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  • Review Article
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Diagnosing antiphospholipid syndrome: 'extra-criteria' manifestations and technical advances

Nature Reviews Rheumatology volume 13, pages 548–560 (2017)Cite this article

Subjects

Key Points

  • Antiphospholipid syndrome (APS) classification criteria, designed to categorize patient cohorts for clinical research, are commonly used in clinical practice; however, their use might not be appropriate for routine diagnosis

  • Patients with APS can have antiphospholipid antibody (aPL)-related clinical features other than thrombosis and pregnancy morbidity, such as livedo reticularis, thrombocytopenia, nephropathy, valvular heart disease, haemolytic anaemia, chorea and myelitis

  • aPL profiling represents the most accurate risk stratification tool for clinical manifestations such as thrombosis in the context of APS

  • New extra-criteria autoantibodies could improve the accuracy of diagnosis for patients suspected of having APS

Abstract

First described in the early 1980s, antiphospholipid syndrome (APS) is a unique form of acquired autoimmune thrombophilia in which patients present with clinical features of recurrent thrombosis and pregnancy morbidity and persistently test positive for the presence of antiphospholipid antibodies (aPL). At least one clinical (vascular thrombosis or pregnancy morbidity) and one lab-based (positive test result for lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein 1 antibodies) criterion have to be met for a patient to be classified as having APS. However, the clinical spectrum of APS encompasses additional manifestations that can affect many organs and cannot be explained exclusively by patients being in a prothrombotic state; clinical manifestations not listed in the classification criteria (known as extra-criteria manifestations) include neurologic manifestations (chorea, myelitis and migraine), haematologic manifestations (thrombocytopenia and haemolytic anaemia), livedo reticularis, nephropathy and valvular heart disease. Increasingly, research interest has focused on the development of novel assays that might be more specific for APS than the current aPL tests. This Review focuses on the current classification criteria for APS, presenting the role of extra-criteria manifestations and lab-based tests. Diagnostic approaches to difficult cases, including so-called seronegative APS, are also discussed.

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Figure 1: Extra-criteria clinical manifestations of antiphospholipid syndrome.
Figure 2: Mechanisms of thrombogenesis induced by antiphospholipid antibodies.

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References

  1. Hughes, G. R. The anticardiolipin syndrome. Clin. Exp. Rheumatol. 3, 285–286 (1985).

    CAS  PubMed  Google Scholar 

  2. Asherson, R. A. et al. The 'primary' antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 68, 366–374 (1989).

    Article  CAS  Google Scholar 

  3. Wilson, W. A. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 42, 1309–1311 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Johnson, S. R. et al. Classification criteria in rheumatic diseases: a review of methodologic properties. Arthritis Rheum. 57, 1119–1133 (2007).

    Article  PubMed  Google Scholar 

  6. Felson, D. T. & Anderson, J. J. Methodological and statistical approaches to criteria development in rheumatic diseases. Baillieres Clin. Rheumatol. 9, 253–266 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Aggarwal, R. et al. Distinctions between diagnostic and classification criteria? Arthritis Care Res. (Hoboken) 67, 891–897 (2015).

    Article  Google Scholar 

  8. Kaul, M., Erkan, D., Sammaritano, L. & Lockshin, M. D. Assessment of the 2006 revised antiphospholipid syndrome classification criteria. Ann. Rheum. Dis. 66, 927–930 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Thomas, R. Hypercoagulability syndromes. Arch. Intern. Med. 161, 2433–2439 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Ruiz-Irastorza, G., Crowther, M., Branch, W. & Khamashta, M. A. Antiphospholipid syndrome. Lancet 376, 1498–1509 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Sciascia, S. et al. 8-isoprostane, prostaglandin E2, C-reactive protein and serum amyloid A as markers of inflammation and oxidative stress in antiphospholipid syndrome: a pilot study. Inflamm. Res. 61, 809–816 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Giannakopoulos, B. & Krilis, S. A. The pathogenesis of the antiphospholipid syndrome. N. Engl. J. Med. 368, 1033–1044 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Cervera, R. et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann. Rheum. Dis. 74, 1011–1018 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Toubi, E. & Shoenfeld, Y. Livedo reticularis as a criterion for antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 32, 138–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Abreu, M. M. et al. The relevance of 'non-criteria' clinical manifestations of antiphospholipid syndrome: 14 th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features. Autoimmun. Rev. 14, 401–414 (2015).

