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DOI: 10.1055/s-0032-1311827
Pathogenesis of the Antiphospholipid Syndrome
Publication History
Publication Date:
17 April 2012 (online)
Abstract
The presence of pathogenic antiphospholipid antibodies (aPL) is the characterizing feature of the antiphospholipid syndrome (APS), mediating the recurrent pregnancy loss and thrombosis typical of the disease, through their action on various antigenic targets. Despite the available knowledge regarding the mechanisms by which aPL induce a procoagulant phenotype in the vasculature and abnormal cellular proliferation and differentiation in placental tissues to cause the typical clinical features, these processes still remain incompletely understood. It is also known that inflammation serves as a necessary link between the observed procoagulant phenotype and actual thrombus development, and is an important mediator of the placental injury in APS patients. Even less well understood are the processes underlying the ontogeny of these pathogenic antibodies. This review seeks to highlight what is known about the mechanisms that contribute to the origin of pathogenic aPL and to the action of these antibodies on target antigens that produce the pathological features of APS. We will also examine the feasibility of classifying patients in clinical phenotypes related to underlying pathophysiological mechanisms, and how this could impact the management of patients with novel “targeted” therapeutic strategies.
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References
- 1 Harris EN. Syndrome of the black swan. Br J Rheumatol 1987; 26 (5) 324-326
- 2 Wilson WA, Gharavi AE, 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
- 3 Miyakis S, Lockshin MD, 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
- 4 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87 (11) 4120-4124
- 5 Galli M, Comfurius P, Maassen C , et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335 (8705) 1544-1547
- 6 Amengual O, Atsumi T, Koike T. Antiprothombin antibodies and the diagnosis of antiphospholipid syndrome. Clin Immunol 2004; 112 (2) 144-149
- 7 Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83 (10) 2878-2892
- 8 Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GRV. Thrombosis in SLE: striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) 1983; 287: 1021-1023
- 9 Ginsburg KS, Liang MH, Newcomer L , et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117 (12) 997-1002
- 10 McClain MT, Arbuckle MR, Heinlen LD , et al. The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum 2004; 50 (4) 1226-1232
- 11 Tincani A, Balestrieri G, Danieli E , et al. Pregnancy complications of the antiphospholipid syndrome. Autoimmunity 2003; 36 (1) 27-32
- 12 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346 (10) 752-763
- 13 Sailer T, Zaglami C, Kurz C , et al. Anti-beta(2)-glycoprotein-I antibodies are associated with pregnancy loss in women with the lupus anticoagulant. Thromb Haemost 2006; 95: 796-801
- 14 Petri M. Update on anti-phospholipid antibodies in SLE: the Hopkins' Lupus Cohort. Lupus 2010; 19 (4) 419-423
- 15 Chen PP, Giles I. Antibodies to serine proteases in the antiphospholipid syndrome. Curr Rheumatol Rep 2010; 12 (1) 45-52
- 16 Meroni PL, Raschi E, Camera M , et al. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J Autoimmun 2000; 15 (2) 237-240
- 17 Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus 2008; 17 (10) 888-894
- 18 Nojima J, Suehisa E, Kuratsune H , et al. Platelet activation induced by combined effects of anticardiolipin and lupus anticoagulant IgG antibodies in patients with systemic lupus erythematosus—possible association with thrombotic and thrombocytopenic complications. Thromb Haemost 1999; 81 (3) 436-441
- 19 Krone KA, Allen KL, McCrae KR. Impaired fibrinolysis in the antiphospholipid syndrome. Curr Rheumatol Rep 2010; 12 (1) 53-57
