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Pathogenesis of antiphospholipid syndrome

Peter H Schur, MD
Section Editor
David S Pisetsky, MD, PhD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


Antiphospholipid syndrome (APS) is defined by the presence of two major components:

Presence in the plasma of at least one type of autoantibody known as an antiphospholipid antibody (aPL)

The occurrence of at least one of the following clinical manifestations: venous or arterial thromboses, or pregnancy morbidity

The mechanisms by which aPLs cause thrombosis are not completely understood.

APS occurs either as a primary condition or in the setting of an underlying disease, particularly systemic lupus erythematosus (SLE).


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Literature review current through: Sep 2016. | This topic last updated: Jun 3, 2016.
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  1. Forastiero R, Martinuzzo M. Prothrombotic mechanisms based on the impairment of fibrinolysis in the antiphospholipid syndrome. Lupus 2008; 17:872.
  2. Urbanus RT, Derksen RH, de Groot PG. Platelets and the antiphospholipid syndrome. Lupus 2008; 17:888.
  3. Chen PP, Giles I. Antibodies to serine proteases in the antiphospholipid syndrome. Curr Rheumatol Rep 2010; 12:45.
  4. Rand JH, Wu XX, Quinn AS, Taatjes DJ. Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome. Lupus 2008; 17:922.
  5. Raschi E, Borghi MO, Grossi C, et al. Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome. Lupus 2008; 17:937.
  6. Cockrell E, Espinola RG, McCrae KR. Annexin A2: biology and relevance to the antiphospholipid syndrome. Lupus 2008; 17:943.
  7. Kinev AV, Roubey RA. Tissue factor in the antiphospholipid syndrome. Lupus 2008; 17:952.
  8. Bu C, Gao L, Xie W, et al. beta2-glycoprotein i is a cofactor for tissue plasminogen activator-mediated plasminogen activation. Arthritis Rheum 2009; 60:559.
  9. Canaud G, Bienaimé F, Tabarin F, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 2014; 371:303.
  10. Mackworth-Young CG. Antiphospholipid syndrome: multiple mechanisms. Clin Exp Immunol 2004; 136:393.
  11. Erkan D, Lockshin MD. What is antiphospholipid syndrome? Curr Rheumatol Rep 2004; 6:451.
  12. Merrill JT, Zhang HW, Shen C, et al. Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein. Thromb Haemost 1999; 81:748.
  13. Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu Rev Med 1996; 47:533.
  14. Male C, Mitchell L, Julian J, et al. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2001; 97:844.
  15. Galli M, Willems GM, Rosing J, et al. Anti-prothrombin IgG from patients with anti-phospholipid antibodies inhibits the inactivation of factor Va by activated protein C. Br J Haematol 2005; 129:240.
  16. Hurtado V, Montes R, Gris JC, et al. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 2004; 104:1369.
  17. Yoshida K, Arai T, Kaburaki J, et al. Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome. Blood 2002; 99:2499.
  18. De Jong A, Ziboh V, Robbins D. Antiphospholipid antibodies and platelets. Curr Rheumatol Rep 2000; 2:238.
  19. 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.
  20. Vlachoyiannopoulos PG, Mavragani CP, Bourazopoulou E, et al. Anti-CD40 antibodies in antiphospholipid syndrome and systemic lupus erythematosus. Thromb Haemost 2004; 92:1303.
  21. Yellin MJ, Brett J, Baum D, et al. Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals. J Exp Med 1995; 182:1857.
  22. Silver RK, Mullen TA, Caplan MS, et al. Inducible platelet adherence to human umbilical vein endothelium by anticardiolipin antibody-positive sera. Am J Obstet Gynecol 1995; 173:702.
  23. Nojima J, Kuratsune H, Suehisa E, et al. Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/beta2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies--Co-existence of these antibodies enhances ADP-induced platelet activation in vitro. Thromb Haemost 2004; 91:967.
  24. 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.
  25. Simantov R, LaSala JM, Lo SK, et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 1995; 96:2211.
  26. Del Papa N, Guidali L, Spatola L, et al. Relationship between anti-phospholipid and anti-endothelial cell antibodies III: beta 2 glycoprotein I mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules. Clin Exp Rheumatol 1995; 13:179.
  27. 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.
  28. Hamid C, Norgate K, D'Cruz DP, et al. Anti-beta2GPI-antibody-induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome. Ann Rheum Dis 2007; 66:1000.
  29. 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.
  30. Salmon JE, Girardi G, Holers VM. Activation of complement mediates antiphospholipid antibody-induced pregnancy loss. Lupus 2003; 12:535.
  31. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10:1222.
  32. 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; 196:167.e1.
  33. 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.
  34. Bakimer R, Fishman P, Blank M, et al. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89:1558.
  35. 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; 109:797.
  36. Gharavi AE, Wilson W, Pierangeli S. The molecular basis of antiphospholipid syndrome. Lupus 2003; 12:579.
  37. Giles IP, Isenberg DA, Latchman DS, Rahman A. How do antiphospholipid antibodies bind beta2-glycoprotein I? Arthritis Rheum 2003; 48:2111.
  38. Oku K, Atsumi T, Bohgaki M, et al. Complement activation in patients with primary antiphospholipid syndrome. Ann Rheum Dis 2009; 68:1030.
  39. Roubey RA. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996; 39:1444.
  40. Cabral AR, Cabiedes J, Alarcón-Segovia D. Antibodies to phospholipid-free beta 2-glycoprotein-I in patients with primary antiphospholipid syndrome. J Rheumatol 1995; 22:1894.