    Article  PubMed  Google Scholar 

  16. Bertolaccini, M. L. et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun. Rev. 13, 917–930 (2014).

    Article  PubMed  Google Scholar 

  17. Atsumi, T., Furukawa, S., Amengual, O. & Koike, T. Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis. Lupus 14, 499–504 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Amigo, M.-C. What do we know about the cardiac valve lesion in the antiphospholipid syndrome (APS)? Lupus 23, 1259–1261 (2014).

    Article  PubMed  Google Scholar 

  19. Zuily, S. et al. Valvular heart disease in antiphospholipid syndrome. Curr. Rheumatol. Rep. 15, 320 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Noureldine, M. H. A. et al. Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies? Lupus 25, 1397–1411 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Islam, M. A. et al. 'Non-criteria' neurologic manifestations of antiphospholipid syndrome: a hidden kingdom to be discovered. CNS Neurol. Disord. Drug Targets 15, 1253–1265 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Rosati, A., Guerrini, R. & Cimaz, R. Lupus, antiphospholipid syndrome and epilepsy: an update. Lupus 26, 3–5 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Gris, J.-C., Nobile, B. & Bouvier, S. Neuropsychiatric presentations of antiphospholipid antibodies. Thromb. Res. 135 (Suppl. 1), S56–S59 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Gris, J.-C. & Brenner, B. Antiphospholipid antibodies: neuropsychiatric presentations. Semin. Thromb. Hemost. 39, 935–942 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Bertolaccini, M. L. et al. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome. J. Autoimmun. 75, 30–38 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sciascia, S. et al. The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review. Ann. Rheum. Dis. 74, 2028–2033 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Sciascia, S., Bertolaccini, M. L., Roccatello, D., Khamashta, M. A. & Sanna, G. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: a systematic review. J. Neurol. 261, 1706–1714 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl Acad. Sci. USA 103, 19854–19859 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Meroni, P. L., Chighizola, C. B., Rovelli, F. & Gerosa, M. Antiphospholipid syndrome in 2014: more clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res. Ther. 16, 209 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gerosa, M. et al. Antiglutamate receptor antibodies and cognitive impairment in primary antiphospholipid syndrome and systemic lupus erythematosus. Front. Immunol. 7, 5 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hanly, J. G. et al. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1726–1732 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kozora, E. et al. Functional magnetic resonance imaging of working memory and executive dysfunction in systemic lupus erythematosus and antiphospholipid antibody-positive patients. Arthritis Care Res. (Hoboken) 68, 1655–1663 (2016).

    Article  CAS  Google Scholar 

  33. Christodoulou, C., Sangle, S. & D'Cruz, D. P. Vasculopathy and arterial stenotic lesions in the antiphospholipid syndrome. Rheumatology (Oxford) 46, 907–910 (2007).

    Article  CAS  Google Scholar 

  34. Canaud, G. et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am. J. Transplant. 10, 2051–2060 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Sciascia, S., Khamashta, M. A. & D'Cruz, D. P. Targeted therapy in antiphospholipid syndrome. Curr. Opin. Rheumatol. 26, 269–275 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Espinosa, G. & Cervera, R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat. Rev. Rheumatol. 11, 586–596 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Canaud, G. et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N. Engl. J. Med. 371, 303–312 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Canaud, G., Legendre, C. & Terzi, F. AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game [editorial]. Lupus 24, 227–230 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Hidalgo, L. G. Inhibition of the mTORC pathway in the antiphospholipid syndrome [correspondence]. N. Engl. J. Med. 371, 1554 (2014).

