Antiphospholipid Antibodies and the Antiphospholipid Syndrome: Pathogenic Mechanisms

ABSTRACT

Antiphospholipid antibodies (Abs) are associated with thrombosis and are a risk factor for recurrent pregnancy loss and obstetric complications in patients with the antiphospholipid syndrome. It is generally accepted that the major autoantigen for aPL Abs is β₂ glycoprotein I, which mediates the binding of aPL Abs to target cells (i.e., endothelial cells, monocytes, platelets, trophoblasts, etc.) leading to thrombosis and fetal loss.

This article addresses molecular events triggered by aPL Abs on endothelial cells, platelets, and monocytes and complement activation, as well as a review of the current knowledge with regard to the putative receptor(s) recognized by aPL Abs on target cells as well as novel mechanisms that involve fibrinolytic processes. A section is devoted to the description of thrombotic and inflammatory processes that lead to obstetric complications mediated by aPL Abs.

Based on experimental evidence using in vitro and in vivo models, new targeted therapies for treatment and/or prevention of thrombosis and pregnancy loss in antiphospholipid syndrome are proposed.

KEYWORDS

Antiphospholipid antibodies - thrombosis - endothelial cell activation - platelet activation - anti–β₂ glycoprotein I antibodies - lupus anticoagulant - pregnancy loss - trophoblast - decidual cells

REFERENCES

• 1 Harris E N. Syndrome of the black swan.  Br J Rheumatol. 1987;  26 324-326
• 2 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 1309-1311
• 3 Miyakis S, Lockshin M D, Atsumi I et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 295-306
• 4 Brandt J T, Barna L K, Triplett D A. Laboratory identification of lupus anticoagulants: results of the second international workshop for identification of lupus anticoagulants – on behalf of the Second International Workshop for identification of lupus anticoagulants and antiphospholipid antibodies of the ISTH.  Thromb Haemost. 1995;  74 1597-1603
• 5 McNeil H P, Simpson R J, Cherterman C N, Krilis S A. Antiphospholipid antibodies are directed against a complex antigen that includes lipid binding inhibitor of coagulation: β₂ glycoprotein I (apolipoprotein H).  Proc Natl Acad Sci U S A. 1990;  87 4120-4124
• 6 Atsumi T, Koike T. Clinical relevance of antiprothrombin antibodies.  Autoimmun Rev. 2002;  1 49-53
• 7 Fleck R A, Rapaport S I, Rao L V. Antiprothrombin antibodies and the lupus anticoagulant.  Blood. 1988;  72 512-519
• 8 Oosting J D, Derksen R HWM, Bobbink I WG, Hacking T M, Bouma B N, deGroot P G. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C or protein S: an explanation for their pathogenic mechanism?.  Blood. 1993;  83 2618-2625
• 9 Permpikul P, Rao L VM, Rapaport S I. Functional and binding studies of the roles of prothrombin and β₂glycoprotein I in the expression of lupus anticoagulant activity.  Blood. 1994;  83 2878-2892
• 10 Marciniak E, Romond E H. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant.  Blood. 1989;  74 2426-2432
• 11 Lin W S, Chen P C, Yang C D et al.. Some antiphospholipid antibodies recognize conformational epitopes shared by β₂glycoprotein I and the homologous catalytic domains of several serine proteases.  Arthritis Rheum. 2007;  56 1638-1647
• 12 Chen X X, Gu Y Y, Li S J et al.. Some plasmin-induced antibodies bind to cardiolipin, display lupus anticoagulant activity and induce fetal loss in mice.  J Immunol. 2007;  178 5351-5356
• 13 Cesarman-Maus G, Rios-Luna N P, Deora A B et al.. Autoantibodies against the fibrinolytic receptor, annexin A2, in antiphospholipid syndrome.  Blood. 2006;  107 4375-4382
• 14 Ginsburg K S, Liang M H, Newcomer L et al.. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis.  Ann Intern Med. 1992;  117 997-1002
• 15 Tincani A, Balestrieri G, Danieli E et al.. Pregnancy complications of the antiphospholipid syndrome.  Autoimmunity. 2003;  36 27-32
