Annexin-A5 resistance and non-criteria antibodies for the diagnosis of seronegative antiphospholipid syndrome


In this study, we aimed to analyze the value of annexin-A5 anticoagulant ratio (A5R) and non-criteria antibodies for the diagnosis of APS in patients with clinical seronegative APS. Three groups were defined, including 21 seronegative APS patients with unexplained obstetrical adverse events or thrombosis history, 15 confirmed APS patients with triple aPL positivity, and a control group of 20 healthy patients without any history of thrombosis or pregnancy complications. Seronegative APS patients have similar levels of A5R in comparison to healthy controls (202% [171%–238%] versus 191% [178%–221%]; p = 0.65), whereas triple-positive APS patients have significantly more reduced A5R in comparison to both seronegative and healthy patients (149% [138%–158%] versus 202% [171%–238%] and 191% [178%–221%], respectively, p < 0.001). The non-criteria aPL were found in 24% of seronegative APS: anti-PE IgM in 3 cases (14%) and anti-PS/PT IgG and anti-PS/PT IgM in 1 (5%) case each. The frequency of non-criteria APL was significantly more frequent in comparison to healthy controls (p = 0.048). All triple-positive APS patients have at least one non-criteria aPL, and the non-criteria aPL were significantly more frequent in these patients compared to seronegative APS and healthy controls (p < 0.001). Whereas A5R levels do not allow to discriminate seronegative APS from healthy controls, our results demonstrate that non-criteria aPL can help to APS diagnosis in clinical seronegative APS.

Key points
Annexin-A5 resistance testing does not help for the diagnosis of seronegative APS.
The non-criteria antiphospholipid antibodies can contribute to APS diagnosis in patients without conventional antibodies.

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Fig. 1


  1. 1.

    Cervera R (2017) Antiphospholipid syndrome. Thromb Res 151(Suppl 1):S43–SS7.

  2. 2.

    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RHWM, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295–306.

  3. 3.

    Rodriguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, Sanna G, Ateka-Barrutia O, Khamashta MA (2012) Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called 'seronegative APS'). Ann Rheum Dis 71(2):242–244.

  4. 4.

    Mekinian A, Bourrienne MC, Carbillon L, Benbara A, Noémie A, Chollet-Martin S, Tigaizin A, Montestruc F, Fain O, Nicaise-Roland P (2016) Non-conventional antiphospholipid antibodies in patients with clinical obstetrical APS: prevalence and treatment efficacy in pregnancies. Semin Arthritis Rheum 46(2):232–237.

  5. 5.

    Pregnolato F, Chighizola CB, Encabo S, Shums Z, Norman GL, Tripodi A, Chantarangkul V, Bertero T, De Micheli V, Borghi MO, Meroni PL (2013) Antiphosphatidylserine/prothrombin antibodies: an additional diagnostic marker for APS? Immunol Res 56(2–3):432–438.

  6. 6.

    Sanmarco M, Alessi MC, Harle JR, Sapin C, Aillaud MF, Gentile S, Juhan-Vague I, Weiller PJ (2001) Antibodies to phosphatidylethanolamine as the only antiphospholipid antibodies found in patients with unexplained thromboses. Thromb Haemost 85:800–805.

  7. 7.

    Rand JH, Wu XX, Quinn AS, Chen PP, KR MC, Bovill EG, Taatjes DJ (2003) Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay. Am J Pathol 163(3):1193–1200.

  8. 8.

    Rand JH, Wu XX, Quinn AS, Taatjes DJ (2008) Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome. Lupus 17(10):922–930.

  9. 9.

    Foley JH (2016) Examining coagulation-complement crosstalk: complement activation and thrombosis. Thromb Res 141(suppl 2):S50–S54.

  10. 10.

    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, de Groot PG (2009) Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 7(10):1737–1740.

  11. 11.

    Rand JH, Wu XX, Lapinski R, van Heerde WL, Reutelingsperger CP, Chen PP, Ortel TL (2004) Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood 104(9):2783–2790.

  12. 12.

    Espinosa G, Cervera R (2015) Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol 11(10):586–596.

  13. 13.

    De Laat B, Wu X, van Lummel M, Derksen RH, de Groot PG, Rand JH (2007) Correlation between antiphospholipid antibodies that recognize domain I of β2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood 109(4):1490–1494.

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Correspondence to Arsene Mékinian.

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Ferreira, T.G., Delhommeau, F., Johanet, C. et al. Annexin-A5 resistance and non-criteria antibodies for the diagnosis of seronegative antiphospholipid syndrome. Clin Rheumatol (2020) doi:10.1007/s10067-019-04915-5

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  • Annexin-A5
  • Annexin-A5 resistance
  • Antiphospholipid antibodies
  • Antiphospholipid syndrome
  • Non-criteria antibodies
  • Seronegative