    PubMed  Google Scholar 

  40. Girardi, G. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest. 112, 1644–1654 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Girardi, G., Redecha, P. & Salmon, J. E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat. Med. 10, 1222–1226 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, C. J., Romero, R., Chaemsaithong, P. & Kim, J.-S. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. Gynecol. 213, S53–S69 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lood, C. et al. Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus. PLoS ONE 9, e99386 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chenoweth, D. E. & Hugli, T. E. Human C5a and C5a analogs as probes of the neutrophil C5a receptor. Mol. Immunol. 17, 151–161 (1980).

    Article  CAS  PubMed  Google Scholar 

  45. Ripoll, V. M. et al. Changes in regulation of human monocyte proteins in response to IgG from patients with antiphospholipid syndrome. Blood 124, 3808–3816 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Oku, K. et al. Complement and thrombosis in the antiphospholipid syndrome. Autoimmun. Rev. 15, 1001–1004 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Oku, K. et al. Complement activation in patients with primary antiphospholipid syndrome. Ann. Rheum. Dis. 68, 1030–1035 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Peerschke, E. I. B. et al. Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 18, 530–538 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gropp, K. et al. β2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator. Blood 118, 2774–2783 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Foltyn Zadura, A. et al. Factor H autoantibodies in patients with antiphospholipid syndrome and thrombosis. J. Rheumatol. 42, 1786–1793 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Meroni, P. L. et al. Complement activation in antiphospholipid syndrome and its inhibition to prevent rethrombosis after arterial surgery. Blood 127, 365–367 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Kronbichler, A. et al. Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syndrome: a case report. Medicine (Baltimore) 93, e143 (2014).

    Article  CAS  Google Scholar 

  53. Lonze, B. E. et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am. J. Transplant. 14, 459–465 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Wig, S., Chan, M., Thachil, J., Bruce, I. & Barnes, T. A case of relapsing and refractory catastrophic anti-phospholipid syndrome successfully managed with eculizumab, a complement 5 inhibitor. Rheumatology (Oxford) 55, 382–384 (2016).

    Article  Google Scholar 

  55. Sciascia, S. et al. Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence. Rheumatol. Int. http://dx.doi.org/10.1007/s00296-017-3686-5 (2017).

  56. Canaud, G. et al. Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am. J. Transplant. 13, 2179–2185 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Legendre, C. M. et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368, 2169–2181 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Hadaya, K. et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am. J. Transplant. 11, 2523–2527 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Andreoli, L. et al. Clinical significance of IgA anti-cardiolipin and IgA anti-β2 glycoprotein I antibodies. Curr. Rheumatol. Rep. 15, 343 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Martínez-Flores, J. A. et al. Heterogeneity between diagnostic tests for IgA anti-β2 glycoprotein I: explaining the controversy in studies of association with vascular pathology. Anal. Chem. 85, 12093–12098 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Cousins, L. et al. Antibodies to domain I of β-2-glycoprotein I and IgA antiphospholipid antibodies in patients with 'seronegative' antiphospholipid syndrome. Ann. Rheum. Dis. 74, 317–319 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Cies´la, M., Wypasek, E. & Undas, A. IgA antiphospholipid antibodies and anti-domain 1 of β2 glycoprotein 1 antibodies are associated with livedo reticularis and heart valve disease in antiphospholipid syndrome. Adv. Clin. Exp. Med. 23, 729–733 (2014).

    Article  Google Scholar 

  63. Mattia, E. et al. IgA anticardiolipin and IgA anti-β2 glycoprotein I antibody positivity determined by fluorescence enzyme immunoassay in primary antiphospholipid syndrome. Clin. Chem. Lab. Med. 52, 1329–1333 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Despierres, L. et al. Contribution of anti-β2 glycoprotein I IgA antibodies to the diagnosis of anti-phospholipid syndrome: potential interest of target domains to discriminate thrombotic and non-thrombotic patients. Rheumatology (Oxford) 53, 1215–1218 (2014).