• 16 Levine J S, Branch D W, Rauch J. The antiphospholipid syndrome.  N Engl J Med. 2002;  346 752-763
• 17 Sailer T, Zoghlami C, Kurz C et al.. Anti-β₂glycoprotein I antibodies are associated with pregnancy loss in women with the lupus anticoagulant.  Thromb Haemost. 2006;  95 796-801
• 18 McClain M T, Arbuckle M R, Heinlen L D et al.. The prevalence, onset and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus.  Arthritis Rheum. 2004;  50 1226-1232
• 19 Asherson R A. Multiorgan failure and antiphospholipid antibodies: the catastrophic antiphospholipid (Asherson's) syndrome.  Immunobiology. 2005;  210 727-733
• 20 Gharavi A E, Pierangeli S S, Harris E N. Origin of antiphospholipid antibodies.  Rheum Dis Clin North Am. 2001;  27 551-563
• 21 Crowther M A, Ginsberg J S, Julian J et al.. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.  N Engl J Med. 2003;  349 1133-1138
• 22 Finazzi G, Marchioli R, Brancaccio V et al.. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).  J Thromb Haemost. 2005;  3 848-853
• 23 Erkan D, Yazici Y, Peterson M G, Sammaritano L, Lockshin M D. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome.  Rheumatology (Oxford). 2002;  41 924-929
• 24 Garcia D A, Khamashta M A, Crowther M A. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review.  Blood. 2007;  110 3122-3127
• 25 Erkan D, Harrison M J, Levy R et al.. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome.  Arthritis Rheum. 2007;  56 2382-2391
• 26 Pierangeli S S, Colden-Stanfield M, Liu X et al.. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. .  Circulation. 1999;  99 1997-2000
• 27 Jankowski M, Vreys I, Wittevrongel C et al.. Thrombogenicity of β₂ glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster.  Blood. 2003;  101 157-162
• 28 Malia R G, Kitchen S, Greaves M, Preston F E. Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies.  Br J Haematol. 1990;  76 101-107
• 29 Ieko M, Ichikawa K, Triplett D A et al.. β₂-glycoprotein I is necessary to inhibit protein C activity by monoclonal anticardiolipin antibodies.  Arthritis Rheum. 1999;  42 167-174
• 30 Escolar G, Font J, Reverter J C et al.. Plasma from systemic lupus erythematosus patients with antiphospholipid antibodies promotes platelet aggregation.  Arterioscler Thromb. 1992;  12 196-200
• 31 Campbell A L, Pierangeli S S, Wellhausen S, Harris E N. Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation.  Thromb Haemost. 1995;  73 529-534
• 32 Khamashta M A, Harris E N, Gharavi A E et al.. Immune mediated mechanism for thrombosis:antiphospholipid antibody binding to platelet membranes.  Ann Rheum Dis. 1988;  47 849-854
• 33 Kornberg A, Blank M, Kaufman S, Shoenfeld Y. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies.  J Immunol. 1994;  153 1328-1332
• 34 Simantov R, LaSala J M, Lo S K et al.. Activation of cultured vascular endothelial cells by antiphospholipid antibodies.  J Clin Invest. 1995;  96 2211-2219
• 35 Del Papa N, Guidali L, Sala A et al.. Endothelial cells as target for antiphospholipid antibodies—human polyclonal and monoclonal anti-β₂ glycoprotein I antibodies react in vitro with endothelial cells through adherent β₂ glycoprotein I and induce endothelial activation.  Arthritis Rheum. 1997;  40 551-561
• 36 Cuadrado M J, López-Pedrera C, Khamashta M A et al.. Thrombosis in primary antiphospholipid syndrome—a pivotal role for monocyte tissue factor expression.  Arthritis Rheum. 1997;  40 834-841
• 37 Amengual O, Atsumi T, Khamashta M A, Hughes G RV. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome.  Thromb Haemost. 1998;  79 276-281
• 38 Vega-Ostertag M, Casper K, Swerlick R, Ferrara D, Harris E N, Pierangeli S S. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies.  Arthritis Rheum. 2005;  52 1545-1554
• 39 Chamley L W, McKay E J, Pattison N S. Inhibition of heparin/antithrombin III cofactor activity by anticardiolipin antibodies: a mechanism for thrombosis.  Thromb Res. 1993;  71 103-111