- 20 Ames PR, Antinolfi I, Ciampa A , et al. Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease?. Rheumatology (Oxford) 2008; 47 (12) 1832-1837
- 21 Abrahams VM. Mechanisms of antiphospholipid antibody-associated pregnancy complications. Thromb Res 2009; 124 (5) 521-525
- 22 Erkan D, Lockshin MD. Non-criteria manifestations of antiphospholipid syndrome. Lupus 2010; 19 (4) 424-427
- 23 D'Ippolito S, Di Simone N, Di Nicuolo F, Castellani R, Caruso A. Antiphospholipid antibodies: effects on trophoblast and endothelial cells. Am J Reprod Immunol 2007; 58 (2) 150-158
- 24 Di Simone N, Luigi MP, Marco D , et al. Pregnancies complicated with antiphospholipid syndrome: the pathogenic mechanism of antiphospholipid antibodies: a review of the literature. Ann N Y Acad Sci 2007; 1108: 505-514
- 25 Katsiari CG, Giavri I, Mitsikostas DD, Yiannopoulou KG, Sfikakis PP. Acute transverse myelitis and antiphospholipid antibodies in lupus. No evidence for anticoagulation. Eur J Neurol 2011; 18 (4) 556-563
- 26 Gharavi AE, Pierangeli SS, Harris EN. Origin of antiphospholipid antibodies. Rheum Dis Clin North Am 2001; 27 (3) 551-563
- 27 Rauch J, Dieudé M, Subang R, Levine JS. The dual role of innate immunity in the antiphospholipid syndrome. Lupus 2010; 19 (4) 347-353
- 28 Lambrianides A, Carroll CJ, Pierangeli SS , et al. Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways. J Immunol 2010; 184 (12) 6622-6628
- 29 Jiang H, Chess L. How the immune system achieves self-nonself discrimination during adaptive immunity. Adv Immunol 2009; 102: 95-133
- 30 Hashimoto Y, Kawamura M, Ichikawa K , et al. Anticardiolipin antibodies in NZW x BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol 1992; 149 (3) 1063-1068
- 31 Hang LM, Izui S, Dixon FJ. (NZW x BXSB)F1 hybrid. A model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med 1981; 154 (1) 216-221
- 32 Oyaizu N, Yasumizu R, Miyama-Inaba M , et al. (NZW x BXSB)F1 mouse. A new animal model of idiopathic thrombocytopenic purpura. J Exp Med 1988; 167 (6) 2017-2022
- 33 Kita Y, Sumida T, Iwamoto I, Yoshida S, Koike T. V gene analysis of anti-cardiolipin antibodies from (NZW x BXSB) F1 mice. Immunology 1994; 82 (3) 494-501
- 34 Gharavi AE, Sammaritano LR, Wen J, Elkon KB. Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H). J Clin Invest 1992; 90 (3) 1105-1109
- 35 Gharavi AE, Pierangeli SS, Colden-Stanfield M, Liu XW, Espinola RG, Harris EN. GDKV-induced antiphospholipid antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. J Immunol 1999; 163 (5) 2922-2927
- 36 Gharavi AE, Pierangeli SS, Gharavi EE , et al. Thrombogenic properties of antiphospholipid antibodies do not depend on their binding to beta2 glycoprotein 1 (beta2GP1) alone. Lupus 1998; 7 (5) 341-346
- 37 Gharavi EE, Chaimovich H, Cucurull E , et al. Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides. Lupus 1999; 8 (6) 449-455
- 38 Gharavi AE, Pierangeli SS, Espinola RG, Liu X, Colden-Stanfield M, Harris EN. 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
- 39 Gharavi AE, Vega-Ostertag M, Espinola RG , et al. Intrauterine fetal death in mice caused by cytomegalovirus-derived peptide induced aPL antibodies. Lupus 2004; 13 (1) 17-23
- 40 Blank M, Krause I, Fridkin M , et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 2002; 109 (6) 797-804
- 41 Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31 (4) 256-263
- 42 Sène D, Piette JC, Cacoub P. [Antiphospholipid antibodies, antiphospholipid syndrome and viral infections]. Rev Med Interne 2009; 30 (2) 135-141
- 43 Van O S GM, Meijers JC, Agar C , et al. Induction of anti-β2 -glycoprotein I autoantibodies in mice by protein H of Streptococcus pyogenes. J Thromb Haemost 2011; 9 (12) 2447-2456
- 44 Passam FH, Giannakopoulos B, Mirarabshahi P, Krilis SA. Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I. J Thromb Haemost 2011; 9 (1) 275-282
- 45 Aguilar-Valenzuela R, Nickerson K, Romay-Penabad Z , et al. Involvement of TLR7 and TLR9 in the production of antiphospholipid antibodies. Arthritis Rheum 2011; 63 (10) s281 (abstract 723)
