Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 30, 2016

Distribution of antiphospholipid antibodies in a large population-based German cohort

  • Davit Manukyan , Heidi Rossmann , Andreas Schulz , Tanja Zeller , Norbert Pfeiffer , Harald Binder , Thomas Münzel , Manfred E. Beutel , Nadine Müller-Calleja , Philipp S. Wild and Karl J. Lackner EMAIL logo

Abstract

Background:

Antiphospholipid syndrome (APS) is the most common acquired thrombophilia. Diagnosis is based on clinical criteria and the presence of antiphospholipid antibodies (aPLs) above the 99th percentile of a reference group. Data on the distribution of aPL in the population are limited. The distribution of aPL including diagnostic cutoffs should be determined in a population-based cohort.

Methods:

The Gutenberg Health Study (GHS) is a population-based cohort aged 35–74 years. We determined the presence of antibodies against cardiolipin (aCL, IgG, and IgM), β2-glycoprotein I (anti-β2GPI, IgG, and IgM), and domain 1 of β2-glycoprotein I (anti-domain 1, IgG) in a sample of 4979 participants.

Results:

aPL titers were similar in the whole sample and in an apparently healthy subgroup of 1049 individuals. There was a strong age-dependent increase of both aCL and anti-β2GPI IgM, while aPL IgG titers were stable or tended to decrease with age. A relevant decrease was observed for aCL IgG in women and anti-domain 1 IgG in both sexes. There was no association of aPL titers with a history of venous thromboembolism (VTE).

Conclusions:

Our data show that for IgM aPL, age-dependent reference ranges should be used. In fact, the controversy regarding the clinical utility of IgM aPL might be related to the use of inappropriate reference ranges among other causes. In our population, aPLs were not associated with a history of VTE.


Corresponding author: Dr. Karl J. Lackner, Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany, Phone: +49 6131 177190, E-mail:

Acknowledgments

The competent technical assistance of Martina Hermanns is gratefully acknowledged.

  1. Author contributions: D. Manukyan designed the study, performed research, and analyzed data; H. Rossmann performed research and analyzed data; A. Schulz performed statistical analysis; T. Zeller designed the cohort study; N. Pfeiffer designed the cohort study; H. Binder analyzed data and critically discussed data; T. Münzel designed the cohort study; M.E. Beutel designed the cohort study; N. Müller-Calleja designed the study and critically discussed data; P. Wild designed and coordinated the cohort study; and K.J. Lackner designed the cohort study and the actual analysis, and wrote the article. All the authors approved the final version of the article submitted for publication. All the authors have accepted responsibility for the entire content of this submitted article and approved submission.

  2. Research funding: This study was supported by a grant of the Foundation for Pathobiochemistry and Molecular Diagnostics of the Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (DGKL). The GHS is funded through the Government of Rhineland-Palatinate (“Stiftung Rheinland-Pfalz für Innovation”, contract AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the GHS.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. 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. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of the antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011;7:330–9.10.1038/nrrheum.2011.52Search in Google Scholar

2. Willis R, Harris EN, Pierangeli SS. Pathogenesis of the antiphospholipid syndrome. Semin Thromb Hemost 2012;38:305–21.10.1055/s-0032-1311827Search in Google Scholar

3. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013;368:1033–44.10.1056/NEJMra1112830Search in Google Scholar

4. de Groot PG, Urbanus RT, Derksen RH. Pathophysiology of thrombotic APS: where do we stand? Lupus 2012;21:704–7.10.1177/0961203312438631Search in Google Scholar

5. Poulton K, Rahman A, Giles I. Examining how antiphospholipid antibodies activate intracellular signaling pathways: a systematic review. Semin Arthritis Rheum 2012;41:720–36.10.1016/j.semarthrit.2011.09.004Search in Google Scholar

6. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120–4.10.1073/pnas.87.11.4120Search in Google Scholar

7. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990;335:1544–7.10.1016/0140-6736(90)91374-JSearch in Google Scholar

8. de Groot PG, Urbanus RT. The significance of autoantibodies against β2-glycoprotein I. Blood 2012;120:266–74.10.1182/blood-2012-03-378646Search in Google Scholar PubMed

9. Pelkmans L, de Laat B. Antibodies against domain I of β2-glycoprotein I: the one and only? Lupus 2012;21:769–72.10.1177/0961203312437439Search in Google Scholar PubMed

10. Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost 2014;40:163–71.10.1055/s-0033-1364185Search in Google Scholar PubMed

