Blood Reviews
Volume 22, Issue 2 , Pages 93-105 , March 2008

Current insight into diagnostics and pathophysiology of the antiphospolipid syndrome

  • Rolf T. Urbanus

      Affiliations

    • Department of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
  • ,
  • Ronald H.M.W. Derksen

      Affiliations

    • Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
  • ,
  • Philip G. de Groot

      Affiliations

    • Department of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
    • Corresponding Author InformationCorresponding author. Tel.: +31 30 250 7769; fax: +31 30 250 5418.

References 

  1. 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;4:295–306
  2. Moore JE, Mohr CF. Biologically false positive serologic tests for syphilis; type, incidence, and cause. J Am Med Assoc. 1952;150:467–473
  3. Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest. 1952;31:621–622
  4. Conley CL. Disorders of the blood in disseminated lupus erythematosus. Am J Med. 1952;13:1–2
  5. Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemost Thromb. 1972;1:75–95
  6. Bowie EJ, Thompson JH, PascuzzI CA, Owen CA. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin.Med. 1963;62:416–430
  7. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med. 1980;92:156–159
  8. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211–1214
  9. 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;42:1309–1311
  10. Kutteh WH, Franklin RD. Assessing the variation in antiphospholipid antibody (APA) assays: comparison of results from 10 centers. Am J Obstet Gynecol. 2004;191:440–448
  11. Audrain MA, Colonna F, Morio F, Hamidou MA, Muller JY. Comparison of different kits in the detection of autoantibodies to cardiolipin and beta2glycoprotein 1. Rheumatology (Oxford). 2004;43:181–185
  12. Reber G, Arvieux J, Comby E, et al. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. The Working Group on Methodologies in Haemostasis from the GEHT (Groupe d’Etudes sur l’Hemostase et la Thrombose). Thromb Haemost. 1995;73:444–452
  13. Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the ISTH. Thromb Haemost. 1995;74:1597–1603
  14. Brandt JT, Triplett DA, Rock WA, Bovill EG, Arkin CF. Effect of lupus anticoagulants on the activated partial thromboplastin time. Results of the College of American Pathologists survey program. Arch Pathol Lab Med. 1991;115:109–114
  15. Brandt JT, Triplett DA, Musgrave K, Orr C. The sensitivity of different coagulation reagents to the presence of lupus anticoagulants. Arch Pathol Lab Med. 1987;111:120–124
  16. Denis-Magdelaine A, Flahault A, Verdy E. Sensitivity of sixteen APTT reagents for the presence of lupus anticoagulants. Haemostasis. 1995;25:98–105
  17. Jacobsen EM, Barna-Cler L, Taylor JM, Triplett DA, Wisloff F. The Lupus Ratio test–an interlaboratory study on the detection of Lupus anticoagulants by an APTT-based, integrated, and semi-quantitative test. Fifth International Survey of Lupus Anticoagulants–ISLA 5. Thromb Haemost. 2000;83:704–708
  18. 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;101:1827–1832
  19. Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33:2214–2221
  20. McNeil HP, Chesterman CN, Krilis SA. Anticardiolipin antibodies and lupus anticoagulants comprise separate antibody subgroups with different phospholipid binding characteristics. Br J Haematol. 1989;73:506–513
  21. Chamley LW, Pattison NS, McKay EJ. Separation of lupus anticoagulant from anticardiolipin antibodies by ion-exchange and gel filtration chromatography. Haemostasis. 1991;21:25–29
  22. Simmelink MJ, Derksen RH, Arnout J, De Groot PG. A simple method to discriminate between beta2-glycoprotein I- and prothrombin-dependent lupus anticoagulants. J Thromb Haemost. 2003;1:740–747
  23. Pengo V, Biasiolo A, Pegoraro C, Iliceto S. A two-step coagulation test to identify antibeta-glycoprotein I lupus anticoagulants. J Thromb Haemost. 2004;2:702–707
  24. de Laat HB, Derksen RH, Urbanus RT, Roest M, De Groot PG. beta2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood. 2004;104:3598–3602
  25. Harris EN, Pierangeli SS. Revisiting the anticardiolipin test and its standardization. Lupus. 2002;11:269–275
  26. Naess IA, Christiansen SC, Cannegieter SC, Rosendaal FR, Hammerstroem J. A prospective study of anticardiolipin antibodies as a risk factor for venous thrombosis in a general population (the HUNT study). J Thromb Haemost. 2006;4:44–49
  27. Runchey SS, Folsom AR, Tsai MY, Cushman M, McGovern PD. Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study. Br J Haematol. 2002;119:1005–1010
  28. Pengo V, Biasiolo A, Pegoraro C, et al. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost. 2005;93:1147–1152