    Article  CAS  Google Scholar 

  65. Meijide, H., Sciascia, S., Sanna, G., Khamashta, M. A. & Bertolaccini, M. L. The clinical relevance of IgA anticardiolipin and IgA anti-β2 glycoprotein I antiphospholipid antibodies: a systematic review. Autoimmun. Rev. 12, 421–425 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Murthy, V. et al. Value of isolated IgA anti-β2-glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome. Arthritis Rheum. 65, 3186–3193 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pericleous, C. et al. Measuring IgA anti-β2-glycoprotein I and IgG/IgA anti-domain i antibodies adds value to current serological assays for the antiphospholipid syndrome. PLoS ONE 11, e0156407 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tebo, A. E. et al. Clinical significance and correlations between anti-β2 glycoprotein I IgA assays in antiphospholipid syndrome and/or systemic lupus erythematosus. Clin. Chim. Acta 460, 107–113 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Bertolaccini, M. L. et al. Prevalence of antibodies to prothrombin in solid phase (aPT) and to phosphatidylserine-prothrombin complex (aPS/PT) in patients with and without lupus anticoagulant. Thromb. Haemost. 109, 207–213 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Sciascia, S. et al. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb. Haemost. 111, 354–364 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Sciascia, S. & Bertolaccini, M. L. Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome. Lupus 23, 1309–1312 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Bertolaccini, M. L. & Sanna, G. Recent advances in understanding antiphospholipid syndrome. F1000 Res. 5, 2908 (2016).

    Article  CAS  Google Scholar 

  73. 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. 135, 214–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. López-Pedrera, C. et al. Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-κB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis Rheum. 54, 301–311 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Oku, K. et al. Essential role of the p38 mitogen-activated protein kinase pathway in tissue factor gene expression mediated by the phosphatidylserine-dependent antiprothrombin antibody. Rheumatology (Oxford) 52, 1775–1784 (2013).

    Article  CAS  Google Scholar 

  76. Haj-Yahia, S. et al. Anti-prothrombin antibodies cause thrombosis in a novel qualitative ex-vivo animal model. Lupus 12, 364–369 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Forastiero, R., Martinuzzo, M., Adamczuk, Y. & Carreras, L. O. Occurrence of anti-prothrombin and anti-β2-glycoprotein I antibodies in patients with history of thrombosis. J. Lab. Clin. Med. 134, 610–615 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Forastiero, R. R., Martinuzzo, M. E., Cerrato, G. S., Kordich, L. C. & Carreras, L. O. Relationship of anti β2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb. Haemost. 78, 1008–1014 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Sciascia, S., Khamashta, M. A. & Bertolaccini, M. L. New tests to detect antiphospholipid antibodies: antiprothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Curr. Rheumatol. Rep. 16, 415 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Amengual, O. et al. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus 26, 266–276 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Iverson, G. M., Victoria, E. J. & Marquis, D. M. Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI. Proc. Natl Acad. Sci. USA 95, 15542–15546 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Iverson, G. M. et al. Use of single point mutations in domain I of β2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J. Immunol. 169, 7097–7103 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Chighizola, C. B., Gerosa, M. & Meroni, P. L. New tests to detect antiphospholipid antibodies: anti-domain I β-2-glycoprotein-I antibodies. Curr. Rheumatol. Rep. 16, 402 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. De Craemer, A.-S., Musial, J. & Devreese, K. M. J. Role of anti-domain 1-β2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J. Thromb. Haemost. 14, 1779–1787 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. de Laat, B. et al. Immune responses against domain I of β2-glycoprotein I are driven by conformational changes: domain I of β2-glycoprotein I harbors a cryptic immunogenic epitope. Arthritis Rheum. 63, 3960–3968 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Ioannou, Y. et al. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human β2-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum. 56, 280–290 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Meroni, P. L. Anti-β-2 glycoprotein I epitope specificity: from experimental models to diagnostic tools. Lupus 25, 905–910 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Pericleous, C. & Rahman, A. Domain I: the hidden face of antiphospholipid syndrome. Lupus 23, 1320–1323 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Agostinis, C. et al. A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood 123, 3478–3487 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Ioannou, Y. et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of β2-glycoprotein I: proof of concept. J. Thromb. Haemost. 7, 833–842 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Pericleous, C. et al. Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of β2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis. Rheumatology (Oxford) 54, 722–727 (2015).

