Standardization of Antiphospholipid Antibody Testing—Historical Perspectives and Ongoing Initiatives^[*]

Abstract

The measurement of antiphospholipid antibodies (aPL) has been an important aspect of antiphospholipid syndrome (APS) characterization since the disease was first described in the 1980s. Despite significant efforts geared toward the standardization of immunoassays that measure anticardiolipin antibodies and anti-β₂-glycoprotein I spanning three decades, there are still reports of significant interassay and interlaboratory variation in the results of these assays. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13–16, 2010, Galveston, TX), a task force composed of internationally recognized experts in the field of APS was formed to address these issues. In this review, we discuss approaches that have been used in the past to achieve harmonization among aPL immunoassays as well as the ongoing efforts of the APLA task force. Our review also highlights the importance of cutoff determination in aPL assays and the clinical significance of positive aPL results of varying magnitudes.

Keywords

anticardiolipin antibodies - antiphospholipid antibodies - anti-β₂ glycoprotein I antibodies - standardization

^* Dedicated to the memory of Silvia Pierangeli, PhD (1955–2013)

• 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 (2) 295-306
• 2 Tincani A, Allegri F, Balestrieri G , et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res 2004; 114 (5-6) 553-558
• 3 Wong RCW, Gillis D, Adelstein S , et al. Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology 2004; 36 (1) 63-68
• 4 Wong RC, Favaloro EJ, Adelstein S , et al. Consensus guidelines on anti-beta 2 glycoprotein I testing and reporting. Pathology 2008; 40 (1) 58-63
• 5 Wong RC, Adelstein S, Gillis D, Favaloro EJ. Development of consensus guidelines for anticardiolipin and lupus anticoagulant testing. Semin Thromb Hemost 2005; 31 (1) 39-48
• 6 Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC ; Standardization group of the European Forum on Antiphospholipid Antibodies. Proposals for the measurement of anti-β₂-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2004; 2 (10) 1860-1862
• 7 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 (1) 66-73
• 8 Wong RCW, Favaloro EJ, Pollock W , et al. A multi-centre evaluation of the intra-assay and inter-assay variation of commercial and in-house anti-cardiolipin antibody assays. Pathology 2004; 36 (2) 182-192
• 9 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 (2) 142-147
• 10 Lakos G, Favaloro EJ, Harris EN , et al. International consensus guidelines on anticardiolipin and anti-β2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64 (1) 1-10
• 11 Harris EN, Gharavi AE, Boey ML , et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2 (8361) 1211-1214
• 12 Levine SR, Salowich-Palm L, Sawaya KL , et al. IgG anticardiolipin antibody titer > 40 GPL and the risk of subsequent thrombo-occlusive events and death. A prospective cohort study. Stroke 1997; 28 (9) 1660-1665
• 13 Harris EN, Chan JK, Asherson RA, Aber VR, Gharavi AE, Hughes GR. Thrombosis, recurrent fetal loss, and thrombocytopenia. Predictive value of the anticardiolipin antibody test. Arch Intern Med 1986; 146 (11) 2153-2156
• 14 Harris EN, Gharavi AE, Patel SP, Hughes GRC. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68 (1) 215-222
• 15 Harris EN. Special report. The Second International Anti-cardiolipin Standardization Workshop/the Kingston Anti-Phospholipid Antibody Study (KAPS) group. Am J Clin Pathol 1990; 94 (4) 476-484
• 16 Ichikawa K, Tsutsumi A, Atsumi T , et al. A chimeric antibody with the human gamma1 constant region as a putative standard for assays to detect IgG beta2-glycoprotein I-dependent anticardiolipin and anti-beta2-glycoprotein I antibodies. Arthritis Rheum 1999; 42 (11) 2461-2470
• 17 Ichikawa K, Khamashta MA, Koike T, Matsuura E, Hughes GR. beta 2-glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum 1994; 37 (10) 1453-1461
