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Clinical and Experimental Medicine

, Volume 19, Issue 3, pp 339–345 | Cite as

Anti-domain 1 of beta2-glycoprotein I aids risk stratification in lupus anticoagulant-positive patients

  • Han Guo
  • Yuncong Zhang
  • Aiwei Li
  • Chanjuan Wang
  • Shuo Yang
  • Yinmei Zhang
  • Jie Zhang
  • Rui QiaoEmail author
Original Article

Abstract

Lupus anticoagulant (LA) is considered a risk factor for thromboembolism (TE) and adverse pregnancy outcomes (APOs). However, quite a few patients diagnosed with LA positivity do not suffer these adverse events. Further testing of anticardiolipin (aCL), anti-beta2-glycoprotein I (anti-β2GPI) or anti-domain 1 of β2GPI (anti-D1) may help to assess the occurrence risk of TE and APOs. Therefore, we aimed to study how to stratify LA-positive patients. In our study, 167 LA-positive patients were consecutively enrolled from January 2015 to December 2016. Serum aCL and anti-β2GPI (IgG, IgM and IgA) and anti-D1 IgG were simultaneously measured. Among these patients, 114 (68.3%) were followed for an average of 36.5 months for TE and APOs. The outcomes showed that 105 patients experienced TE and/or APOs, and 62 patients were LA carriers. Anti-D1 had good consistency with triple positivity (LA+, aCL+, anti-β2GPI+) (kappa = 0.742). Elevated anti-D1 was related to increased risks for TE [odds ratio (OR) 29.87, 95% confidence interval (CI) 8.05–110.74] and APOs (OR 8.73, 95% CI 3.41–22.31). Area under curve showed that the diagnostic power of anti-D1 for TE and APOs was 0.856 (95% CI 0.743–0.970) and 0.682 (95% CI 0.599–0.765), respectively. Survival analysis revealed that patients with high anti-D1 titres had a high cumulative incidence of APOs (hazard ratio 4.66, 95% CI 1.46–14.87). In conclusion, anti-D1, based on good consistency with triple positivity in LA-positive patients, has a stronger association with TE and APOs and, to some degree, could predict pregnancy outcomes. Therefore, anti-D1 may aid risk stratification in LA-positive patients.

Keywords

Lupus anticoagulant Thromboembolism Adverse pregnancy outcomes Anti-domain 1 of beta2-glycoprotein I Antiphospholipid antibodies 

Notes

Acknowledgements

This work was supported by Natural Science Foundation of China (Grant No. 81601824) and the interdisciplinary medicine Seed Fund of Peking University (Grant No. BMU2017MX013).

Author contributions

HG designed the research, interpreted data, performed statistical analysis and wrote the manuscript; YZ designed the research, interpreted data, AL and CW collected samples; SY and YZ analysed samples; JZ reviewed the manuscript; and RQ designed the research, identified sample characteristics and reviewed the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies were got approval from the Ethics Committee of Peking University Third Hospital according to the 1964 Helsinki Declaration and its latter amendments or comparable ethical standards.

Informed consent

Informed consent was signed from all participants included in the study.

