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Cited by 72Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVasculitis and related conditions

Identification of high thrombotic risk triple‐positive antiphospholipid syndrome patients is dependent on anti‐cardiolipin and anti‐β2glycoprotein I antibody detection assays

Open access
Chayoua, W., Kelchtermans, H., Moore, G.W., Musiał, J., Wahl, D., de Laat, B., Devreese, K.M.J.·2018·Journal of Thrombosis and Haemostasis
DOI 10.1111/jth.14261
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Abstract

Essentials Triple‐positivity is associated with a high risk for a first thrombotic event and recurrence. Identification of triple‐positives is dependent on the solid phase assay used. In triple‐positivity, IgM only adds value in thrombotic risk stratification together with IgG. Thrombotic risk in triple‐positive patients with IgM only, depends on the platform.

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective multicenter study of 851 patients, detection of triple-positive antiphospholipid syndrome varied substantially across four commercial aCL/ab2GPI solid-phase assays, but triple-positivity remained associated with thrombosis regardless of assay. Isotype and assay platform affected the strength of association, with positivity for all tested aPL giving the highest odds ratios.

Key findings

  • Among 274 LAC-positive samples, triple-positivity ranged from 106 (39%) by QUANTA Lite ELISA to 146 (53%) by BioPlex 2200. In thrombotic APS patients (n = 258), 202 were LAC-positive, and triple-positives were 118, 101, 111, and 89 for BioPlex 2200, ImmunoCap EliA, ACL AcuStar, and QUANTA Lite ELISA, respectively; BioPlex 2200 vs QUANTA Lite ELISA differed significantly (P = 0.0122).
  • Triple-positivity was statistically correlated with thrombosis independent of the solid-phase assay used, with odds ratios ranging from 4.3 (95% CI, 2.7–6.8) to 5.2 (95% CI, 3.0–8.9); LAC positivity alone had an OR of 3.63 (95% CI, 2.76–4.76). Sensitivity of triple-positivity for thrombosis was low (19–26%), while specificity was high (93–96%).
  • Isotype mattered: IgM triple-positivity was more correlated with thrombosis than IgG triple-positivity for BioPlex 2200, ImmunoCap EliA, and ACL AcuStar, whereas IgG triple-positivity was more strongly correlated for QUANTA Lite ELISA. Positivity for all tested aPL (LAC, aCL IgG, aCL IgM, ab2GPI IgG, ab2GPI IgM) gave the highest ORs, from 8.6 (95% CI, 3.1–24.4) to 28.9 (95% CI, 3.9–212.4).
  • In thrombotic APS, 118 triple-positives were detected by BioPlex 2200, of which 86 were triple-positive across all assays and 32 were negative by all other tested solid-phase assays; most patients with discrepant results had a history of thrombosis.

Methods

  • Retrospective multicenter study including 851 patients from seven European medical centers: 258 thrombotic APS, 204 non-APS thrombosis, 196 autoimmune disease controls, and 193 controls; women classified with obstetric APS were excluded. LAC positivity was determined locally according to ISTH-SSC guidelines.
  • Four commercially available solid-phase assays were tested at one location by a single technician: BioPlex 2200, ImmunoCap EliA, ACL AcuStar, and QUANTA Lite ELISA, measuring aCL IgG/IgM and ab2GPI IgG/IgM. Manufacturer-recommended cut-offs were used after confirmation in 20 healthy volunteers.
  • Differences in aPL titers were assessed with Mann-Whitney U-test; diagnostic efficacy was assessed by sensitivity, specificity, and odds ratios using SPSS 23.0 and MedCalc 17.7.2, with significance at P < 0.05.

Limitations

  • The paper states that thrombotic patients under treatment at blood collection could increase the risk of false-positive LAC tests, and that variation introduced by LAC assays was not assessed, so the presented variation in triple-positivity detection may be underestimated.
  • The paper notes that cut-offs were manufacturer-recommended after confirmation, and the clinical relevance of aCL and/or ab2GPI results below the 99th percentile needs further study.
  • Evident from the text: the reported sample counts are inconsistent across sections (851 included, 833 measured, Table 1 total 853), and the retrospective design does not establish prospective thrombotic outcomes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/jth.14261

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 18 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Agreement of triple-positivity detection by solid phase assays showed discrepancies between 14 (BioPlex 2200 vs ACL AcuStar) and 48 (BioPlex 2200 vs QUANTA Lite ELISA) individuals.

