Download PDF
Thromb Haemost 2019; 119(05): 797-806
DOI: 10.1055/s-0039-1679901
New Technologies, Diagnostic Tools and Drugs
Georg Thieme Verlag KG Stuttgart · New York

Detection of Anti-Cardiolipin and Anti-β2glycoprotein I Antibodies Differs between Platforms without Influence on Association with Clinical Symptoms

Walid Chayoua
1   Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands
2   Synapse Research Institute, Maastricht, The Netherlands
,
Hilde Kelchtermans
1   Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands
2   Synapse Research Institute, Maastricht, The Netherlands
,
Gary W. Moore
3   Department of Haemostasis and Thrombosis, Viapath Analytics, Guy's & St. Thomas' Hospitals, London, United Kingdom
,
Jean-Christophe Gris
4   Centre Hospitalier Universitaire de Nîmes et Université de Montpellier, Montpellier, France
5   Ivan Sechenov First Moscow State Medical University, Moscow, Russia
,
Jacek Musial
6   2nd Department of Internal Medicine, Jagiellonian University Medical College, Jagiellonian University, Krakow, Poland
,
Denis Wahl
7   Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Centre Hospitalier Regional Universitaire de Nancy, Université de Lorraine, Inserm, DCAC, Nancy, France
,
Stéphane Zuily
7   Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Centre Hospitalier Regional Universitaire de Nancy, Université de Lorraine, Inserm, DCAC, Nancy, France
,
Francesca Gianniello
8   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
,
Pierre Fontana
9   Division of Angiology and Haemostasis, University Hospital Geneva, University of Geneva, Geneva, Switzerland
,
Jasper Remijn
10   Department of Clinical Chemistry and Hematology, Gelre Hospitals, Apeldoorn, The Netherlands
,
Rolf T. Urbanus
11   Department of Clinical Chemistry and Haematology, Center for Circulatory Health, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Bas de Laat
1   Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands
2   Synapse Research Institute, Maastricht, The Netherlands
,
Katrien M. J. Devreese
12   Coagulation Laboratory, Department of Diagnostic Sciences, Ghent University Hospital, Ghent University, Ghent, Belgium
› Author Affiliations
Further Information

Publication History

19 June 2018

04 January 2019

Publication Date:
01 March 2019 (online)

Also available at
    Permissions and Reprints

Abstract

Background The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-β2 glycoprotein I (aβ2GPI) or anti-cardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results.

Objective We aimed to investigate the agreement and diagnostic accuracy of solid phase assays.

Materials and Methods In this multi-centre study, 1,168 patient samples were tested on one site for aCL and aβ2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of β2GPI. LAC was determined by the local centre.

Results aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and aβ2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of β2GPI.

Conclusion Poor agreement was observed between different commercially available aCL and aβ2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of β2GPI reached the highest OR for thrombosis.

Keywords

solid phase assays - anti-cardiolipin - β2 glycoprotein I - epitope - thrombosis

Supplementary Material

 