References

  1. 1.
    Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.  https://doi.org/10.1111/j.1538-7836.2006.01753.x.CrossRefGoogle Scholar
  2. 2.
    Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–9.CrossRefGoogle Scholar
  3. 3.
    Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013;368:1033–44.CrossRefGoogle Scholar
  4. 4.
    Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 2012;64:2311–8.  https://doi.org/10.1002/art.34402.CrossRefGoogle Scholar
  5. 5.
    Yelnik CM, Laskin CA, Porter TF, et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med. 2016;3:e000131.  https://doi.org/10.1136/lupus-2015-000131.CrossRefGoogle Scholar
  6. 6.
    Gebhart J, Posch F, Koder S, et al. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood. 2015;125:3477–83.  https://doi.org/10.1182/blood-2014-11-611129.CrossRefGoogle Scholar
  7. 7.
    Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 2009;8:998–1005.  https://doi.org/10.1016/S1474-4422(09)70239-X.CrossRefGoogle Scholar
  8. 8.
    Pengo V, Biasiolo A, Gresele P, et al. A comparison of lupus anticoagulant-positive patients with clinical picture of antiphospholipid syndrome and those without. Arterioscler Thromb Vasc Biol. 2007;27:e309–10.  https://doi.org/10.1161/ATVBAHA.107.153536.CrossRefGoogle Scholar
  9. 9.
    Bertolaccini ML, Amengual O, Andreoli L, et al. 14th international congress on antiphospholipid antibodies task force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13:917–30.  https://doi.org/10.1016/j.autrev.2014.05.001.CrossRefGoogle Scholar
  10. 10.
    de Groot PG, Urbanus RT. The significance of autoantibodies against beta2-glycoprotein I. Blood. 2012;120:266–74.  https://doi.org/10.1182/blood-2012-03-378646.CrossRefGoogle Scholar
  11. 11.
    de Laat B, de Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep. 2011;13:70–6.CrossRefGoogle Scholar
  12. 12.
    de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood. 2005;105:1540–5.  https://doi.org/10.1182/blood-2004-09-3387.CrossRefGoogle Scholar
  13. 13.
    de Laat B, Pengo V, Pabinger I, et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost. 2009;7:1767–73.  https://doi.org/10.1111/j.1538-7836.2009.03588.x.CrossRefGoogle Scholar
  14. 14.
    Pengo V, Ruffatti A, Tonello M, et al. Antiphospholipid syndrome: antibodies to domain 1 of beta2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost. 2015;13:782–7.  https://doi.org/10.1111/jth.12865.CrossRefGoogle Scholar
  15. 15.
    Pericleous C, Ruiz-Limon P, Romay-Penabad Z, et al. Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of beta2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis. Rheumatology. 2015;54:722–7.  https://doi.org/10.1093/rheumatology/keu360.CrossRefGoogle Scholar
  16. 16.
    Agostinis C, Durigutto P, Sblattero D, et al. A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood. 2014;123:3478–87.  https://doi.org/10.1182/blood-2013-11-537704.CrossRefGoogle Scholar
  17. 17.
    Ioannou Y, Romay-Penabad Z, Pericleous C, et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I: proof of concept. J Thromb Haemost. 2009;7:833–42.  https://doi.org/10.1111/j.1538-7836.2009.03316.x.CrossRefGoogle Scholar
  18. 18.
    Pengo V, Tripodi A, Reber G, 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. 2009;7:1737–40.  https://doi.org/10.1111/j.1538-7836.2009.03555.x.CrossRefGoogle Scholar
  19. 19.
    de Laat B, Wu XX, van Lummel M, Derksen RH, de Groot PG, Rand JH. Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood. 2007;109:1490–4.  https://doi.org/10.1182/blood-2006-07-030148.CrossRefGoogle Scholar
  20. 20.
    Amengual O, Forastiero R, Sugiura-Ogasawara M, et al. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017;26:266–76.  https://doi.org/10.1177/0961203316660203.CrossRefGoogle Scholar
  21. 21.
    Lee JS, Gu J, Park HS, Yoo HJ, Kim HK. Coexistence of anti-beta2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk. Clin Chem Lab Med. 2017;55:882–9.  https://doi.org/10.1515/cclm-2016-0676.CrossRefGoogle Scholar
  22. 22.
    Bertolaccini ML, Sciascia S, Murru V, Garcia-Fernandez C, Sanna G, Khamashta MA. 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. 2013;109:207–13.CrossRefGoogle Scholar
  23. 23.
    Otomo K, Atsumi T, Amengual O, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 2012;64(2):504–12.  https://doi.org/10.1002/art.33340.CrossRefGoogle Scholar
  24. 24.
    Oku K, Amengual O, Atsumi T. Antiphospholipid scoring: significance in diagnosis and prognosis. Lupus. 2014;23:1269–72.  https://doi.org/10.1177/0961203314537361.CrossRefGoogle Scholar
  25. 25.
    De Craemer AS, Musial J, Devreese KM. Role of anti-domain 1-beta2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J Thromb Haemost. 2016;14:1779–87.  https://doi.org/10.1111/jth.13389.CrossRefGoogle Scholar
  26. 26.
    Iwaniec T, Kaczor MP, Celinska-Lowenhoff M, Polanski S, Musial J. Clinical significance of anti-domain 1 beta2-glycoprotein I antibodies in antiphospholipid syndrome. Thromb Res. 2017;153:90–4.  https://doi.org/10.1016/j.thromres.2017.02.019.CrossRefGoogle Scholar
  27. 27.
    Chighizola CB, Pregnolato F, Andreoli L, et al. Beyond thrombosis: anti-beta2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. J Autoimmun. 2018;90:76–83.  https://doi.org/10.1016/j.jaut.2018.02.002.CrossRefGoogle Scholar
  28. 28.
    Chighizola CB, Pregnolato F, Andreoli L, et al. Autoantibodies specific to a peptide of beta2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes. Blood. 2012;120:3360–70.  https://doi.org/10.1182/blood-2011-09-378851.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Han Guo
    • 1
  • Yuncong Zhang
    • 2
  • Aiwei Li
    • 1
  • Chanjuan Wang
    • 1
  • Shuo Yang
    • 1
  • Yinmei Zhang
    • 1
  • Jie Zhang
    • 1
  • Rui Qiao
    • 1
    Email author
  1. 1.Laboratory MedicinePeking University Third HospitalBeijingChina
  2. 2.Department of Clinical LaboratoryPeking University International HospitalBeijingChina

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