  29. Bizzaro N, Ghirardello A, Zampieri S, et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study. J Thromb Haemost. 2007;5:1158–1164
  30. Galli M, Borrelli G, Jacobsen EM, et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood. 2007;110:1178–1183
  31. Reber G, Tincani A, Sanmarco M, de MP, Boffa MC. Variability of anti-beta2 glycoprotein I antibodies measurement by commercial assays. Thromb Haemost. 2005;94:665–672
  32. Pengo V, Biasiolo A, Bison E, Chantarangkul V, Tripodi A. Antiphospholipid antibody ELISAs: survey on the performance of clinical laboratories assessed by using lyophilized affinity-purified IgG with anticardiolipin and anti-beta2-Glycoprotein I activity. Thromb Res. 2007;120:127–133
  33. Iverson GM, Matsuura E, Victoria EJ, Cockerill KA, Linnik MD. The orientation of beta2GPI on the plate is important for the binding of anti-beta2GPI autoantibodies by ELISA. J Autoimmun. 2002;18:289–297
  34. de Laat B, Derksen RH, De Groot PG. High-avidity anti-beta glycoprotein I antibodies highly correlate with thrombosis in contrast to low-avidity anti-beta glycoprotein I antibodies. J Thromb Haemost. 2006;4:1619–1621
  35. Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood. 2003;102:2717–2723
  36. De Groot PG, Lutters B, Derksen RH, et al. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost. 2005;3:1993–1997
  37. Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost. 1991;66:629–632
  38. Previtali S, Barbui T, Galli M. Anti-beta2-glycoprotein I and anti-prothrombin antibodies in antiphospholipid-negative patients with thrombosis: a case control study. Thromb Haemost. 2002;88:729–732
  39. Forastiero R, Martinuzzo M, Pombo G, et al. A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost. 2005;3:1231–1238
  40. Hudson M, Herr AL, Rauch J, et al. The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol. 2003;30:2385–2391
  41. de Groot PG, Lutters B, Derksen RH, et al. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost. 2005;3:1993–1997
  42. 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;47:1008–1015
  43. de Groot PG, Lutters B, Derksen RH, et al. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost. 2005;3:1993–1997
  44. Zoghlami-Rintelen C, Vormittag R, Sailer T, et al. The presence of IgG antibodies against beta2-glycoprotein I predicts the risk of thrombosis in patients with the lupus anticoagulant. J Thromb Haemost. 2005;3:1160–1165
  45. Sailer T, Zoghlami C, Kurz C, et al. Anti-beta2-glycoprotein I antibodies are associated with pregnancy loss in women with the lupus anticoagulant. Thromb Haemost. 2006;95:796–801
  46. Ruffatti A, Tonello M, Del RT, et al. Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity. Thromb Haemost. 2006;96:337–341
  47. de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood. 2005;105:1540–1545
  48. Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood. 1988;72:512–519
  49. Oosting JD, Derksen RH, Bobbink IW, et al. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood. 1993;81:2618–2625
  50. Ruiz-Arguelles GJ, Ruiz-Arguelles A, Perez-Romano B, arcon-Segovia D. Protein S deficiency associated to anti-protein S antibodies in a patient with mixed connective-tissue disease and its reversal by danazol. Acta Haematol. 1993;89:206–208
  51. Sorice M, Griggi T, Arcieri P, et al. Protein S and HIV infection. The role of anticardiolipin and anti-protein S antibodies. Thromb Res. 1994;73:165–175
  52. Nakamura N, Kuragaki C, Shidara Y, Yamaji K, Wada Y. Antibody to annexin V has anti-phospholipid and lupus anticoagulant properties. Am J Hematol. 1995;49:347–348
  53. Bertolaccini ML, Mepani K, Sanna G, Hughes GR, Khamashta MA. Factor XII autoantibodies as a novel marker for thrombosis and adverse obstetric history in patients with systemic lupus erythematosus. Ann Rheum Dis. 2007;66:533–536
  54. Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990;335:1544–1547
  55. 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: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA. 1990;87:4120–4124
  56. Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K. beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemost. 1996;75:49–55
  57. Sheng Y, Reddel SW, Herzog H, et al. Impaired thrombin generation in beta 2-glycoprotein I null mice. J Biol Chem. 2001;276:13817–13821
  58. Shi T, Iverson GM, Qi JC, et al. Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-glycoprotein I. Proc Natl Acad Sci USA. 2004;101:3939–3944
  59. Hulstein JJ, Lenting PJ, de Laat B, et al. Beta2-Glycoprotein I inhibits von Willebrand factor-dependent platelet adhesion and aggregation. Blood. 2007;110:1483–1491
  60. Lopez-Lira F, Rosales-Leon L, Martinez VM, Ruiz Ordaz BH. The role of beta2-glycoprotein I (beta2GPI) in the activation of plasminogen. Biochim Biophys Acta. 2006;1764:815–823