• 40 Holers V M, Girardi G, Mo L et al.. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss.  J Exp Med. 2002;  195 211-220
• 41 Pierangeli S S, Girardi G, Vega-Ostertag M, Liu X, Espinola R G, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia.  Arthritis Rheum. 2005;  52 2120-2124
• 42 Espinola R G, Pierangeli S S, Gharavi A E, Harris E N. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies.  Thromb Haemost. 2002;  87 518-522
• 43 Edwards M H, Pierangeli S, Liu X, Barker J H, Anderson G, Harris E N. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice.  Circulation. 1997;  96 4380-4384
• 44 Martinuzzo M E, Maclouf J, Carreras L O, Levy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation.  Thromb Haemost. 1993;  70 667-671
• 45 Forastiero R, Martinuzzo M, Carreras L O, Maclouf J. Anti-β₂ glycoprotein I antibodies and platelet activation in patients with antiphospholipid antibodies: association with increased excretion of platelet-derived thromboxane urinary metabolites.  Thromb Haemost. 1998;  79 42-45
• 46 Robbins D L, Leung S, Miller-Blair D J, Ziboh V. Effect of anticardiolipin/β₂ glycoprotein I complexes on production of thromboxane A2 by platelets from patients with the antiphospholipid syndrome.  J Rheumatol. 1998;  25 51-56
• 47 Opara R, Robbins D L, Ziboh V A. Cyclic-AMP agonists inhibit antiphospholipid/β₂glycoprotein I induced synthesis of human platelet thromboxane A2 in vitro.  J Rheumatol. 2003;  30 55-59
• 48 Vega-Ostertag M, Harris E N, Pierangeli S S. Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin.  Arthritis Rheum. 2004;  50 2911-2919
• 49 van Lummel M, Pennings M T, Derksen R H et al.. The binding site in β₂glycoprotein I for apoER2' on platelets is located in domain V.  J Biol Chem. 2005;  280 36729-36736
• 50 Lutters B C, Derksen R H, Tekelenburg W L, Lenting P J, Arnout J, de Groot P G. Dimers of β₂glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2'.  J Biol Chem. 2003;  278 33831-33838
• 51 Shi T, Giannakopulos B, Yan X et al.. Anti-β₂ glycoprotein I antibodies in complex with β₂glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib/IX-V.  Arthritis Rheum. 2006;  54 2558-2567
• 52 Hulstein J J, Lenting P J, De Laat B et al.. β₂glycoprotein I inhibits von Willebrand factor-dependent platelet adhesion and aggregation.  Blood. 2007;  110 1483-1491
• 53 Pierangeli S S, Espinola R G, Liu X, Harris E N. Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin.  Circ Res. 2001;  88 245-250
• 54 Espinola R G, Liu X, Colden-Stanfield M, Hall J, Harris E N, Pierangeli S S. E-selectin mediated pathogenic effects of antiphospholipid antibodies.  J Thromb Haemost. 2003;  1 843-848
• 55 Forastiero R R, Martinuzzo M, De Larranaga G. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprous related antiphospholipid antibodies.  Lupus. 2005;  14 129-136
• 56 Williams F MK, Parmar K, Hughes G RV, Hunt B J. Systemic endothelial cell markers in primary antiphospholipid syndrome.  Thromb Haemost. 2000;  84 742-746
• 57 Dobado-Berrios M, Lopez-Pedrera C, Velasco F, Aguirre M A, Torres A, Cuadrado M J. Increased levels of TF mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome.  Thromb Haemost. 1999;  82 1578-1582
• 58 Martini F, Farsi A, Gori A M et al.. Antiphospholipid antibodies (aPL) increase the potential monocyte procoagulant activity in patients with systemic lupus erythematosus.  Lupus. 1996;  5 206-211
• 59 Reverter J C, Tassies D, Font J et al.. Effects of human monoclonal anticardiolipin antibodies on platelet function and on tissue factor expression on monocytes.  Arthritis Rheum. 1998;  41 1420-1427
• 60 Zhou H, Wolberg A S, Roubey R A. Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep.  Blood. 2004;  104 2353-2358
• 61 Ferrara D E, Liu X, Espinola R G et al.. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model.  Arthritis Rheum. 2003;  48 3272-3279