    Article  CAS  Google Scholar 

  92. Agostinis, C. et al. In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions. Blood 118, 4231–4238 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. de Laat, B. et al. The association between circulating antibodies against domain I of β2-glycoprotein I and thrombosis: an international multicenter study. J. Thromb. Haemost. 7, 1767–1773 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Andreoli, L. et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against β2 -glycoprotein i domain 1 and domain 4/5: ratio of anti-domain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome. Arthritis Rheumatol. 67, 2196–2204 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Blaschek, M. A. et al. Relation of antivimentin antibodies to anticardiolipin antibodies in systemic lupus erythematosus. Ann. Rheum. Dis. 47, 708–716 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Podor, T. J. et al. Vimentin exposed on activated platelets and platelet microparticles localizes vitronectin and plasminogen activator inhibitor complexes on their surface. J. Biol. Chem. 277, 7529–7539 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Ortona, E. et al. Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome. Blood 116, 2960–2967 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Bec´arevic´, M. The IgG and IgM isotypes of anti-annexin A5 antibodies: relevance for primary antiphospholipid syndrome. J. Thromb. Thrombolysis 42, 552–557 (2016).

    Article  CAS  Google Scholar 

  99. de Laat, B. et al. Annexin A5 polymorphism (-1C→T) and the presence of anti-annexin A5 antibodies in the antiphospholipid syndrome. Ann. Rheum. Dis. 65, 1468–1472 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Meroni, P. L. et al. Standardization of autoantibody testing: a paradigm for serology in rheumatic diseases. Nat. Rev. Rheumatol. 10, 35–43 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Willis, R. et al. International standards for IgG and IgM anti-β2 glycoprotein antibody measurement. Lupus 23, 1317–1319 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Willis, R. et al. Performance characteristics of commercial immunoassays for the detection of IgG and IgM antibodies to β2 glycoprotein I and an initial assessment of newly developed reference materials for assay calibration. Am. J. Clin. Pathol. 145, 796–805 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. 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 101, 1827–1832 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Favaloro, E. J. Variability and diagnostic utility of antiphospholipid antibodies including lupus anticoagulants. Int. J. Lab. Hematol. 35, 269–274 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Abdel-Wahab, N., Lopez-Olivo, M. A., Pinto-Patarroyo, G. P. & Suarez-Almazor, M. E. Systematic review of case reports of antiphospholipid syndrome following infection. Lupus 25, 1520–1531 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Vasan, R. S. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113, 2335–2362 (2006).

    Article  PubMed  Google Scholar 

  107. Zuo, Y. et al. A unique antiphospholipid assay recognizing phospholipid mixture compared with criteria antiphospholipid immunoassays in lupus patients. Lupus 26, 606–615 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Suh-Lailam, B. B., Cromar, A., Davis, K. W. & Tebo, A. E. APhL antibody ELISA as an alternative to anticardiolipin test for the diagnosis of antiphospholipid syndrome. Int. J. Clin. Exp. Pathol. 5, 210–215 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Roggenbuck, D. et al. Antiphospholipid antibodies detected by line immunoassay differentiate among patients with antiphospholipid syndrome, with infections and asymptomatic carriers. Arthritis Res. Ther. 18, 111 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Devreese, K. & Hoylaerts, M. F. Laboratory diagnosis of the antiphospholipid syndrome: a plethora of obstacles to overcome. Eur. J. Haematol. 83, 1–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Persijn, L., Decavele, A.-S., Schouwers, S. & Devreese, K. Evaluation of a new set of automated chemiluminescense assays for anticardiolipin and anti-β2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Thromb. Res. 128, 565–569 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Van Hoecke, F., Persijn, L., Decavele, A.-S. & Devreese, K. Performance of two new, automated chemiluminescence assay panels for anticardiolipin and anti-β2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Int. J. Lab. Hematol. 34, 630–640 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Capozzi, A. et al. Detection of antiphospholipid antibodies by automated chemiluminescence assay. J. Immunol. Methods 379, 48–52 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. De Moerloose, P., Reber, G., Musial, J. & Arnout, J. Analytical and clinical performance of a new, automated assay panel for the diagnosis of antiphospholipid syndrome. J. Thromb. Haemost. 8, 1540–1546 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Capuano, F. et al. Development of automated assays for anticardiolipin antibodies determination: addressing antigen and standardization issues. Ann. NY Acad. Sci. 1109, 493–502 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Noubouossie, D. et al. An automated chemiluminescence immunoassay may detect mostly relevant IgG anticardiolipin antibodies according to revised Sydney criteria. Acta Clin. Belg. 67, 184–189 (2012).

