Review14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends
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
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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.
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A weak LA results should be considered positive when making clinical decisions.
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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.
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All authors contributed equally to the preparation of this manuscript.