• 62 Ferrara D E, Swerlick R, Casper K et al.. Fluvastatin inhibits upregulation of tissue factor expression by antiphospholipid antibodies on endothelial cells.  J Thromb Haemost. 2004;  2 1558-1563
• 63 Cuadrado M J, Buendia P, Velasco F et al.. Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome.  J Thromb Haemost. 2006;  4 2461-2469
• 64 Dunoyer-Geindre S, deMoerloose P, Galve-de Rochemonteiz B, Reber G, Kruithof E KO. NF-κB is an essential intermediate in the activation of endothelial cells by anti- β₂glycoprotein I antibodies.  Thromb Haemost. 2002;  88 851-857
• 65 López-Pedrera C, Buendia P, Cuadrado M J et al.. Antiphopholipid antibodies from patients with the antiphospholipid syndrome induce tissue factor expression through the simultaneous activation of NF-KappaB/Rel proteins via p38 mitogen activated protein kinase pathway, and of the MEK-1/ERK pathway.  Arthritis Rheum. 2006;  54 301-311
• 66 Simoncini S, Sapet C, Camoin-Jau L et al.. Role of reactive oxygen species and p38 MAPK in the induction of the pro-adhesive endothelial state mediated by IgG from patients with anti-phospholipid syndrome.  Int Immunol. 2005;  17 489-500
• 67 Vega-Ostertag M E, Ferrara D E, Romay-Penabad Z et al.. Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation.  J Thromb Haemost. 2007;  5 1828-1834
• 68 Montiel-Manzano G, Romay-Penabad E, Papalardo de Martinez E et al.. In vivo effects of an inhibitor of nuclear factor-kappa (κ) B on thrombogenic properties of antiphospholipid antibodies.  Ann N Y Acad Sci. 2007;  1108 540-553
• 69 Del Papa N, Sheng Y H, Raschi E et al.. Human β₂glycoprotein I binds to endothelial cells through a cluster of lysine residues that are critical for anionic phospholipids binding and offers epitopes for anti-β₂glycoprotein I antibodies.  J Immunol. 1998;  160 5572-5578
• 70 Ostertag M V, Liu X, Henderson V, Pierangeli S S. A peptide that mimics the V^th region of β₂glycoprotein I reverses antiphospholipid-mediated thrombosis in mice.  Lupus. 2006;  15 358-365
• 71 Ioannou J, Harper T, Romay-Penabad Z et al.. Domain I of β₂glycoprotein I ameliorates thrombosis induced by antiphospholipid antibodies in mice [abstract].  Arthritis Rheum. 2006;  54(Suppl) S559
• 72 Ma K, Simantov R, Zhang J, Silverstein R, Hajjar K, McCrae K. High affinity binding of β₂glycoprotein I to human endothelial cells is mediated by annexin II.  J Biol Chem. 2000;  275 15541-15548
• 73 Zhang J, McCrae K R. Annexin A2 mediates endothelial cell activation by antiphospholipid/β₂glycoprotein I antibodies.  Blood. 2005;  105 1964-1969
• 74 Raschi E, Testoni C, Bosisio D et al.. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies.  Blood. 2003;  101 3495-3500
• 75 Pierangeli S S, Vega-Ostertag M E, Raschi E et al.. Toll like receptor 4 is involved in antiphospholipid-mediated thrombosis: in vivo studies.  Ann Rheum Dis. 2007;  66 1327-1333
• 76 Sorice M, Longo A, Capozzi A et al.. Anti-β₂glycoprotein I antibodies induce monocyte release of tumor necrosis factor alpha and tissue factor by signal transduction pathways involving lipid rafts.  Arthritis Rheum. 2007;  56 2687-2697
• 77 Romay-Penabad Z, Liu X, Montiel-Manzano G et al.. C5a receptor-deficient mice are protected from thrombophilia and endothelial cell activation induced by some antiphospholipid antibodies.  Ann N Y Acad Sci. 2007;  1108 554-566
• 78 Fischetti F, Durigutto P, Pellis V et al.. Thrombus formation induced by antibodies to β₂glycoprotein I is complement-dependent and requires a priming factor.  Blood. 2005;  106 2340-2346
• 79 Munakata Y, Saito T, Matsuda K, Seino J, Shibata S, Sasaki T. Detection of complement-fixing antiphospholipid antibodies in association with thrombosis.  Thromb Haemost. 2000;  83 728-731
• 80 Carbone J, Orera M, Rodriguez-Mahou M et al.. Immunological abnormalities in primary APS evolving into SLE: 6 years follow-up in women with repeated pregnancy loss.  Lupus. 1999;  8 274-278
• 81 Davis W D, Brey R L. Antiphospholipid antibodies and complement activation in patients with cerebral ischemia.  Clin Exp Rheumatol. 1992;  10 455-460