    CAS  PubMed  Google Scholar 

  117. Mahler, M. et al. Autoantibodies to domain 1 of β2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome. Lupus 25, 911–916 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Conrad, K., Roggenbuck, D., Reinhold, D. & Dörner, T. Profiling of rheumatoid arthritis associated autoantibodies. Autoimmun. Rev. 9, 431–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Metzger, J. et al. Biosensor analysis of β2-glycoprotein I-reactive autoantibodies: evidence for isotype-specific binding and differentiation of pathogenic from infection-induced antibodies. Clin. Chem. 53, 1137–1143 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Alexandrova, E. et al. Comparison of multi-line dot assay and enzyme-linked immunosorbent assay for detection of autoantibody profile in antiphospholipid syndrome [abstract]. Ann. Rheum. Dis. 72 (Suppl. 3), A907–A908 (2013).

    Google Scholar 

  121. Egerer, K. et al. Single-step autoantibody profiling in antiphospholipid syndrome using a multi-line dot assay. Arthritis Res. Ther. 13, R118 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Misasi, R. et al. 'New' antigenic targets and methodological approaches for refining laboratory diagnosis of antiphospholipid syndrome. J. Immunol. Res. 2015, 858542 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Taki, T., Kasama, T., Handa, S. & Ishikawa, D. A simple and quantitative purification of glycosphingolipids and phospholipids by thin-layer chromatography blotting. Anal. Biochem. 223, 232–238 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Conti, F. et al. TLC immunostaining for detection of 'antiphospholipid' antibodies. Methods Mol. Biol. 1134, 95–101 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Sorice, M. et al. Specificity of anti-phospholipid antibodies in infectious mononucleosis: a role for anti-cofactor protein antibodies. Clin. Exp. Immunol. 120, 301–306 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Alessandri, C. et al. Antiphospholipid reactivity against cardiolipin metabolites occurring during endothelial cell apoptosis. Arthritis Res. Ther. 8, R180 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Conti, F. et al. Thin-layer chromatography immunostaining in detecting anti-phospholipid antibodies in seronegative anti-phospholipid syndrome. Clin. Exp. Immunol. 167, 429–437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Conti, F. et al. The mosaic of 'seronegative' antiphospholipid syndrome. J. Immunol. Res. 2014, 389601 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sciascia, S. et al. GAPSS: the Global Anti-Phospholipid Syndrome Score. Rheumatology (Oxford) 52, 1397–1403 (2013).

    Article  Google Scholar 

  130. Sciascia, S., Cosseddu, D., Montaruli, B., Kuzenko, A. & Bertero, M. T. Risk Scale for the diagnosis of antiphospholipid syndrome. Ann. Rheum. Dis. 70, 1517–1518 (2011).

    Article  PubMed  Google Scholar 

  131. Otomo, K. et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 64, 504–512 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Sciascia, S. et al. Thrombotic risk assessment in systemic lupus erythematosus: validation of the global antiphospholipid syndrome score in a prospective cohort. Arthritis Care Res. (Hoboken) 66, 1915–1920 (2014).

    Article  Google Scholar 

  133. Sciascia, S. et al. The global anti-phospholipid syndrome score in primary APS. Rheumatology (Oxford) 54, 134–138 (2015).

    Article  CAS  Google Scholar 

  134. Oku, K. et al. An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases. Lupus 24, 774–775 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Zuo, Y., Li, C., Karp, D. R. & Li, Z. Clinical and epidemiological correlates of the adjusted global anti-phospholipid syndrome score in a large cohort of chinese APS patients [abstract]. Arthritis Rheumatol. 67 (Suppl. 10), A2183 (2015).