  61. Bancsi LF, van dL, I, Bertina RM. Beta 2-glycoprotein I deficiency and the risk of thrombosis. Thromb.Haemost. 1992;67:649-653.
  62. Bouma B, De Groot PG, van den Elsen JM, et al. Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids based on its crystal structure. EMBO J. 1999;18:5166–5174
  63. Schwarzenbacher R, Zeth K, Diederichs K, et al. Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome. EMBO J. 1999;18:6228–6239
  64. Hammel M, Kriechbaum M, Gries A, et al. Solution structure of human and bovine beta(2)-glycoprotein I revealed by small-angle X-ray scattering. J Mol Biol. 2002;321:85–97
  65. Arvieux J, Regnault V, Hachulla E, et al. Heterogeneity and immunochemical properties of anti-beta2-glycoprotein I autoantibodies. Thromb Haemost. 1998;80:393–398
  66. Gamsjaeger R, Johs A, Gries A, et al. Membrane binding of beta2-glycoprotein I can be described by a two-state reaction model: an atomic force microscopy and surface plasmon resonance study. Biochem J. 2005;389:665–673
  67. de Laat B, Derksen RH, van Lummel M, Pennings MT, De Groot PG. Pathogenic anti-beta2-glycoprotein I antibodies recognize domain I of beta2-glycoprotein I only after a conformational change. Blood. 2006;107:1916–1924
  68. Koike T, Ichikawa K, Kasahara H, et al. Epitopes on beta2-GPI recognized by anticardiolipin antibodies. Lupus. 1998;7(Suppl 2):S14–S17
  69. Yang CD, Chen SL, Shen N, Qi M, Xu F. Detection of anti-recombinant beta 2-glycoprotein 1 and anti-recombinant beta 2-glycoprotein 1 fifth-domain antibodies in sera from patients with systemic lupus erythematosus. Rheumatol Int. 1998;18:5–10
  70. Blank M, Shoenfeld Y, Cabilly S, et al. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci USA. 1999;96:5164–5168
  71. Reddel SW, Wang YX, Sheng YH, Krilis SA. Epitope studies with anti-beta 2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimmun. 2000;15:91–96
  72. Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci USA. 1998;95:15542–15546
  73. McNeeley PA, Dlott JS, Furie RA, et al. Beta2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of beta2-glycoprotein I. Thromb Haemost. 2001;86:590–595
  74. Ioannou Y, Pericleous C, Giles I, et al. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum. 2007;56:280–290
  75. Lutters BC, Meijers JC, Derksen RH, Arnout J, De Groot PG. Dimers of beta 2-glycoprotein I mimic the in vitro effects of beta 2-glycoprotein I-anti-beta 2-glycoprotein I antibody complexes. J Biol Chem. 2001;276:3060–3067
  76. van Lummel M, Pennings MT, Derksen RH, et al. The binding site in {beta}2-glycoprotein I for ApoER2′ on platelets is located in domain V. J Biol Chem. 2005;280:36729–36736
  77. Pennings MT, van Lummel M, Derksen RH, et al. Interaction of beta2-glycoprotein I with members of the low density lipoprotein receptor family. J Thromb Haemost. 2006;4:1680–1690
  78. Ma K, Simantov R, Zhang JC, et al. High affinity binding of beta 2-glycoprotein I to human endothelial cells is mediated by annexin II. J Biol Chem. 2000;275:15541–15548
  79. Lutters BC, Derksen RH, Tekelenburg WL, et al. 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;278:33831–33838
  80. Pennings MT, Derksen RH, van Lummel M, et al. Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2′. J Thromb Haemost. 2007;5:369–377
  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;54:2558–2567
  82. Satta N, Dunoyer-Geindre S, Reber G, et al. The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies. Blood. 2007;109:1507–1514
  83. 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
  84. Pendu RP, Weeterings C, Urbanus RT, et al. PSGL-1 and LDL-receptors mediate adhesion of leucocytes to Beta2-Glycoprotein I [abstract]. J Thromb Haemost. 2007;5(supplement 2):PM-463
  85. Satta N, Dunoyer-Geindre S, Fish RJ, et al. Antiphospholipid antibodies and TLR2 colocalized in HUVEC endosomes [abstract]. J Thromb Haemost. 2007;5(supplement 2):O-S-010
  86. Zhang J, McCrae KR. Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-beta2 glycoprotein I antibodies. Blood. 2005;105:1964–1969
  87. Del Papa N, Guidali L, Sala A, et al. Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-beta 2-glycoprotein I antibodies react in vitro with endothelial cells through adherent beta 2-glycoprotein I and induce endothelial activation. Arthritis Rheum. 1997;40:551–561
  88. Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B, Reber G, Kruithof EK. NFkappaB is an essential intermediate in the activation of endothelial cells by anti-beta(2)-glycoprotein 1 antibodies. Thromb Haemost. 2002;88:851–857
  89. Ferrara DE, Swerlick R, Casper K, et al. Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost. 2004;2:1558–1563