  • References

  • 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 (02) 295-306
    CrossrefPubMedSearch in Google Scholar
  • 2 Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010; 376 (9751): 1498-1509
    CrossrefPubMedSearch in Google Scholar
  • 3 Gris J-C, Bouvier S, Molinari N. , et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012; 119 (11) 2624-2632
    CrossrefPubMedSearch in Google Scholar
  • 4 Male C, Foulon D, Hoogendoorn H. , et al. Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2005; 106 (13) 4152-4158
    CrossrefPubMedSearch in Google Scholar
  • 5 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101 (05) 1827-1832
    CrossrefPubMedSearch in Google Scholar
  • 6 Devreese KMJ. Antiphospholipid antibody testing and standardization. Int J Lab Hematol 2014; 36 (03) 352-363
    CrossrefPubMedSearch in Google Scholar
  • 7 Devreese K, Kelchtermans H. De laat B. Differences in sensitivity of two automated assay panels for anticardiolipin and anti beta2glycoprotein I antibodies in the laboratory diagnosis of antiphospholipid syndrome due to the exposure of the domain I epitope of beta2glycoprotein I on the solid phase. ISTH SSC 2014 meeting abstracts [Internet]; 2014. Available at: http://hdl.handle.net/1854/LU-8043838 . Accessed April 26, 2018
    PubMed
  • 8 Devreese KM, Poncet A, Lindhoff-Last E, Musial J, de Moerloose P, Fontana P. A multicenter study to assess the reproducibility of antiphospholipid antibody results produced by an automated system. J Thromb Haemost 2017; 15 (01) 91-95
    CrossrefPubMedSearch in Google Scholar
  • 9 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 (07) 1540-1546
    CrossrefPubMedSearch in Google Scholar
  • 10 Van Hoecke F, Persijn L, Decavele A-S, 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 (06) 630-640
    CrossrefPubMedSearch in Google Scholar
  • 11 Favaloro EJ, Silvestrini R, Mohammed A. Clinical utility of anticardiolipin antibody assays: high inter-laboratory variation and limited consensus by participants of external quality assurance programs signals a cautious approach. Pathology 1999; 31 (02) 142-147
    CrossrefPubMedSearch in Google Scholar
  • 12 Favaloro EJ, Wheatland L, Jovanovich S, Roberts-Thomson P, Wong RC. Internal quality control and external quality assurance in testing for antiphospholipid antibodies: part I--anticardiolipin and anti-β2-glycoprotein I antibodies. Semin Thromb Hemost 2012; 38 (04) 390-403
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 de Laat B, Derksen RHWM, 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 (04) 1540-1545
    CrossrefPubMedSearch in Google Scholar
  • 14 de Laat B, Derksen RHWM, 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 (05) 1916-1924
    CrossrefPubMedSearch in Google Scholar
  • 15 Pelkmans L, Kelchtermans H, de Groot PG. , et al. Variability in exposure of epitope G40-R43 of domain i in commercial anti-beta2-glycoprotein I IgG ELISAs. PLoS One 2013; 8 (08) e71402
    CrossrefPubMedSearch in Google Scholar
  • 16 Devreese KMJ, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL. ; Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12 (05) 792-795
    CrossrefPubMedSearch in Google Scholar
  • 17 Dienava-Verdoold I, Boon-Spijker MG, de Groot PG. , et al. Patient-derived monoclonal antibodies directed towards beta2 glycoprotein-1 display lupus anticoagulant activity. J Thromb Haemost 2011; 9 (04) 738-747
    CrossrefPubMedSearch in Google Scholar
  • 18 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44 (03) 837-845
    CrossrefPubMedSearch in Google Scholar
  • 19 Mehrani T, Petri M. Chapter 2 Epidemiology of the Antiphospholipid Syndrome. In: Cervera R, Reverter JC, Khamashta M. , eds. Antiphospholipid Syndrome in Systemic Autoimmune Diseases [Internet]. Elsevier; 2009: 13-34 . Available at: http://www.sciencedirect.com/science/article/pii/S1571507808004029 . Accessed February 5, 2019
    Search in Google Scholar
  • 20 Cervera R, Espinosa G, Reverter JC. Chapter 8 Systemic Manifestations of the Antiphospholipid Syndrome. In: Cervera R, Reverter JC, Khamashta M. , eds. Antiphospholipid Syndrome in Systemic Autoimmune Diseases. Elsevier; 2009: 105-116 . Available at: http://www.sciencedirect.com/science/article/pii/S157150780800408X . Accessed February 5, 2019
    Search in Google Scholar
  • 21 Audrain MAP, Colonna F, Morio F, Hamidou MA, Muller JY. Comparison of different kits in the detection of autoantibodies to cardiolipin and beta2glycoprotein 1. Rheumatology (Oxford) 2004; 43 (02) 181-185
    PubMedSearch in Google Scholar
  • 22 Andreoli L, Rizzini S, Allegri F, Meroni P, Tincani A. Are the current attempts at standardization of antiphospholipid antibodies still useful? Emerging technologies signal a shift in direction. Semin Thromb Hemost 2008; 34 (04) 356-360
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Reber G, Schousboe I, Tincani A. , et al. Inter-laboratory variability of anti-beta2-glycoprotein I measurement. A collaborative study in the frame of the European Forum on Antiphospholipid Antibodies Standardization Group. Thromb Haemost 2002; 88 (01) 66-73
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Decavele AS, Schouwers S, Devreese KMJ. Evaluation of three commercial ELISA kits for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Int J Lab Hematol 2011; 33 (01) 97-108
    CrossrefPubMedSearch in Google Scholar
  • 25 Persijn L, Decavele A-S, Schouwers S, Devreese K. Evaluation of a new set of automated chemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 2011; 128 (06) 565-569
    CrossrefPubMedSearch in Google Scholar
  • 26 Martins TB, Heikal N, Miller J, Willis R, Schmidt RL, Tebo AE. Assessment of diagnostic methods for the detection of anticardiolipin and anti-βeta2 glycoprotein I antibodies in patients under routine evaluation for antiphospholipid syndrome. Clin Chim Acta 2018; 485: 7-13
    CrossrefPubMedSearch in Google Scholar
  • 27 Devreese KMJ, Ortel TL, Pengo V, de Laat B. ; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
    CrossrefPubMedSearch in Google Scholar
  • 28 Arachchillage DRJ, Machin SJ, Mackie IJ, Cohen H. Diagnosis and management of non-criteria obstetric antiphospholipid syndrome. Thromb Haemost 2015; 113 (01) 13-19
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Ruffatti A, Olivieri S, Tonello M. , et al. Influence of different IgG anticardiolipin antibody cut-off values on antiphospholipid syndrome classification. J Thromb Haemost 2008; 6 (10) 1693-1696
    CrossrefPubMedSearch in Google Scholar
  • 30 Devreese K, Hoylaerts MF. Laboratory diagnosis of the antiphospholipid syndrome: a plethora of obstacles to overcome. Eur J Haematol 2009; 83 (01) 1-16
    CrossrefPubMedSearch in Google Scholar
  • 31 Devreese KMJ. Standardization of antiphospholipid antibody assays. Where do we stand?. Lupus 2012; 21 (07) 718-721
    CrossrefPubMedSearch in Google Scholar
  • 32 Cavazzana A, Pengo V, Tonello M. , et al. Anti-beta(2)-glycoprotein I ELISA assay: the influence of different antigen preparations. Thromb Haemost 2009; 101 (04) 789-791
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem 2010; 56 (06) 930-940
    CrossrefPubMedSearch in Google Scholar
  • 34 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 (11) 1767-1773
    CrossrefPubMedSearch in Google Scholar