  41. Cabiedes J, Cabral AR, Alarcón-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-beta 2-glycoprotein-I than with antiphospholipid antibodies. J Rheumatol 1995; 22:1899.
  42. Tsutsumi A, Matsuura E, Ichikawa K, et al. Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus. Arthritis Rheum 1996; 39:1466.
  43. Roubey RA, Maldonado MA, Byrd SN. Comparison of an enzyme-linked immunosorbent assay for antibodies to beta 2-glycoprotein I and a conventional anticardiolipin immunoassay. Arthritis Rheum 1996; 39:1606.
  44. Galli M, Finazzi G, Norbis F, et al. The risk of thrombosis in patients with lupus anticoagulants is predicted by their specific coagulation profile. Thromb Haemost 1999; 81:695.
  45. Day HM, Thiagarajan P, Ahn C, et al. Autoantibodies to beta2-glycoprotein I in systemic lupus erythematosus and primary antiphospholipid antibody syndrome: clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol 1998; 25:667.
  46. Cabral AR, Amigo MC, Cabiedes J, Alarcon-Segovia D. The antiphospholipid/cofactor syndromes: a primary variant with antibodies to beta 2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays. Am J Med 1996; 101:472.
  47. Cuadrado MJ, López-Pedrera C, Khamashta MA, et al. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum 1997; 40:834.
  48. López-Pedrera C, Cuadrado MJ, Herández V, et al. Proteomic analysis in monocytes of antiphospholipid syndrome patients: deregulation of proteins related to the development of thrombosis. Arthritis Rheum 2008; 58:2835.
  49. Galli M. Non beta 2-glycoprotein I cofactors for antiphospholipid antibodies. Lupus 1996; 5:388.
  50. Puurunen M, Vaarala O, Julkunen H, et al. Antibodies to phospholipid-binding plasma proteins and occurrence of thrombosis in patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1996; 80:16.
  51. Jones DW, MacKie IJ, Gallimore MJ, Winter M. Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome. Br J Haematol 2001; 113:550.
  52. Bidot CJ, Jy W, Horstman LL, et al. Factor VII/VIIa: a new antigen in the anti-phospholipid antibody syndrome. Br J Haematol 2003; 120:618.
  53. Shibata S, Harpel PC, Gharavi A, et al. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. Blood 1994; 83:2532.
  54. Vaarala O. Antiphospholipid antibodies and atherosclerosis. Lupus 1996; 5:442.
  55. Wu R, Nityanand S, Berglund L, et al. Antibodies against cardiolipin and oxidatively modified LDL in 50-year-old men predict myocardial infarction. Arterioscler Thromb Vasc Biol 1997; 17:3159.
  56. Rand JH, Wu XX, Lapinski R, et al. Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood 2004; 104:2783.
  57. Gromnica-Ihle E, Schössler W. Antiphospholipid syndrome. Int Arch Allergy Immunol 2000; 123:67.
  58. Cesarman-Maus G, Ríos-Luna NP, Deora AB, et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood 2006; 107:4375.
  59. Satoh A, Suzuki K, Takayama E, et al. Detection of anti-annexin IV and V antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Rheumatol 1999; 26:1715.
  60. Song KS, Park YS, Kim HK. Prevalence of anti-protein S antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43:557.
  61. Bertolaccini ML, Sanna G, Ralhan S, et al. Antibodies directed to protein S in patients with systemic lupus erythematosus: prevalence and clinical significance. Thromb Haemost 2003; 90:636.
  62. Muñoz-Rodríguez FJ, Reverter JC, Font J, et al. Prevalence and clinical significance of antiprothrombin antibodies in patients with systemic lupus erythematosus or with primary antiphospholipid syndrome. Haematologica 2000; 85:632.
  63. Tektonidou MG, Petrovas CA, Ioannidis JP, et al. Clinical importance of antibodies against platelet activating factor in antiphospholipid syndrome manifestations. Eur J Clin Invest 2000; 30:646.
  64. 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; 103:2121.
  65. Dignat-George F, Camoin-Jau L, Sabatier F, et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost 2004; 91:667.
  66. Ambrozic A, Bozic B, Kveder T, et al. Budding, vesiculation and permeabilization of phospholipid membranes-evidence for a feasible physiologic role of beta2-glycoprotein I and pathogenic actions of anti-beta2-glycoprotein I antibodies. Biochim Biophys Acta 2005; 1740:38.
  67. Morel O, Jesel L, Freyssinet JM, Toti F. Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis. Thromb J 2005; 3:15.
  68. Brouwer JL, Bijl M, Veeger NJ, et al. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004; 104:143.
  69. Nojima J, Kuratsune H, Suehisa E, et al. Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. Br J Haematol 2002; 118:577.
  70. Goldberg SN, Conti-Kelly AM, Greco TP. A family study of anticardiolipin antibodies and associated clinical conditions. Am J Med 1995; 99:473.
  71. Schur PH. Genetics of systemic lupus erythematosus. Lupus 1995; 4:425.
  72. Lundström E, Gustafsson JT, Jönsen A, et al. HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus. Ann Rheum Dis 2013; 72:1018.
  73. Karassa FB, Bijl M, Davies KA, et al. Role of the Fcgamma receptor IIA polymorphism in the antiphospholipid syndrome: an international meta-analysis. Arthritis Rheum 2003; 48:1930.
  74. Jiménez S, Tàssies D, Espinosa G, et al. Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus. Ann Rheum Dis 2008; 67:835.
  75. 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; 42:1655.
  76. Sanchez ML, Katsumata K, Atsumi T, et al. Association of HLA-DM polymorphism with the production of antiphospholipid antibodies. Ann Rheum Dis 2004; 63:1645.
  77. Yin H, Borghi MO, Delgado-Vega AM, et al. Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome. Arthritis Rheum 2009; 60:2468.