- 46 Papalardo E, Romay-Penabad Z, Christadoss P, Pierangeli S. Induction of pathogenic antiphospholipid antibodies in vivo are dependent on expression of MHC-II genes. Lupus 2010; 19: 496 (abstract)
- 47 Dagenais P, Urowitz MB, Gladman DD, Norman CS. A family study of the antiphospholipid syndrome associated with other autoimmune diseases. J Rheumatol 1992; 19 (9) 1393-1396
- 48 Asherson RA, Doherty DG, Vergani D, Khamashta MA, Hughes GR. Major histocompatibility complex associations with primary antiphospholipid syndrome. Arthritis Rheum 1992; 35 (1) 124-125
- 49 Caliz R, Atsumi T, Kondeatis E , et al. HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. Rheumatology (Oxford) 2001; 40 (1) 31-36
- 50 Galeazzi M, Sebastiani GD, Tincani A , et al. HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Lupus 2000; 9 (1) 47-55
- 51 Wilson WA, Perez MC, Michalski JP, Armatis PE. Cardiolipin antibodies and null alleles of C4 in black Americans with systemic lupus erythematosus. J Rheumatol 1988; 15 (12) 1768-1772
- 52 Hirose N, Williams R, Alberts AR , et al. A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome. Arthritis Rheum 1999; 42 (8) 1655-1661
- 53 Pierangeli SS, Barker JH, Stikovac D , et al. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice. Thromb Haemost 1994; 71 (5) 670-674
- 54 Stockmans F, Deckmyn H, Gruwez J, Vermylen J, Acland R. Continuous quantitative monitoring of mural, platelet-dependent, thrombus kinetics in the crushed rat femoral vein. Thromb Haemost 1991; 65 (4) 425-431
- 55 Barker JH, Gu JM, Anderson GL , et al. The effects of heparin and dietary fish oil on embolic events and the microcirculation downstream from a small-artery repair. Plast Reconstr Surg 1993; 91 (2) 335-343
- 56 Pierangeli SS, Liu XW, Barker JH, Anderson G, Harris EN. Induction of thrombosis in a mouse model by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemost 1995; 74 (5) 1361-1367
- 57 Olee T, Pierangeli SS, Handley HH , et al. Generation and characterization of monoclonal IgG anticardiolipin antibodies from a patient with the antiphospholipid syndrome. Proc Natl Acad Sci U S A 1996; 93: 8606-8611
- 58 Pierangeli SS, Liu SW, Anderson G, Barker JH, Harris EN. Thrombogenic properties of murine anti-cardiolipin antibodies induced by β 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies. Circulation 1996; 94 (7) 1746-1751
- 59 Jankowski M, Vreys I, Wittevrongel C , et al. Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood 2003; 101 (1) 157-162
- 60 Fischetti F, Durigutto P, Pellis V , et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood 2005; 106 (7) 2340-2346
- 61 Arad A, Proulle V, Furie RA, Furie BC, Furie B. β2-glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model. Blood 2011; 117 (12) 3453-3459
- 62 Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1999; 99 (15) 1997-2002
- 63 Pierangeli SS, Espinola RG, Liu X, Harris EN. 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 (2) 245-250
- 64 Pierangeli SS, Liu X, Espinola R , et al. Functional analyses of patient-derived IgG monoclonal anticardiolipin antibodies using in vivo thrombosis and in vivo microcirculation models. Thromb Haemost 2000; 84 (3) 388-395
- 65 Aron AL, Cuellar ML, Brey RL , et al. Early onset of autoimmunity in MRL/++ mice following immunization with beta 2 glycoprotein I. Clin Exp Immunol 1995; 101 (1) 78-81
- 66 Branch DW, Dudley DJ, Mitchell MD , 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
- 67 Bakimer R, Fishman P, Blank M, Sredni B, Djaldetti M, Shoenfeld Y. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89 (5) 1558-1563
- 68 Fishman P, Falach-Vaknine E, Zigelman R , et al. Prevention of fetal loss in experimental antiphospholipid syndrome by in vivo administration of recombinant interleukin-3. J Clin Invest 1993; 91 (4) 1834-1837
- 69 Holers VM, 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
- 70 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
