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

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


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.


  1. 1

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

  2. 2

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

  3. 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).

  4. 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).

  5. 5

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

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 10

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

  11. 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).

  12. 12

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

  13. 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).

  14. 14

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

  15. 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).

  16. 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).

  17. 17

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

  18. 18

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

  19. 19

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

  20. 20

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

  21. 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).

  22. 22

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

  23. 23

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

  24. 24

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

  25. 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).

  26. 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).

  27. 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).

  28. 28

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

  29. 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).

  30. 30

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

  31. 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).

  32. 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).

  33. 33

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

  34. 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).

  35. 35

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

  36. 36

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

  37. 37

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

  38. 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).

  39. 39

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

  40. 40

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

  41. 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).

  42. 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).

  43. 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).

  44. 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).

  45. 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).

  46. 46

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

  47. 47

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

  48. 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).

  49. 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).

  50. 50

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

  51. 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).

  52. 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).

  53. 53

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

  54. 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).

  55. 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. 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).

  57. 57

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

  58. 58

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

  59. 59

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

  60. 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).

  61. 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).

  62. 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).

  63. 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).

  64. 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).

  65. 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).

  66. 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).

  67. 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).

  68. 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).

  69. 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).

  70. 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).

  71. 71

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

  72. 72

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

  73. 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).

  74. 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).

  75. 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).

  76. 76

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

  77. 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).

  78. 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).

  79. 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).

  80. 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).

  81. 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).

  82. 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).

  83. 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).

  84. 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).

  85. 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).

  86. 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).

  87. 87

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

  88. 88

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

  89. 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).

  90. 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).

  91. 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).

  92. 92

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

  93. 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).

  94. 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).

  95. 95

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

  96. 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).

  97. 97

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

  98. 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).

  99. 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).

  100. 100

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

  101. 101

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

  102. 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).

  103. 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).

  104. 104

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

  105. 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).

  106. 106

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

  107. 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).

  108. 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).

  109. 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).

  110. 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).

  111. 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).

  112. 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).

  113. 113

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

  114. 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).

  115. 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).

  116. 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).

  117. 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).

  118. 118

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

  119. 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).

  120. 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).

  121. 121

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

  122. 122

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

  123. 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).

  124. 124

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

  125. 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).

  126. 126

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

  127. 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).

  128. 128

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

  129. 129

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

  130. 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).

  131. 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).

  132. 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).

  133. 133

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

  134. 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).

  135. 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).

  136. 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).

  137. 137

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

  138. 138

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

  139. 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).

  140. 140

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

  141. 141

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

  142. 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).

  143. 143

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

  144. 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).

  145. 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).

  146. 146

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

  147. 147

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

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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.

Correspondence to Munther Khamashta.

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The authors declare no competing financial interests.

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Livedo reticularis

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


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, M., 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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