  90. Gharavi AE, Pierangeli SS, Espinola RG, et al. Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo. Arthritis Rheum. 2002;46:545–552
  91. Pierangeli SS, Colden-Stanfield M, Liu X, et al. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation. 1999;99:1997–2002
  92. Simantov R, LaSala JM, Lo SK, et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest. 1995;96:2211–2219
  93. Vega-Ostertag M, Casper K, Swerlick R, et al. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum. 2005;52:1545–1554
  94. Shigeoka AA, Holscher TD, King AJ, et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J Immunol. 2007;178:6252–6258
  95. Cesarman-Maus G, Rios-Luna NP, Deora AB, et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood. 2006;107:4375–4382
  96. Zhou H, Ling S, Yu Y, Wang T, Hu H. Involvement of annexin A2 in anti-beta(2)GPI/beta(2)GPI-induced tissue factor expression on monocytes. Cell Res. 2007;17:737–739
  97. Giesen PL, Rauch U, Bohrmann B, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA. 1999;96:2311–2315
  98. Morel O, Toti F, Hugel B, et al. Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler. Thromb Vasc Biol. 2006;26:2594–2604
  99. Falati S, Liu Q, Gross P, et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003;197:1585–1598
  100. Bohgaki M, Atsumi T, Yamashita Y, et al. The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-beta2Glycoprotein I antibodies. Int Immunol. 2004;16:1633–1641
  101. Conti F, Sorice M, Circella A, et al. Beta-2-glycoprotein I expression on monocytes is increased in anti-phospholipid antibody syndrome and correlates with tissue factor expression. Clin Exp Immunol. 2003;132:509–516
  102. Cuadrado MJ, Lopez-Pedrera C, Khamashta MA, et al. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum. 1997;40:834–841
  103. 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
  104. Reverter JC, 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
  105. Zhou H, Wolberg AS, Roubey RA. Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood. 2004;104:2353–2358
  106. Lopez-Pedrera C, Buendia 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;54:301–311
  107. Aird WC. Vascular bed-specific thrombosis. J Thromb Haemost. 2007;5(Suppl 1):283–291
  108. Matsushima N, Tanaka T, Enkhbaya P, et al. Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genomics. 2007;8:124
  109. Meroni PL, Raschi E, Testoni C, et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 2001;44:2870–2878
  110. Neumann FJ, Ott I, Marx N, et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol. 1997;17:3399–3405
  111. Ikeda K, Nagasawa K, Horiuchi T, et al. C5a induces tissue factor activity on endothelial cells. Thromb Haemost. 1997;77:394–398
  112. Ritis K, Doumas M, Mastellos D, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006;177:4794–4802
  113. 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;106:2340–2346
  114. 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;prepublished online May 29:-DOI doi:10.1182/blood-2007-01-070631.
  115. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001;19:275–290
  116. Sammaritano LR. Significance of aPL IgG subclasses. Lupus. 1996;5:436–439
  117. Atsumi T, Caliz R, Amengual O, Khamashta MA, Hughes GR. Fcgamma receptor IIA H/R131 polymorphism in patients with antiphospholipid antibodies. Thromb Haemost. 1998;79:924–927
  118. 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;101:157–162
  119. Kornberg A, Renaudineau Y, Blank M, Youinou P, Shoenfeld Y. Anti-beta 2-glycoprotein I antibodies and anti-endothelial cell antibodies induce tissue factor in endothelial cells. Isr Med Assoc J. 2000;2(Suppl):27–31
  120. Vega-Ostertag M, Harris EN, Pierangeli SS. Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin. Arthritis Rheum. 2004;50:2911–2919
  121. Faure E, Thomas L, Xu H, et al. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol. 2001;166:2018–2024
  122. Wisloff F, Jacobsen EM, Liestol S. Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res. 2002;108:263–271
  123. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995;74:1185–1190
  124. Tincani A, Allegri F, Sanmarco M, et al. Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations–a cooperative project of the European Antiphospholipid Forum. Thromb Haemost. 2001;86:575–583
  125. Wong RC, Gillis D, Adelstein S, et al. Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology. 2004;36:63–68
  126. Reber G, Tincani A, Sanmarco M, de MP, Boffa MC. Proposals for the measurement of anti-beta2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost. 2004;2:1860–1862

PII: S0268-960X(07)00052-5

doi: 10.1016/j.blre.2007.09.001

Blood Reviews
Volume 22, Issue 2 , Pages 93-105 , March 2008