• 82 Zhao Y, Rumold R, Ahmed A E et al.. An IgG anti-prothrombin antibody enhances prothrombin binding to damaged endothelial cells and shortens plasma coagulation times.  Arthritis Rheum. 1999;  42 2132-2138
• 83 Vega-Ostertag M, Liu X, Kwna-ki H, Chen P, Pierangeli S. A human monoclonal antiprothrombin antibody is thrombogenic in vivo and upregulates expression of tissue factor and E-selectin on endothelial cells.  Br J Haematol. 2006;  135 214-219
• 84 Hwang K K, Grossman J, Visvanathan S et al.. Identification of anti-thrombin antibodies in the antiphospholipid syndrome that interfere with the inactivation of thrombin by antithrombin.  J Immunol. 2001;  167 7192-7198
• 85 Hwang K K, Yang C D, Yan W et al.. A thrombin cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C.  Arthritis Rheum. 2003;  48 1622-1630
• 86 Yang C D, Hwang K K, Yan W et al.. Identification of anti-plasmin antibodies in the antiphospholipid syndrome that inhibit degradation of fibrin.  J Immunol. 2004;  172 5765-5773
• 87 Kolev K, Gombás J, Váradi B et al.. Immunoglobulin G from patients with antiphospholipid syndrome impairs the fibrin dissolution with plasmin.  Thromb Haemost. 2002;  87 502-508
• 88 Lu C S, Horizon A A, Hwang K K et al.. Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome.  Arthritis Rheum. 2005;  52 4018-4027
• 89 Cugno M, Caribbe M, Galli M et al.. Antibodies to tissue plasmanogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in patients.  Blood. 2004;  103 2121-2126
• 90 Yang Y H, Hwang K K, Fitzgerald J et al.. Antibodies against the activated coagulation factor X (FXa) in the antiphospholipid syndrome that interfere with the FXa inactivation by antithrombin.  J Immunol. 2006;  177 8219-8225
• 91 Lin W S, Chen P C, Yang C D et al.. Some antiphospholipid antibodies recognize conformational epitopes shared by β₂glycoprotein I and the homologous catalytic domains of several serine proteases.  Arthritis Rheum. 2007;  56 1638-1647
• 92 Van Horn J T, Craven C, Ward K, Branch D W, Silver R M. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes.  Placenta. 2004;  25 642-648
• 93 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;  27 201-206
• 94 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 1403-1406
• 95 Rand J H. Molecular pathogenesis of the antiphospholipid syndrome.  Circ Res. 2002;  90 29-37
• 96 de Laat B, Wu X X, van Lummel M, Derksen R H, de Groot P G, Rand J H. Correlation between antiphospholipid antibodies that recognize domain I of β₂-glycoprotein I and a reduction in the anticoagulant activity of annexin A5.  Blood. 2007;  109 1490-1494
• 97 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
• 98 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;  41 179-186
• 99 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 1067-1071
• 100 Lyden T W, Vogt E, Ng A K, Johnson P M, Rote N S. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast.  J Reprod Immunol. 1992;  22 1-14
• 101 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 6464-6467
• 102 Di Simone N, Meroni P L, Del Papa N et al.. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β₂glycoprotein I.  Arthritis Rheum. 2000;  43 140-150
• 103 Ornoy A, Yacobi S, Matalon S 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;  12 573-578
• 104 Chamley L W, Duncalf A M, Mitchell M D, Johnson P M. Action of anticardiolipin and antibodies to β₂-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death.  Lancet. 1998;  352 1037-1038
• 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;  174 700-707
• 106 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 50-58
• 107 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies.  Proc Natl Acad Sci U S A. 1991;  88 3069-3073
• 108 Ikematsu W, Luan F L, La Rosa L et al.. Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice.  Arthritis Rheum. 1998;  41 1026-1039
