Elsevier

Autoimmunity Reviews

Volume 13, Issue 9, September 2014, Pages 917-930
Autoimmunity Reviews

Review
14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends

https://doi.org/10.1016/j.autrev.2014.05.001Get rights and content

Abstract

Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-β2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive.

This report summarizes the findings, conclusions and recommendations of the “APS Task Force 3—Laboratory Diagnostics and Trends” meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18–21, Rio de Janeiro, RJ, Brazil).

Introduction

Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome [1]. Anticardiolipin antibodies (aCL), anti-β2 glycoprotein I (anti-β2GPI) antibodies and the lupus anticoagulant (LA) are the laboratory tests included in the revised criteria for the classification of the APS.

However, several other autoantibodies shown to be directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine–prothrombin complexes) or their complex with phospholipids other than cardiolipin, or to some domains of β2GPI, have been proposed to be relevant to APS [2] but their clinical utility and their diagnostic value remain elusive. The clinical relevance of IgA aPL and whether these isotype tests should be part of the routine diagnostic algorithm is also being a subject of hot debate.

A task force of worldwide scientists in the field firstly met, discussed and analysed critical questions related to “criteria” and “non-criteria” aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13–16, Galveston, TX, USA) [3], [4]. Members of these task forces continued to work and reunited to evaluate the utility of various laboratory assays.

This report summarizes the findings, conclusions and recommendations of the “APS Task Force 3—Laboratory Diagnostics and Trends” meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18–21, Rio de Janeiro, RJ, Brazil). This task force comprised a group of clinical laboratory scientists, researchers and clinicians, involved within 7 subgroups (Table 1) according to their expertise. All available data was assigned a level of evidence according to the design of the study [5] (Table 2) and the grading system was applied to evaluate the quality of that available evidence (Table 3) [6], [7].

Last but not least, this manuscript is dedicated to the memory of Prof. Silvia Pierangeli (1955–2013), an exceptional friend, a remarkable colleague and one of the main contributors to the study of APS, including the standardization of aPL tests. Prof. Pierangeli embarked on a tireless effort to promote standard test performance through multiple publications and workshops, and by providing proficient advice worldwide. Her efforts culminated in the assembly of experts for this task force to which she devotedly dedicated during the last months of her life.

This session was dedicated to the memory of Drs. John A McIntyre and Doug A Triplett.

Section snippets

Standardization of antiphospholipid immunoassays

A report from the ‘criteria’ aPL task force formed at the 13th International Congress on Antiphospholipid Antibodies outlined critical issues relating to the performance of antiphospholipid (aPL) immunoassays and made several recommendations to improve their standardization [3]. Among these recommendations were the need for an international consensus protocol for anticardiolipin (aCL) and anti-βeta2 glycoprotein I (anti-β2GPI) tests (which have subsequently been published) as well as the

Development of polyclonal and monoclonal reference material and international units for anti-β2GPI measurement

According to an approved protocol prepared by Drs Silvia Pierangeli, Pier Luigi Meroni and Gabriella Lakos, IgG and IgM polyclonal reference sera (IgG and IgM reference material) were each prepared by pooling serum from well-characterized APS patients with very high anti-β2GPI levels of the desired isotype. Once prepared, IgG and IgM anti-β2GPI fractions were purified from their respective reference material utilizing combinations of affinity and ion-exchange chromatography; then were

Proficiency testing programs report—College of American Pathology (CAP)

Proficiency testing programs for aPL are offered by a number of organizations, including the College of American Pathologists (CAP). The CAP defines qualitative agreement for the aCL survey as ≥ 80% positive/negative agreement across all participants, regardless of specific assay method or test kit. Therefore, a review of the participant consensus results within the aCL survey can provide some information regarding standardization of clinical tests and laboratory performance. Between 2007 and

Cut-off establishment and the significance of low positive aPL antibody levels

The method of cut-off establishment and the accuracy of the cut-off value are key factors in determining the diagnostic performance characteristics of an assay. Consequently, reaching consensus on the method of cut-off establishment is important from the point of view of harmonization of aPL assays. Fortunately, this is an area, where researchers and laboratory scientists alike have the highest level of agreement. Reference ranges for aCL and anti-β2GPI test results must be established by

Conclusions

This report summarises the findings, conclusions and recommendations of the “APS Task Force 3—Laboratory Diagnostics and Trends” meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18–21, Rio de Janeiro, RJ, Brazil). Along with other already published recommendations [153], [154], [155], we are expected to update this report at the next International Congress (September 2016 in Istanbul, Turkey—www.apsistanbul2016.org).

Take-home message

  • The development of international units and polyclonal and monoclonal reference materials for anti-β2GPI testing is under way. These on-going efforts will significantly contribute towards the much-needed improvement of inter-laboratory and inter-assay agreement for aPL immunoassays.

  • A weak LA results should be considered positive when making clinical decisions.

  • While the LA can be measured in plasma of patients on vitamin K antagonists under certain consitions, detection of LA in plasmas

Acknowledgments

This work is dedicated to the memory of Prof. Silvia Pierangeli, Antiphospholipid Standardization Laboratory. Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.

Maria Laura Bertolaccini is funded by the Louise Gergel Fellowship. Michelle Petri is supported by NIH AR43727.

References (155)

  • E. Cucurull et al.

    IgA anticardiolipin and anti-beta2-glycoprotein I are the most prevalent isotypes in African American patients with systemic lupus erythematosus

    Am J Med Sci

    (1999)
  • P.A. Merkel et al.

    The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases

    Am J Med

    (1996)
  • G.M. Iverson et al.

