Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk

Jee-Soo Lee 1 , JaYoon Gu 1 , 2 , Hee Sue Park 1 , Hyun Ju Yoo 1 , 2 ,  and Hyun Kyung Kim 1 , 2
  • 1 Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
  • 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Jee-Soo Lee, JaYoon Gu, Hee Sue Park, Hyun Ju Yoo and Hyun Kyung Kim

Abstract

Background:

Highly specific assays for measuring antiphospholipid antibodies (aPLs) are required for accurate assessment of thrombotic risk. aPLs against β2-glycoprotein I domain I (anti-β2GPIdI) and against prothrombin complexed with phosphatidylserine (anti-PS/PT) have been recently identified as being associated with a hypercoagulable state. This study evaluated the synergism between anti-β2GPIdI and anti-PS/PT for predicting thrombotic events.

Methods:

A total of 180 patients with clinical suspicion of hypercoagulability were evaluated. The plasma levels of lupus anticoagulant (LA) and antibodies against anticardiolipin (anti-CL) (IgG and IgM), β2GPI (IgG and IgM), PS/PT (IgG and IgM), and β2GPI dI (IgG) were measured.

Results:

IgG anti-β2GPIdI and LA were highly associated with thrombosis. Mean values and positivity rates of IgG anti-β2GPI dI and IgG anti-PS/PT were significantly higher in the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+) than in the other groups. Interestingly, the thrombotic risk [odds ratio (OR) 24.400, 95% confidence interval (CI) 1.976–63.273, p<0.001] of the newly defined triple positive group (LA+, IgG anti-CL+, IgG anti-β2GPIdI+; OR 11.182, 95% CI 1.976–63.273, p=0.006) was more than twice that of the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+). Double positivity for IgG anti-PS/PT and IgG anti-β2GPI also indicated significant thrombotic risk (OR 7.467, 95% CI 2.350–23.729, p=0.001). Furthermore, the thrombotic risk associated with double positivity for IgG anti-PS/PT and IgG anti-β2GPIdI was markedly elevated (OR 33.654, 95% CI 6.322-179.141, p<0.001).

Conclusions:

Our data suggest that simultaneous measurement of IgG anti-β2GPIdI and IgG anti-PS/PT may improve clinical decision-making for aPL-positive patients.

    • Supplementary material
  • 1.

    Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood 2009;113:985–94.

    • Crossref
    • PubMed
    • Export Citation
  • 2.

    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.

    • Crossref
    • Export Citation
  • 3.

    Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007;9:212–8.

    • Crossref
    • PubMed
    • Export Citation
  • 4.

    Gomez-Puerta JA, Cervera R, Espinosa G, Aguilo S, Bucciarelli S, Ramos-Casals M, et al. Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum 2006;35:322–32.

    • Crossref
    • PubMed
    • Export Citation
  • 5.

    Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200–2.

    • Crossref
    • PubMed
    • Export Citation
  • 6.

    Dlott JS, Roubey RA. Drug-induced lupus anticoagulants and antiphospholipid antibodies. Curr Rheumatol Rep 2012;14:71–8.

    • Crossref
    • PubMed
    • Export Citation
  • 7.

    Lillicrap DP, Pinto M, Benford K, Ford PM, Ford S. Heterogeneity of laboratory test results for antiphospholipid antibodies in patients treated with chlorpromazine and other phenothiazines. Am J Clin Pathol 1990;93:771–5.

    • Crossref
    • PubMed
    • Export Citation
  • 8.

    de Laat HB, Derksen RH, Urbanus RT, Roest M, de Groot PG. beta2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 2004;104:3598–602.

    • Crossref
    • PubMed
    • Export Citation
  • 9.

    de Laat B, Derksen RH, van Lummel M, Pennings MT, de Groot PG. Pathogenic anti-beta2-glycoprotein I antibodies recognize domain I of beta2-glycoprotein I only after a conformational change. Blood 2006;107:1916–24.

    • Crossref
    • Export Citation
  • 10.

    Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev 2014;13:917–30.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Oku K, Atsumi T, Amengual O, Koike T. Antiprothrombin antibody testing: detection and clinical utility. Semin Thromb Hemost 2008;34:335–9.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Manukyan D, Rossmann H, Schulz A, Zeller T, Pfeiffer N, Binder H, et al. Distribution of antiphospholipid antibodies in a large population-based German cohort. Clin Chem Lab Med 2016;54:1663–70.

  • 13.

    Zhang S, Wu Z, Chen S, Li J, Wen X, Li L, et al. Evaluation of the diagnostic potential of antibodies to beta2-glycoprotein 1 domain 1 in Chinese patients with antiphospholipid syndrome. Sci Rep 2016;6:23839.

    • Crossref
    • PubMed
    • Export Citation
  • 14.

    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, 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.

    • PubMed
    • Export Citation
  • 15.

