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.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood 2009;113:985–94.10.1182/blood-2007-12-129627Search in Google Scholar PubMed
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;4:295–306.10.1111/j.1538-7836.2006.01753.xSearch in Google Scholar PubMed
3. Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007;9:212–8.10.1007/s11926-007-0034-xSearch in Google Scholar PubMed
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;35:322–32.10.1016/j.semarthrit.2005.07.003Search in Google Scholar PubMed
5. Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200–2.10.1016/j.autrev.2009.04.001Search in Google Scholar PubMed
6. Dlott JS, Roubey RA. Drug-induced lupus anticoagulants and antiphospholipid antibodies. Curr Rheumatol Rep 2012;14:71–8.10.1007/s11926-011-0227-1Search in Google Scholar PubMed
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;93:771–5.10.1093/ajcp/93.6.771Search in Google Scholar PubMed
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;104:3598–602.10.1182/blood-2004-03-1107Search in Google Scholar PubMed
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;107:1916–24.10.1182/blood-2005-05-1943Search in Google Scholar PubMed
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;13:917–30.10.1016/j.autrev.2014.05.001Search in Google Scholar PubMed
11. Oku K, Atsumi T, Amengual O, Koike T. Antiprothrombin antibody testing: detection and clinical utility. Semin Thromb Hemost 2008;34:335–9.10.1055/s-0028-1085475Search in Google Scholar PubMed
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;54:1663–70.10.1515/cclm-2016-0014Search in Google Scholar PubMed
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;6:23839.10.1038/srep23839Search in Google Scholar PubMed PubMed Central
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;7:1737–40.10.1111/j.1538-7836.2009.03555.xSearch in Google Scholar PubMed
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;25:10–5.10.1097/MBC.0b013e32836466b5Search in Google Scholar PubMed
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;12:792–5.10.1111/jth.12537Search in Google Scholar PubMed
17. Pelkmans L, de Laat B. Antibodies against domain I of beta2-glycoprotein I: the one and only? Lupus 2012;21:769–72.10.1177/0961203312437439Search in Google Scholar PubMed
18. de Laat B, de Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep 2011;13:70–6.10.1007/s11926-010-0144-8Search in Google Scholar PubMed PubMed Central
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;63:3960–8.10.1002/art.30633Search in Google Scholar PubMed
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;70:380–3.10.1136/ard.2010.137281Search in Google Scholar PubMed
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;13:782–7.10.1111/jth.12865Search in Google Scholar PubMed
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;67:2196–204.10.1002/art.39187Search in Google Scholar PubMed
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;7:1767–73.10.1111/j.1538-7836.2009.03588.xSearch in Google Scholar PubMed
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;12:313–7.10.1016/j.autrev.2012.05.006Search in Google Scholar PubMed
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;14:1779–87.10.1111/jth.13389Search in Google Scholar PubMed
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:e0156407.10.1371/journal.pone.0156407Search in Google Scholar PubMed PubMed Central
27. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–63.10.1056/NEJMra002974Search in Google Scholar PubMed
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;410:19–24.10.1016/j.cca.2009.09.006Search in Google Scholar PubMed
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;19:289–96.10.1177/1076029612437578Search in Google Scholar PubMed
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;111:354–64.10.1160/TH13-06-0509Search in Google Scholar PubMed
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;20:442–7.10.1177/1076029613497424Search in Google Scholar PubMed
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.Search in Google Scholar
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;10:2512–8.10.1111/jth.12014Search in Google Scholar PubMed
34. Bertolaccini ML. Antibodies to prothrombin. Lupus 2012;21:729–31.10.1177/0961203312443299Search in Google Scholar PubMed
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;56:432–8.10.1007/s12026-013-8421-zSearch in Google Scholar PubMed
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The online version of this article (DOI: 10.1515/cclm-2016-0676) offers supplementary material, available to authorized users.
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