• 18 Pierangeli SS, Harris EN. A quarter of a century in anticardiolipin antibody testing and attempted standardization has led us to here, which is?. Semin Thromb Hemost 2008; 34 (4) 313-328
• 19 Sène D, Piette JC, Cacoub P. [Antiphospholipid antibodies, antiphospholipid syndrome and viral infections]. Rev Med Interne 2009; 30 (2) 135-141
• 20 Galli M, Comfurius P, Maassen C , et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335 (8705) 1544-1547
• 21 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 U S A 1990; 87 (11) 4120-4124
• 22 Harris EN. Antiphospholipid antibodies. Br J Haematol 1990; 74 (1) 1-9
• 23 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143 (2) 223-229
• 24 Iverson GM, Matsuura E, Victoria EJ, Cockerill KA, Linnik MD. The orientation of beta2GPI on the plate is important for the binding of anti-beta2GPI autoantibodies by ELISA. J Autoimmun 2002; 18 (4) 289-297
• 25 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β₂-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179 (2) 457-462
• 26 Roubey RA, Eisenberg RA, Harper MF, Winfield JB. “Anticardiolipin” autoantibodies recognize β 2-glycoprotein I in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995; 154 (2) 954-960
• 27 Sammaritano LR, Lockshin MD, Gharavi AE. Antiphospholipid antibodies differ in aPL cofactor requirement. Lupus 1992; 1 (2) 83-90
• 28 Chamley LW, Pattison NS, McKay EJ. Anomalous anticardiolipin antibody results may be due to cofactor variability. Am J Hematol 1991; 37 (4) 289
• 29 Schlame M, Haller I, Sammaritano LR, Blanck TJ. Effect of cardiolipin oxidation on solid-phase immunoassay for antiphospholipid antibodies. Thromb Haemost 2001; 86 (6) 1475-1482
• 30 Arvieux J, Darnige L, Hachulla E, Roussel B, Bensa JC, Colomb MG. Species specificity of anti-beta 2 glycoprotein I autoantibodies and its relevance to anticardiolipin antibody quantitation. Thromb Haemost 1996; 75 (5) 725-730
• 31 Favaloro EJ, Wheatland L, Jovanovich S, Roberts-Thomson P, Wong RCW. 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 (4) 390-403
• 32 Lakos G. Analytical detection capabilities of immunoassay-based antiphospholipid antibody tests: do they matter?. Drug Dev Res Drug Development Research 2013; 74: 575-581
• 33 Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth International Symposium on antiphospholipid antibodies. Am J Clin Pathol 1994; 101 (5) 616-624
• 34 Pierangeli SS, de Groot PG, Dlott J , et al. 'Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011; 20 (2) 182-190
• 35 Pierangeli SS, Favaloro EJ, Lakos G , et al. Standards and reference materials for the anticardiolipin and anti-β2glycoprotein I assays: a report of recommendations from the APL Task Force at the 13th International Congress on Antiphospholipid Antibodies. Clin Chim Acta 2012; 413 (1-2) 358-360
• 36 Willis R, Grossi C, Borghi MO , et al. Establishment of Standardized International Units for IgG Anti-β2glycoprotein Antibody Measurement. Arthritis Rheum 2012; 64 (S10): s1033 (abstract 2455)
• 37 Willis R, Grossi C, Borghi MO , et al. Establishment of Standardized International Units for IgM Anti-β2glycoprotein Antibody Measurement. Arthritis Rheum 2013; 65 (S10): s1 (abstract 15)
• 38 Grossi C, Borghi MO, Willis R , et al. Evaluation of monoclonal antibodies as reference material for IgG anti-β2glycoprotein I antibody measurement (abstract); September 2013; 14th International Congress on Antiphospholipid Antibodies
• 39 Escalante A, Brey RL, Mitchell Jr BD, Dreiner U. Accuracy of anticardiolipin antibodies in identifying a history of thrombosis among patients with systemic lupus erythematosus. Am J Med 1995; 98 (6) 559-565
• 40 Devreese KM, Van Hoecke F. Anticardiolipin and anti-β2glycoprotein-I antibody cut-off values in the diagnosis of antiphospholipid syndrome: more than calculating the in-house 99th percentiles, even for new automated assays. Thromb Res 2011; 128 (6) 598-600