- 71 Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10 (11) 1222-1226
- 72 Simantov R, Lo SK, Gharavi A, Sammaritano LR, Salmon JE, Silverstein RL. Antiphospholipid antibodies activate vascular endothelial cells. Lupus 1996; 5 (5) 440-441
- 73 Kornberg A, Blank M, Kaufman S, Shoenfeld Y. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J Immunol 1994; 153 (3) 1328-1332
- 74 Reverter JC, Tàssies 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 (8) 1420-1427
- 75 Forastiero R, Martinuzzo M, Carreras LO, Maclouf J. Anti-beta2 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 (1) 42-45
- 76 Lellouche F, Martinuzzo M, Said P, Maclouf J, Carreras LO. Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 1991; 78 (11) 2894-2899
- 77 Khamashta MA, Harris EN, Gharavi AE , et al. Immune mediated mechanism for thrombosis: antiphospholipid antibody binding to platelet membranes. Ann Rheum Dis 1988; 47 (10) 849-854
- 78 Lutters BC, Derksen RH, Tekelenburg WL, Lenting PJ, Arnout J, de Groot PG. Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′. J Biol Chem 2003; 278 (36) 33831-33838
- 79 Espinola RG, Pierangeli SS, Gharavi AE, Harris EN. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 2002; 87 (3) 518-522
- 80 Pierangeli SS, Vega-Ostertag M, Harris EN. Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: a pathway to targeted therapies. Thromb Res 2004; 114 (5–6) 467-476
- 81 Shi T, Giannakopoulos B, Yan X , et al. Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Arthritis Rheum 2006; 54 (8) 2558-2567
- 82 Urbanus RT, Pennings MT, Derksen RH, de Groot PG. Platelet activation by dimeric beta2-glycoprotein I requires signaling via both glycoprotein Ibalpha and apolipoprotein E receptor 2′. J Thromb Haemost 2008; 6 (8) 1405-1412
- 83 Sikara MP, Routsias JG, Samiotaki M, Panayotou G, Moutsopoulos HM, Vlachoyiannopoulos PG. beta2 Glycoprotein I (beta2GPI) binds platelet factor 4 (PF4): implications for the pathogenesis of antiphospholipid syndrome. Blood 2010; 115 (3) 713-723
- 84 Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79 (2) 276-281
- 85 Alijotas-Reig J, Palacio-Garcia C, Vilardell-Tarres M. Circulating microparticles, lupus anticoagulant and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 2009; 145 (1) 22-26
- 86 Cuadrado MJ, Buendía P, Velasco F , et al. Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome. J Thromb Haemost 2006; 4 (11) 2461-2469
- 87 Lopez-Pedrera C, Perez-Sandrez C, Ruiz-Limon P , et al. Mitochondrial dysfunction in monocytes from antiphospholipid sundrome patients: implications in the pathogenesis of the disease and effects of coenzyme treatment. Arthritis Rheum 2011; 63 (10) s282 (abstract 725)
- 88 Vega-Ostertag ME, Ferrara DE, 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 (9) 1828-1834
- 89 López-Pedrera C, Buendía P, Cuadrado MJ , et al. Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis Rheum 2006; 54 (1) 301-311
- 90 Romay-Penabad Z, Carrera-Marin AL, Mackman N, Pierangeli S. Pathogenic effects of antiphospholipid antibodies are ameliorated in tissue factor deficient mice. Arthritis Rheum 2011; 63 (10) s5 (abstract 13)
- 91 Romay-Penabad Z, Montiel-Manzano MG, Shilagard T , et al. Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo. Blood 2009; 114 (14) 3074-3083
- 92 Zhang J, McCrae KR. Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies. Blood 2005; 105 (5) 1964-1969
- 93 Raschi E, Testoni C, Bosisio D , et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 2003; 101 (9) 3495-3500
- 94 Pierangeli SS, Vega-Ostertag ME, Raschi E , et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis 2007; 66 (10) 1327-1333
- 95 Sorice M, Longo A, Capozzi A , et al. Anti-beta2-glycoprotein I antibodies induce monocyte release of tumor necrosis factor alpha and tissue factor by signal transduction pathways involving lipid rafts. Arthritis Rheum 2007; 56 (8) 2687-2697
- 96 Allen KL, Fonseca FV, Betapudi V, Willard B, Zhang J, McCrae KR. A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies. Blood 2012; 119: 884-893
