H A et al.. Pregnancy loss in the antiphospholipid-antibody syndrome—a possible thrombogenic mechanism.  N Engl J Med. 1997;  337 (3) 154-160
• 110 Out H J, Bruinse H W, Christiaens G C et al.. A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies.  Am J Obstet Gynecol. 1992;  167 (1) 26-32
• 111 Salafia C M, Cowchock F S. Placental pathology and antiphospholipid antibodies: a descriptive study.  Am J Perinatol. 1997;  14 (8) 435-441
• 112 Greaves M, Cohen H, MacHin S J, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome.  Br J Haematol. 2000;  109 (4) 704-715
• 113 Sebire N J, Fox H, Backos M, Rai R, Paterson C, Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure.  Hum Reprod. 2002;  17 (4) 1067-1071
• 114 Di Simone N, Caliandro D, Castellani R, Ferrazzani S, De Carolis S, Caruso A. Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome.  Hum Reprod. 1999;  14 (2) 489-495
• 115 Sthoeger Z M, Mozes E, Tartakovsky B. Anti-cardiolipin antibodies induce pregnancy failure by impairing embryonic implantation.  Proc Natl Acad Sci U S A. 1993;  90 (14) 6464-6467
• 116 Di Simone N, Castellani R, Caliandro D, Caruso A. Antiphospholid antibodies regulate the expression of trophoblast cell adhesion molecules.  Fertil Steril. 2002;  77 (4) 805-811
• 117 Tedesco F, Narchi G, Radillo O, Meri S, Ferrone S, Betterle C. Susceptibility of human trophoblast to killing by human complement and the role of the complement regulatory proteins.  J Immunol. 1993;  151 (3) 1562-1570
• 118 Holers V M, Girardi G, Mo L et al.. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss.  J Exp Med. 2002;  195 (2) 211-220
• 119 Girardi G, Berman J, Redecha P et al.. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.  J Clin Invest. 2003;  112 (11) 1644-1654
• 120 Salmon J E, Girardi G. The role of complement in the antiphospholipid syndrome.  Curr Dir Autoimmun. 2004;  7 133-148
• 121 Berman J, Girardi G, Salmon J E. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss.  J Immunol. 2005;  174 (1) 485-490
• 122 Blank M, Krause I, Wildbaum G, Karin N, Shoenfeld Y. TNFalpha DNA vaccination prevents clinical manifestations of experimental antiphospholipid syndrome.  Lupus. 2003;  12 (7) 546-549
• 123 Boles J, Mackman N. Role of tissue factor in thrombosis in antiphospholipid antibody syndrome.  Lupus. 2010;  19 (4) 370-378
• 124 Alijotas-Reig J, Vilardell-Tarres M. Is obstetric antiphospholipid syndrome a primary nonthrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies?.  Obstet Gynecol Surv. 2010;  65 (1) 39-45
• 125 Stone S, Pijnenborg R, Vercruysse L et al.. The placental bed in pregnancies complicated by primary antiphospholipid syndrome.  Placenta. 2006;  27 (4–5) 457-467
• 126 Cavazzana I, Manuela N, Irene C et al.. Complement activation in anti-phospholipid syndrome: a clue for an inflammatory process?.  J Autoimmun. 2007;  28 (2–3) 160-164
• 127 Girardi G, Redecha P, Salmon J E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation.  Nat Med. 2004;  10 (11) 1222-1226
• 128 Di Simone N, Castellani R, Raschi E, Borghi M O, Meroni P L, Caruso A. Anti-β-2 glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis.  Ann N Y Acad Sci. 2006;  1069 364-376
• 129 Di Simone N, Di Nicuolo F, Sanguinetti M et al.. Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors.  Placenta. 2007;  28 (4) 298-304
• 130 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 (1) 14-20
• 131 Stephenson M D, Houlihan E, Tsang P, Ensworth S, Lim K, Ballem P J. Concomitant use of IVIG for treatment of the antiphospholipid antibody syndrome (APS) when ASA and heparin results in at least one adverse pregnancy outcome.  Lupus. 2002;  11 694
• 132 Nelson-Piercy C, Letsky E A, de Swiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk.  Am J Obstet Gynecol. 1997;  176 (5) 1062-1068
• 133 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 (5) 693-697
• 134 Farquharson R G, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.  Obstet Gynecol. 2002;  100 (3) 408-413
• 135 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 (8) 729-734
• 136 Noble L S, Kutteh W H, Lashey N, Franklin R D, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin.  Fertil Steril. 2005;  83 (3) 684-690
• 137 Erkan D, Merrill J T, Yazici Y, Sammaritano L, Buyon J P, Lockshin M D. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin.  Arthritis Rheum. 2001;  44 (6) 1466-1467
• 138 Sher G, Feinman M, Zouves C et al.. High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin.  Hum Reprod. 1994;  9 2278-2283
• 139 Balasch J, Creus M, Fábregues F et al.. Antiphospholipid antibodies and human reproductive failure.  Hum Reprod. 1996;  11 (10) 2310-2315
• 140 Geva E, Amit A, Lerner-Geva L, Lessing J B. Autoimmunity and reproduction.  Fertil Steril. 1997;  67 (4) 599-611
• 141 Hornstein M D. Antiphospholipid antibodies in patients undergoing IVF: the data do not support testing.  Fertil Steril. 2000;  74 (4) 635-636
• 142 Silver R M, Draper M L, Scott J R, Lyon J L, Reading J, Branch D W. Clinical consequences of antiphospholipid antibodies: an historic cohort study.  Obstet Gynecol. 1994;  83 (3) 372-377
• 143 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).  BMJ. 1997;  314 (7076) 253-257
• 144 Branch D W, Peaceman A M, Druzin M The Pregnancy Loss Study Group et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy.  Am J Obstet Gynecol. 2000;  182 (1 Pt 1) 122-127
• 145 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 (4) 1008-1012
• 146 Triolo G, Ferrante A, Ciccia F et al.. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies.  Arthritis Rheum. 2003;  48 (3) 728-731
• 147 Goel N, Tuli A, Choudhry R. The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies.  Med Sci Monit. 2006;  12 (3) CR132-CR136
• 148 Laskin C A, Spitzer K A, Clark C A et al.. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial.  J Rheumatol. 2009;  36 (2) 279-287