    “Discrepancies varied between 14 (BioPlex Ò 2200 vs. ACL AcuStar Ò ) and 48 (BioPlex Ò 2200 vs. QUANTA Lite ELISA Ò ) individuals.”
    Quote in the paperSubstantial claim
  • Findingown data

    Triple-positivity was statistically correlated with thrombosis, independent of the solid phase assay used to detect aCL and ab2GPI IgG/IgM antibodies.

    “Triple-positivity was statistically correlated with thrombosis, independent of the solid phase assay used to detect aCL and ab2GPI IgG/IgM antibodies (Fig. 2B).”
    • Also stated in: § Discussion · plain
      “However, triple-positivity (irrespective of the isotype) was statistically correlated with thrombosis, independent of the solid phase assay used.”
    • Also stated in: § Discussion · boosted
      “In our cohort, we confirmed the strong correlation between triple-positivity and thrombosis, as triple-positivity was significantly correlated with thrombosis independent of the platform used.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LAC positivity determined by local centers is sufficiently comparable across centers.
  • Findingown data

    Positivity for all tested aPL (LAC, aCL IgG, aCL IgM, ab2GPI IgG and ab2GPI IgM) resulted in the highest OR for thrombosis, ranging from 8.6 (95% CI 3.1-24.4) to 28.9 (3.9-212.4), detected by BioPlex 2200 and ACL AcuStar, respectively.

    “Positivity for all tested aPL (LAC, aCL IgG, aCL IgM, ab2GPI IgG and ab2GPI IgM) resulted in the highest OR for thrombosis, ranging from 8.6 (95% CI, 3.1-24.4)up to 28.9 (3.9-212.4),detected by BioPlex Ò 2200 and ACL AcuStar Ò , respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    Specificity of triple-positivity for thrombosis ranged from 93% (95% CI 90-95%) to 96% (95% CI 93-97%).

    “However, higher specificity for thrombosis was obtained, ranging from 93% (95% CI, 90-95%) up to 96% (95% CI, 93-97%), as shown in Fig. 2(B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Triple-positivity detection was statistically different between BioPlex 2200 and QUANTA Lite ELISA (P=0.0122).

    “By a comparison of two proportions, triple-positivity detection was found to be statistically different between BioPlex Ò 2200 and QUANTA Lite ELISA Ò (P = 0.0122).”
    Quote in the paperSubstantial claim
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 4
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Among 202 LAC-positive thrombotic APS samples, triple-positive counts were 118 (BioPlex 2200), 101 (ImmunoCap EliA), 111 (ACL AcuStar), and 89 (QUANTA Lite ELISA).

    “From these 202 LAC-positive samples 118, 101, 111 and 89 were defined as triple-positive (positivity for LAC, aCL IgG or IgM and ab2GPI IgG or IgM), detected with the solid phase assays: BioPlex Ò 2200, ImmunoCap Ò EliA, ACL AcuStar Ò and QUANTA Lite ELISA Ò , respectively (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sensitivity of triple-positivity for thrombosis was low compared with LAC alone and varied from 19% (95% CI 16-23%) to 26% (95% CI 22-30%) between tested assays.

    “The sensitivity of triple-positivity for thrombosis was low compared with LAC alone and varied from 19% (95% confidence interval [95% CI], 16-23%) up to 26% (95% CI, 22-30%) between the tested assays (Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We confirmed that ORs for all platforms are higher for triple-positivity with concordance of isotype compared with triple-positivity including combinations of aCL and ab2GPI irrespective of isotype, except for one platform (QUANTA Lite ELISA) with lower OR for IgM triple-positivity compared with the OR for triple-positivity irrespective of the isotype.

    “We confirmed that ORs for all platforms are higher for triple-positivity with concordance of isotype compared with triple-positivity including combinations of aCL and ab2GPI irrespective of isotype, except for one platform (QUANTA Lite ELISA Ò ) with lower OR for IgM triple-positivity compared with the OR for triplepositivity irrespective of the isotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Statistical difference in median aPL titers between agreement and disagreement was reached for BioPlex 2200 (P<0.001), ACL AcuStar (P<0.001), and QUANTA Lite ELISA (P=0.0029), but not for ImmunoCap EliA (P=0.5851).