- 97 Döring Y, Hurst J, Lorenz M , et al. Human antiphospholipid antibodies induce TNFalpha in monocytes via toll-like receptor 8. Immunobiology 2010; 215 (3) 230-241
- 98 Hurst J, Prinz N, Lorenz M , et al. TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1beta and caspase-1 in monocytes and dendritic cells. Immunobiology 2009; 214 (8) 683-691
- 99 Prinz N, Clemens N, Strand D , et al. Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 2011; 118 (8) 2322-2332
- 100 Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006; 7 (1) 49-56
- 101 Raschi E, Broggini V, Grossi C, Borghi MO, Pierangeli SS, Meroni PL. Mechanisms of action of antiphospholipid antibodies. In: Cervera R, Asherson R, Khamashta M, Reverter JC, eds. Handbook of Systemic Autoimmune Diseases. Antiphospholipid Syndrome in Systemic Autoimmune Disease. Oxford, UK: Elsevier; 2009. 10. 55-67
- 102 Romay-Penabad Z, Aguilar-Valenzuela R, Urbanus RT , et al. Apolipoprotein E receptor 2 is involved in the thrombotic complications in a murine model of the antiphospholipid syndrome. Blood 2011; 117 (4) 1408-1414
- 103 Zhao Y, Rumold R, Zhu M , et al. An IgG antiprothrombin antibody enhances prothrombin binding to damaged endothelial cells and shortens plasma coagulation times. Arthritis Rheum 1999; 42 (10) 2132-2138
- 104 Vega-Ostertag M, Liu X, Kwan-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 (2) 214-219
- 105 Atsumi T, Ieko M, Bertolaccini ML , et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43 (9) 1982-1993
- 106 Hwang KK, Grossman JM, 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 (12) 7192-7198
- 107 Escolar G, Font J, Reverter JC , et al. Plasma from systemic lupus erythematosus patients with antiphospholipid antibodies promotes platelet aggregation. Studies in a perfusion system. Arterioscler Thromb 1992; 12 (2) 196-200
- 108 Yang YH, Chien D, Wu M , et al. Novel autoantibodies against the activated coagulation factor IX (FIXa) in the antiphospholipid syndrome that interpose the FIXa regulation by antithrombin. J Immunol 2009; 182 (3) 1674-1680
- 109 Yang YH, Hwang KK, 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 (11) 8219-8225
- 110 Griffin JH, Fernández JA, Gale AJ, Mosnier LO. Activated protein C. J Thromb Haemost 2007; 5 (1) 73-80
- 111 Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989; 74 (7) 2426-2432
- 112 Hwang KK, Yang CD, Yan W, Grossman JM, Hahn BH, Chen PP. A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C. Arthritis Rheum 2003; 48 (6) 1622-1630
- 113 Chamley LW, McKay EJ, Pattison NS. Inhibition of heparin/antithrombin III cofactor activity by anticardiolipin antibodies: a mechanism for thrombosis. Thromb Res 1993; 71 (2) 103-111
- 114 Yang CD, Hwang KK, Yan W , et al. Identification of anti-plasmin antibodies in the antiphospholipid syndrome that inhibit degradation of fibrin. J Immunol 2004; 172 (9) 5765-5773
- 115 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 (3) 502-508
- 116 Lu CS, Horizon AA, Hwang KK , et al. Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome. Arthritis Rheum 2005; 52 (12) 4018-4027
- 117 Cugno M, Cabibbe M, Galli M , et al. Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients. Blood 2004; 103 (6) 2121-2126
- 118 Ames PR, Tommasino C, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies—a crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76 (2) 190-194
- 119 Cesarman GM, Guevara CA, Hajjar KA. An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation. J Biol Chem 1994; 269 (33) 21198-21203
- 120 Ao W, Zheng H, Chen XW, Shen Y, Yang CD. Anti-annexin II antibody is associated with thrombosis and/or pregnancy morbidity in antiphospholipid syndrome and systemic lupus erythematosus with thrombosis. Rheumatol Int 2011; 31 (7) 865-869
- 121 Cesarman-Maus G, Ríos-Luna NP, Deora AB , et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood 2006; 107 (11) 4375-4382
- 122 Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 2005; 52 (7) 2120-2124