11. 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

12. Montaruli B, De Luna E, Mengozzi G, Molinari F, Napolitano E, Napoli P, et al. Anti-cardiolipin and anti-β2-glycoprotein I antibodies: normal reference ranges in northwestern Italy. Lupus 2012;21:799–801.10.1177/0961203312442260Search in Google Scholar PubMed

13. 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 2010;8:1540–6.10.1111/j.1538-7836.2010.03857.xSearch in Google Scholar PubMed

14. Van Hoecke F, Persijn L, Decavele AS, Devreese K. Performance of two new, automated chemiluminescence assay panels for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Int J Lab Hematol 2012;34:630–40.10.1111/j.1751-553X.2012.01448.xSearch in Google Scholar PubMed

15. Apple FS, Collinson PO; IFCC Task Force on Clinical Applications of Cardiac Biomarkers. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem 2012;58:54–61.10.1373/clinchem.2011.165795Search in Google Scholar PubMed

16. Wellek S, Lackner KJ, Jennen-Steinmetz C, Reinhard I, Hoffmann I, Blettner M. Determination of reference limits: statistical concepts and tools for sample size calculation. Clin Chem Lab Med 2014;52:1685–94.10.1515/cclm-2014-0226Search in Google Scholar PubMed

17. Fields RA, Toubbeh H, Searles RP, Bankhurst AD. The prevalence of anticardiolipin antibodies in a healthy elderly population and its association with antinuclear antibodies. J Rheumatol 1989;16:623–5.Search in Google Scholar

18. Budd R, Harley E, Quarshie A, Henderson V, Harris EN, Pierangeli SS. A re-appraisal of the normal cut-off assignment for anticardiolipin IgM tests. J Thromb Haemost 2006;4:2210–4.10.1111/j.1538-7836.2006.02134.xSearch in Google Scholar PubMed

19. Wild PS, Zeller T, Beutel M, Blettner M, Dugi KA, Lackner KJ, et al. The Gutenberg Health Study. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012;55:824–9.10.1007/s00103-012-1502-7Search in Google Scholar PubMed

20. Michal M, Wiltink J, Lackner K, Wild PS, Zwiener I, Blettner M, et al. Association of hypertension with depression in the community: results from the Gutenberg Health Study. J Hypertens 2013;31:893–9.10.1097/HJH.0b013e32835f5768Search in Google Scholar PubMed

21. Schnabel RB, Wilde S, Wild PS, Munzel T, Blankenberg S. Atrial fibrillation: its prevalence and risk factor profile in the German general population. Dtsch Arztebl Int 2012;109:293–9.Search in Google Scholar

22. Wild PS, Sinning CR, Roth A, Wilde S, Schnabel RB, Lubos E, et al. Distribution and categorization of left ventricular measurements in the general population: results from the population-based Gutenberg Heart Study. Circ Cardiovasc Imaging 2010;3:604–13.10.1161/CIRCIMAGING.109.911933Search in Google Scholar PubMed

23. Ichikawa K, Khamashta MA, Koike T, Matsuura E, Hughes GR. β2 glycoprotein-I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum 1994;37:1453–61.10.1002/art.1780371008Search in Google Scholar

24. Ichikawa K, Tsutsumi A, Atsumi T, Matsuura E, Kobayashi S, Hughes GR, et al. A chimeric antibody with the human γ1 constant region as a putative standard for assays to detect IgG β2-glycoprotein I-dependent anticardiolipin and anti-β2-glycoprotein I antibodies. Arthritis Rheum 1999;42:2461–70.10.1002/1529-0131(199911)42:11<2461::AID-ANR25>3.0.CO;2-OSearch in Google Scholar

25. Favaloro EJ, Wong RC. Antiphospholipid antibody testing for the antiphospholipid syndrome: a comprehensive practical review including a synopsis of challenges and recent guidelines. Pathology 2014;46:481–95.10.1097/PAT.0000000000000142Search in Google Scholar

26. Rutjes AW, Reitsma JB, Vandenbroucke JP, Glas AS, Bossuyt PM. Case-control and two-gate designs in diagnostic accuracy studies. Clin Chem 2005;51:1335–41.10.1373/clinchem.2005.048595Search in Google Scholar

27. Runchey SS, Folsom AR, Tsai MY, Cushman M, McGovern PD. Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study. Br J Haematol 2002;119:1005–10.10.1046/j.1365-2141.2002.03949.xSearch in Google Scholar


Supplemental Material:

The online version of this article (DOI: 10.1515/cclm-2016-0014) offers supplementary material, available to authorized users.


Received: 2016-1-7
Accepted: 2016-2-20
Published Online: 2016-3-30
Published in Print: 2016-10-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2024 from https://www.degruyter.com/document/doi/10.1515/cclm-2016-0014/html
Scroll to top button