    Patients with atherosclerotic syndrome, negative in anti-cardiolipin assays, make IgA autoantibodies that preferentially target domain 4 of beta2-GPI

    J Autoimmun

    (2006)
  • R.M. Lee et al.

    Immunoglobulin A anti-beta2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death

    Am J Obstet Gynecol

    (2001)
  • A. Serrano et al.

    IgA antibodies against beta2 glycoprotein I in hemodialysis patients are an independent risk factor for mortality

    Kidney Int

    (2012)
  • M.S. Sater et al.

    Anti-phosphatidylserine, anti-cardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8–12 gestational weeks

    Eur J Obstet Gynecol Reprod Biol

    (2012)
  • R. Budd et al.

    A re-appraisal of the normal cut-off assignment for anticardiolipin IgM tests

    J Thromb Haemost

    (2006)
  • E.N. Harris et al.

    A more specific assay for the detection of antiphospholipid

    Clin Immunol Newsl

    (1995)
  • E.N. Harris et al.

    ‘Equivocal’ antiphospholipid syndrome

    J Autoimmun

    (2000)
  • T. Sugi et al.

    Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses

    Fertil Steril

    (1999)
  • H. Yamada et al.

    Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes

    J Reprod Immunol

    (2009)
  • S. Obayashi et al.

    Antiphosphatidylethanolamine antibodies might not be an independent risk factor for further miscarriage in patients suffering recurrent pregnancy loss

    J Reprod Immunol

    (2010)
  • M.L. Bertolaccini et al.

    The clinical value of testing for antibodies to phosphatidylethanolamine (aPE) in patients with systemic lupus erythematosus (SLE)

    Thromb Res

    (2012)
  • S. Blaise et al.

    Thrombosis of legs arteries: imputability of anti-phosphatidylethanolamine antibodies?

    Ann Dermatol Venereol

    (2005)
  • F. Gonzales-Portillo et al.

    Spectrum of antiphospholipid antibodies (aPL) in patients with cerebrovascular disease

    J Stroke Cerebrovasc Dis

    (2001)
  • M.L. Bertolaccini et al.

    Revisiting antiphospholipid antibodies: from targeting phospholipids to phospholipid binding proteins

    Clin Lab

    (2004)
  • S.S. Pierangeli 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)
  • M.L. Bertolaccini et al.

    'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010

    Lupus

    (2011)
  • G.H. Guyatt et al.

    GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

    BMJ

    (2008)
  • G. Lakos et al.

    International consensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies

    Arthritis Rheum

    (2012)
  • D. Keeling et al.

    British Committee for Standards in H. Guidelines on the investigation and management of antiphospholipid syndrome

    Br J Haematol

    (2012)
  • CLSI

    Defining, Establishing, and Verifying Reference Intrevals in the Clinical Laboratory; Approved Guideline

    CLSI document C28-A3c

    (2010)
  • M. Fangtham et al.

    2013 update: Hopkins lupus cohort

    Curr Rheumatol Rep

    (2013)
  • M.D. Lockshin et al.

    Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies

    Arthritis Rheum

    (2012)
  • G. Reber et al.

    In ECAT veritas?

    Lupus

    (2012)
  • F.R. Dembitzer et al.

    Lupus anticoagulant testing: performance and practices by north american clinical laboratories

    Am J Clin Pathol

    (2010)
  • A.E. Gharavi et al.

    Anticardiolipin antibodies: isotype distribution and phospholipid specificity

    Ann Rheum Dis

    (1987)
  • C.E. Weidmann et al.

    Studies of IgG, IgM and IgA antiphospholipid antibody isotypes in systemic lupus erythematosus

    J Rheumatol

    (1988)
  • D. Alarcon-Segovia et al.

    Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients

    Medicine (Baltimore)

    (1989)
  • J.F. Molina et al.

    Variability of anticardiolipin antibody isotype distribution in 3 geographic populations of patients with systemic lupus erythematosus

    J Rheumatol

    (1997)
  • C. Tajima et al.

    Clinical significance of immunoglobulin A antiphospholipid antibodies: possible association with skin manifestations and small vessel vasculitis

    J Rheumatol

    (1998)
  • L.R. Lopez et al.

    Clinical significance of immunoglobulin A versus immunoglobulins G and M anti-cardiolipin antibodies in patients with systemic lupus erythematosus. Correlation with thrombosis, thrombocytopenia, and recurrent abortion

    Am J Clin Pathol

    (1992)
  • J.G. Hanly et al.

    A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus

    Arthritis Rheum

    (1999)
  • G.D. Sebastiani et al.

    Anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Prevalence and clinical associations. European Concerted Action on the Immunogenetics of SLE

    Scand J Rheumatol

    (1999)
  • M. Samarkos et al.

    Clinical significance of IgA anticardiolipin and anti-beta2-GP1 antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome

    Clin Rheumatol

    (2006)
  • Y.M. Shen et al.

    IgA antiphospholipid antibodies are an independent risk factor for thromboses

    Lupus

    (2008)
  • E. Akhter et al.

    Utility of antiphosphatidylserine/prothrombin and IgA antiphospholipid assays in systemic lupus erythematosus

    J Rheumatol

    (2013)
  • K.L. Wong et al.

    Anticardiolipin antibodies and lupus anticoagulant in Chinese patients with systemic lupus erythematosus

    J Rheumatol

    (1991)
  • S. Loizou et al.

    Immunoglobulin class and IgG subclass distribution of anticardiolipin antibodies in patients with systemic lupus erythematosus and associated disorders

    Clin Exp Immunol

    (1992)
  • A. Selva-O'Callaghan et al.

    IgA anticardiolipin antibodies—relation with other antiphospholipid antibodies and clinical significance

    Thromb Haemost

    (1998)
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