- 123 Romay-Penabad Z, Liu XX, Montiel-Manzano G, Papalardo De Martínez E, Pierangeli SS. 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
- 124 Carrera-Marin AL, Romay-Penabad Z, Qu HC , et al. A C5a Receptor Antagonist Ameliorates In Vivo Effects of Antiphospholipid Antibodies. Arthritis Rheum 2009; 60: s767 (abstract)
- 125 Carrera-Marin AL, Aguilar-Valenzuela R, Romay-Penabad Z , et al. Involvement of C6 and the MAC on in vivo antiphospholipid-mediated pathogenic effects. Lupus 2010; 19: 507 (abstract)
- 126 Carrera-Marin AL, Romay-Penabad Z, Machin S, Cohen H, Pierangeli S. C5 inhibitor rEV576 ameliorates in vivo effects of antiphospholipid antibodies. Arthritis Rheum 2011; 63 (10) s5 (abstract 12)
- 127 Oku K, Atsumi T, Bohgaki M , et al. Complement activation in patients with primary antiphospholipid syndrome. Ann Rheum Dis 2009; 68 (6) 1030-1035
- 128 De Wolf F, Carreras LO, 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
- 129 Peaceman AM, Rehnberg KA. 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
- 130 Hanly JG, Gladman DD, Rose TH, Laskin CA, Urowitz MB. Lupus pregnancy. A prospective study of placental changes. Arthritis Rheum 1988; 31 (3) 358-366
- 131 Nayar R, Lage JM. 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
- 132 Krikun G, Lockwood CJ, Wu XX , et al. The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta 1994; 15 (6) 601-612
- 133 Rand JH, Wu XX, 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 (6) 1566-1572
- 134 Rand JH, Wu XX, Guller S, Scher J, Andree HA, Lockwood CJ. Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am J Obstet Gynecol 1997; 177 (4) 918-923
- 135 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 (4) 1008-1016
- 136 Nojima J, Kuratsune H, Suehisa E , et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem 2001; 47 (6) 1008-1015
- 137 Donohoe S, Kingdom JC, Mackie IJ , et al. Ontogeny of beta 2 glycoprotein I and annexin V in villous placenta of normal and antiphospholipid syndrome pregnancies. Thromb Haemost 2000; 84 (1) 32-38
- 138 Out HJ, Kooijman CD, Bruinse HW, Derksen RH. 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
- 139 McIntyre JA. Immune recognition at the maternal-fetal interface: overview. Am J Reprod Immunol 1992; 28 (3–4) 127-131
- 140 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 (10) 951-958
- 141 Di Simone N, Meroni PL, 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
- 142 Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote NS. Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod 1997; 56 (1) 50-58
- 143 Adler RR, Ng AK, Rote NS. Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR. Biol Reprod 1995; 53 (4) 905-910
- 144 Chamley LW, Duncalf AM, Mitchell MD, Johnson PM. Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet 1998; 352 (9133) 1037-1038
- 145 Rote NS, Vogt E, DeVere G, Obringer AR, Ng AK. The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am J Reprod Immunol 1998; 39 (2) 125-136
- 146 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
- 147 Di Simone N, Marana R, Castellani R , et al. Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum 2010; 62 (5) 1504-1512
- 148 Ornoy A, Yacobi S, Matalon ST , 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
- 149 Matalon ST, 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 (2) 144-151
- 150 di Simone N, Castellani R, Raschi E, Borghi MO, Meroni PL, Caruso A. Anti-beta-2 glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis. Ann N Y Acad Sci 2006; 1069: 364-376
- 151 Borghi MO, Raschi E, Scurati S , et al. Effects of a toll-like receptor antagonist and anti-annexin A2 antibodies on binding and activation of decidual cells by anti-β2glycoprotein I antibodies. Clin Exp Rheumatol 2007; 2: 35
- 152 Francis J, Rai R, Sebire NJ , 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 (7) 435-442
- 153 Di Simone N, Di Nicuolo F, D'Ippolito S , et al. Antiphospholipid antibodies affect human endometrial angiogenesis. Biol Reprod 2010; 83 (2) 212-219