    Google Scholar 

  136. Amigo, M.-C. et al. Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS). Lupus 24, 927–934 (2015).

    Article  PubMed  Google Scholar 

  137. Nayfe, R. et al. Seronegative antiphospholipid syndrome. Rheumatology (Oxford) 52, 1358–1367 (2013).

    Article  Google Scholar 

  138. Alessandri, C. et al. Seronegative autoimmune diseases. Ann. NY Acad. Sci. 1173, 52–59 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Rodriguez-Garcia, J. L. et al. Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called 'seronegative APS'). Ann. Rheum. Dis. 71, 242–244 (2012).

    Article  PubMed  Google Scholar 

  140. Jawad, A. S. M. Seronegative antiphospholipid syndrome. Ann. Rheum. Dis. 63, 608 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Hughes, G. R. V. & Khamashta, M. A. Seronegative antiphospholipid syndrome. Ann. Rheum. Dis. 62, 1127 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Joalland, F. et al. Seronegative antiphospholipid syndrome, catastrophic syndrome, new anticoagulants: learning from a difficult case report [French]. Rev. Med. Interne. 35, 752–756 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Bertolaccini, M. L. et al. Antiphospholipid antibody tests: spreading the net. Ann. Rheum. Dis. 64, 1639–1643 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pengo, V. et al. What have we learned about antiphospholipid syndrome from patients and antiphospholipid carrier cohorts? Semin. Thromb. Hemost. 38, 322–327 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Pengo, V. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J. Thromb. Haemost. 7, 1737–1740 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Sciascia, S., Cuadrado, M. J., Khamashta, M. & Roccatello, D. Renal involvement in antiphospholipid syndrome. Nat. Rev. Nephrol. 10, 279–289 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Sciascia, S., Baldovino, S., Schreiber, K., Solfietti, L. & Roccatello, D. Antiphospholipid syndrome and the kidney. Semin. Nephrol. 35, 478–486 (2015).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical and Biological Sciences, Centre of Research of Immunopathology and Rare Diseases (CMID), Coordinating Centre of Piedmont and Aosta Valley Network for Rare Diseases, St Giovanni Bosco Hospital and the University of Turin, Piazza del Donatore di Sangue 3, Turin, 10154, Italy

    Savino Sciascia & Dario Roccatello

  2. Department of Clinical and Biological Sciences, SCDU Nephrology and Dialysis, St Giovanni Bosco Hospital and the University of Turin, Piazza del Donatore di Sangue 3, Turin, 10154, Italy

    Savino Sciascia & Dario Roccatello

  3. Service of Rheumatology, ABC Medical Center, Sur 136 No. 116, Colonia Las Américas, Mexico City, 01220, Mexico

    Mary-Carmen Amigo

  4. Department of Rheumatology, Dubai Hospital, PO box 7272, Dubai, UAE

    Munther Khamashta

  5. Division of Women's Health, Graham Hughes Lupus Research Laboratory, King's College London, The Rayne Institute, 4th Floor Lambeth Wing, St Thomas' Hospital, London, SE1 7EH, UK

    Munther Khamashta

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  1. Savino Sciascia
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S.S. researched data for the article. All authors contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Munther Khamashta.

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Glossary

Livedo reticularis

Cutaneous manifestation characterized by a transient or persistent blotchy, reddish-blue to purple, net-like pattern.

Phlogosis

Inflammation; from Ancient Greek, literally meaning 'burning heat'.

Organizing thrombi with focal recanalization

Thrombi that organize into fibrocellular and fibrous vascular occlusions, which are then recanalized by endothelialized channels following the acute phase of thrombosis, particularly seen in antiphospholipid antibody-related nephropathy.

Thrombotic microangiopathy

A heterogeneous group of pathological features characterised by vascular damage that manifests as arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall.

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Sciascia, S., Amigo, MC., Roccatello, D. et al. Diagnosing antiphospholipid syndrome: 'extra-criteria' manifestations and technical advances. Nat Rev Rheumatol 13, 548–560 (2017). https://doi.org/10.1038/nrrheum.2017.124

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