    Chung Y, Kim JE, Lim HS, Kim HK. Clinical performance of anticardiolipin and antibeta2 glycoprotein I antibodies using a new automated chemiluminescent assay: superior thrombotic prediction of combined results measured by two different methods. Blood Coagul Fibrinolysis 2014;25:10–5.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Devreese KM, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL, et al. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J Thromb Haemost 2014;12:792–5.

    • Crossref
    • PubMed
    • Export Citation
  • 17.

    Pelkmans L, de Laat B. Antibodies against domain I of beta2-glycoprotein I: the one and only? Lupus 2012;21:769–72.

    • Crossref
    • Export Citation
  • 18.

    de Laat B, de Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep 2011;13:70–6.

    • Crossref
    • Export Citation
  • 19.

    de Laat B, van Berkel M, Urbanus RT, Siregar B, de Groot PG, Gebbink MF, et al. Immune responses against domain I of beta(2)-glycoprotein I are driven by conformational changes: domain I of beta(2)-glycoprotein I harbors a cryptic immunogenic epitope. Arthritis Rheum 2011;63:3960–8.

    • Crossref
    • Export Citation
  • 20.

    Andreoli L, Nalli C, Motta M, Norman GL, Shums Z, Encabo S, et al. Anti-β2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their ‘innocent’ profile? Annals of the Rheumatic Diseases 2011;70:380–3.

    • Crossref
    • Export Citation
  • 21.

    Pengo V, Ruffatti A, Tonello M, Cuffaro S, Banzato A, Bison E, et al. Antiphospholipid syndrome: antibodies to Domain 1 of beta2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015;13:782–7.

    • Crossref
    • PubMed
    • Export Citation
  • 22.

    Andreoli L, Chighizola CB, Nalli C, Gerosa M, Borghi MO, Pregnolato F, et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against beta2-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 2015;67:2196–204.

    • Crossref
    • PubMed
    • Export Citation
  • 23.

    de Laat B, Pengo V, Pabinger I, Musial J, Voskuyl AE, Bultink IE, 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.

    • Crossref
    • Export Citation
  • 24.

    Mahler M, Norman GL, Meroni PL, Khamashta M. Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid syndrome. Autoimmun Rev 2012;12:313–7.

    • Crossref
    • PubMed
    • Export Citation
  • 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.

    • Crossref
    • PubMed
    • Export Citation
  • 26.

    Pericleous C, Ferreira I, Borghi O, Pregnolato F, McDonnell T, Garza-Garcia A, et al. Measuring IgA Anti-beta2-glycoprotein I and IgG/IgA anti-domain I antibodies adds value to current serological assays for the antiphospholipid syndrome. PLoS One 2016;11:e0156407.

    • Crossref
    • PubMed
    • Export Citation
  • 27.

    Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–63.

    • Crossref
    • Export Citation
  • 28.

    Jaskowski TD, Wilson AR, Hill HR, Branch WD, Tebo AE. Autoantibodies against phosphatidylserine, prothrombin and phosphatidylserine-prothrombin complex: identical or distinct diagnostic tools for antiphospholipid syndrome? Clin Chim Acta 2009;410:19–24.

    • Crossref
    • PubMed
    • Export Citation
  • 29.

    Vlagea A, Gil A, Cuesta MV, Arribas F, Diez J, Lavilla P, et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential markers of antiphospholipid syndrome. Clin Appl Thromb Hemost 2013;19:289–96.

    • Crossref
    • PubMed
    • Export Citation
  • 30.

    Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost 2014;111:354–64.

    • Crossref
    • PubMed
    • Export Citation
  • 31.

    Kim H, Kim JE, Hwang SM, Lee HR, Han KS, Kim HK. Synergistic thrombotic risk of antibodies against phosphatidylserine and prothrombin and beta-2-glycoprotein I. Clin Appl Thromb Hemost 2014;20:442–7.

    • Crossref
    • PubMed
    • Export Citation
  • 32.

    Nojima J, Iwatani Y, Suehisa E, Kuratsune H, Kanakura Y. The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus. Haematologica 2006;91:699–702.

    • PubMed
    • Export Citation
  • 33.

    Sciascia S, Murru V, Sanna G, Roccatello D, Khamashta MA, Bertolaccini ML. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities. J Thromb Haemost 2012;10:2512–8.

    • Crossref
    • PubMed
    • Export Citation
  • 34.

    Bertolaccini ML. Antibodies to prothrombin. Lupus 2012;21:729–31.

  • 35.

    Pregnolato F, Chighizola CB, Encabo S, Shums Z, Norman GL, Tripodi A, et al. Anti-phosphatidylserine/prothrombin antibodies: an additional diagnostic marker for APS? Immunol Res 2013;56:432–8.

    • Crossref
    • PubMed
    • Export Citation
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