• 109 Aplin J D, Haigh T, Lacey H, Chen C P, Jones C J. Tissue interactions in the control of trophoblast invasion.  J Reprod Fertil Suppl. 2000;  55 57-64
• 110 Castellucci M, De Matteis R, Meisser A et al.. Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion.  Mol Hum Reprod. 2000;  6 951-958
• 111 Di Simone N, Castellani R, Calandro D, Caruso A. Antiphospholid antibodies regulate the expression of trophoblast cell adhesion molecules.  Fertil Steril. 2002;  77 805-811
• 112 Francis J, Rai R, Sebire N J et al.. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome.  Mol Hum Reprod. 2006;  12 435-442
• 113 Borghi M O, Raschi E, Scurati S et al.. Effects of a Toll-like receptorantagonist and anti-annexin A2 antibodies on binding and activation of decidual cells by anti-β₂glycoprotein I antibodies [abstract].  Clin Exp Rheumatol. 2007;  2 35
• 114 Bose P, Black S, Kadyrov M et al.. Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro.  Am J Obstet Gynecol. 2004;  191 2125-2131
• 115 Matalon S T, Shoenfeld Y, Blank M, Yacobi S, von Landenberg P, Ornoy A. Antiphosphatidylserine antibodies affect rat yolk sacs in culture: a mechanism for fetal loss in antiphospholipid syndrome.  Am J Reprod Immunol. 2004;  51 144-151
• 116 Di Simone N, Castellani R, Raschi E, Borghi M O, Meroni P L, Caruso A. Anti-β₂glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis.  Ann N Y Acad Sci. 2006;  1069 364-376
• 117 Chaouat G. The Th1/Th2 paradigm: still important in pregnancy?.  Semin Immunopathol. 2007;  29 95-113
• 118 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 1644-1654
• 119 Berman J, Girardi G, Salmon J E. TNF-α is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss.  J Immunol. 2005;  174 485-490
• 120 Girardi G, Redecha P, Salmon J. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation.  Nat Med. 2004;  10 1222-1226
• 121 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;  41 427-432
• 122 Martinez de la Torre Y, Buracchi C, Borroni E M et al.. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6.  Proc Natl Acad Sci U S A. 2007;  104 2319-2324
• 123 Redecha P, Tilley R, Tentati M et al.. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury.  Blood. 2007;  110 2423-2431
• 124 Shamonki J M, Salmon J E, Hyjek E, Baergen R N. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies.  Am J Obstet Gynecol. 2007;  196 167el-5
• 125 Cavazzana I, Nebuloni M, Cetin I et al.. Complement activation in anti-phospholipid syndrome: a clue for an inflammatory process?.  J Autoimmun. 2007;  28 160-164
• 126 McIntyre J A. Immune recognition at the maternal-fetal interface: overview.  Am J Reprod Immunol. 1992;  28 127-131
• 127 La Rosa L, Meroni P L, Tincani A et al.. β₂glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome.  J Rheumatol. 1994;  21 1684-1693
• 128 Hunt J, Krilis S A. The fifth domain of β₂glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies.  J Immunol. 1994;  152 653-659
• 129 Sheng Y, Sali A, Herzog H, Lhanstein J, Krilis S A. Site-directed mutagenesis of recombinant human β₂glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity.  J Immunol. 1996;  157 3744-3751
• 130 Di Simone N, Raschi E, Testoni C et al.. Pathogenic role of anti-β₂glycoprotein I antibodies in antiphospholipid associated fetal loss: characterization of β₂glycoprotein I binding to trophoblast cells and functional effects of anti-β₂glycoprotein I antibodies in vitro. .  Ann Rheum Dis. 2005;  64 462-467
• 131 Meroni P, Raschi E, Ronda N, Borghi M O. Humoral autoimmunity against endothelium: theory or reality?.  Trends Immunol. 2005;  26 275-281
• 132 Guerin J, Sheng Y, Reddel S, Iverson G M, Chapman M G, Krilis S A. Heparin inhibits the binding of β₂glycoprotein I to phospholipids and promotes the plasmin-mediated inactivation of this blood protein. Elucidation of the consequences of the two biological events in patients with the anti-phospholipid syndrome.  J Biol Chem. 2002;  277 2644-2649