- 154 Riley JK, Nelson DM. Toll-like receptors in pregnancy disorders and placental dysfunction. Clin Rev Allergy Immunol 2010; 39: 185-193
- 155 Bogic LV, Ohira RH, Yamamoto SY, Okazaki KJ, Millar K, Bryant-Greenwood GD. Tissue plasminogen activator and its receptor in the human amnion, chorion, and decidua at preterm and term. Biol Reprod 1999; 60 (4) 1006-1012
- 156 Mulla MJ, Brosens JJ, Chamley LW , et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol 2009; 62 (2) 96-111
- 157 Mulla MJ, Myrtolli K, Brosens JJ , et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol 2010; 63 (5) 339-348
- 158 Chaouat G. The Th1/Th2 paradigm: still important in pregnancy?. Semin Immunopathol 2007; 29 (2) 95-113
- 159 Martinez de la Torre Y, Buracchi C, Borroni EM , 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 (7) 2319-2324
- 160 Quigg RJ, Kozono Y, Berthiaume D , et al. Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor. J Immunol 1998; 160 (9) 4553-4560
- 161 Redecha P, Tilley R, Tencati M , et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 2007; 110 (7) 2423-2431
- 162 Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 2006; 203 (9) 2165-2175
- 163 Shamonki JM, Salmon JE, Hyjek E, Baergen RN. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am J Obstet Gynecol 2007; 196 (2) 167.e1-167.e5
- 164 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
- 165 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
- 166 Buyon JP, Garabet L, Kim M , et al. Favorable prognosis in a large, prospective multicenter study of lupus pregnancies. Arthritis Rheum 2011; 63 (10) s669 (abstract 1707)
- 167 Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I , et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011; 20 (2) 206-218
- 168 Edwards MH, Pierangeli SS, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 1997; 96 (12) 4380-4384
- 169 Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis 2009; 68 (2) 238-241
- 170 Ferrara DE, Liu X, Espinola RG , et al. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum 2003; 48 (11) 3272-3279
- 171 Murthy V, Erkan D, Jajoria P , et al. Effects of fluvastatin on pro-inflammatory and pro-thrombotic markers in antiphospholipid antibody (aPL)-positive patients: preliminary results from an open-label prospective pilot study. Arthritis Rheum 2011; 63 (10) s283 (abstract 726)
- 172 Erre GL, Pardini S, Faedda R, Passiu G. Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature. Lupus 2008; 17 (1) 50-55
- 173 Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. Rituximab in antiphospholipid syndrome (RITAPS)—a pilot open-label phase II prospective trial for non-criteria manifestations of antiphospholipid antibodies (aPL). Arthritis Rheum 2011; 63 (10) s283 (abstract 727)
- 174 Zhou H, Wolberg AS, Roubey RA. Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood 2004; 104 (8) 2353-2358
- 175 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 (4) 489-500
- 176 Ostertag MV, Liu X, Henderson V, Pierangeli SS. A peptide that mimics the Vth region of beta-2-glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus 2006; 15 (6) 358-365
- 177 Martinez de la Torre Y, Pregnolato F, D'Amelio F, Grossi C, Disimone N , et al. Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the β2 glycoprotein I phospholipid-binding site. Implications for human fetal loss. J Autoimmun 2011; 38: J209-J215
- 178 Sebire NJ, 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
- 179 Shamshirsaz AA, Paidas M, Krikun G. Preeclampsia, hypoxia, thrombosis, and inflammation. J Pregnancy 2012; 2012: 374047
- 180 Lambrianides A, Carroll C, Pericleous C , et al. Differential clinical manifestations of the antiphospholipid syndrome may be predicted by different intracellular signaling pathways. Arthritis Rheum 2007; 56 (S9) S533
- 181 Carroll TY, Mulla MJ, Han CS , et al. Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin. Am J Reprod Immunol 2011; 66 (4) 286-296