    “Statistical difference was reached for BioPlex Ò 2200 (P < 0.001), ACL AcuStar Ò (P < 0.001) and QUANTA Lite ELISA Ò (P = 0.0029), but not for ImmunoCap Ò EliA (P = 0.5851), as shown in Fig. 1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Other pairwise comparisons of triple-positivity detection were not statistically different, although ACL AcuStar vs QUANTA Lite ELISA almost reached significance (P=0.0586).

    “Other combinations proved not to be statistically different, although the comparison of ACL AcuStar Ò and QUANTA Lite ELISA Ò almost reached statistical significance (P = 0.0586).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These data confirm the high association of triple-positivity with thrombosis and show that the isotype and solid phase assay used to detect aPL affect the association with thrombosis.

    “These data confirm the high association of triplepositivity with thrombosis and show that the isotype and solid phase assay used to detect aPL affect the association with thrombosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The majority of triple-positives for the IgM isotype were also positive for the IgG isotype.

    “However, the majority of triple-positives for the IgM isotype were also positive for the IgG isotype (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In thrombotic APS patients (n=258), 118 triple-positives were detected by BioPlex 2200, of which 86 were triple-positive independent of the solid phase assay used.

    “In patients diagnosed with thrombotic APS (n = 258) 118 triple-positives were detected by BioPlex Ò 2200, of which 86 patients were defined as triple-positive, independent of the solid phase assay used (Table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Patient population and aPL detection method may impact the correlation of thrombosis with triple-positivity and the role of aCL and ab2GPI antibodies in addition to LAC.

    “Patient population and aPL detection method may impact the correlation of thrombosis with triple-positivity and the role of aCL and ab2GPI antibodies in addition to LAC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study showed a strong association between single aPL positivity and thrombosis in pediatric APS patients.

    “On the other hand, another study showed a strong association between single aPL positivity and thrombosis in pediatric APS patients [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We did not assess the variation of triple-positivity detection introduced by LAC assays.

    “In addition, we did not assess the variation of triple-positivity detection introduced by LAC assays.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent studies showed that the risk of thrombotic events increases with the number of positive tests in APS patients and the creation of antibody profiles and test combinations increases the association with thrombosis.

    “Recent studies showed that the risk of thrombotic events increases with the number of positive tests in APS patients and the creation of antibody profiles and test combinations increases the association with thrombosis [7,8,[28][29][30].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Combined positivity for LAC, aCL and ab2GPI antibodies (triple-positivity) is associated with a high risk of both a first thrombotic event and recurrence.

    “Combined positivity for LAC, aCL and ab2GPI antibodies (i.e.triple-positivity) has been shown to be associated with a high risk of both a first thrombotic event and recurrence [8][9][10].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • The quote only partly states this claim.

    Premisecitation

    In an Italian cohort, a statistically significant correlation between LAC and thrombosis was found (OR 4.4; 95% CI 1.5-13.3).

    “A statistically significant correlation between LAC and thrombosis was found (OR, 4.4; 95% CI, 1.5-13.3)[7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Computed risks for thrombosis of LAC positivity and triple-positivity were globally concordant, with the exception of pulmonary embolism.

    “However, computed risks for thrombosis of LAC positivity and triple-positivity were globally concordant, with the exception of pulmonary embolism [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Triple-positivity was a predictor for pulmonary embolism, whereas LAC positivity alone was not.

    “However, triple-positivity was a predictor for pulmonary embolism, whereas LAC positivity alone was not [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

16 of 16

  • The authors state this as an assumption.

    The cut-off calculated by the 99th percentile of a normal population is the best consensus between sensitivity and specificity.

    “We accept that the cut-off calculated by the 99th percentile of a normal population is the best consensus between sensitivity and specificity, and the clinical relevance of aCL and/or ab2GPI results that are below the 99th percentile needs to be further studied [25].”

  • The paper relies on this without support.

    The four selected solid phase assays are representative of commercially available aPL solid phase assays.

    “Commercially available solid phase assays (Table S1) were selected based on frequently used assays in the external quality control program of the ECAT (External quality Control of diagnostic Assays and Tests, Leiden, the Netherlands) and the willingness of manufacturers to collaborate.”

  • The paper relies on this without support.

    LAC positivity determined by local centers is sufficiently comparable across centers.

    “Lupus anticoagulant positivity was determined by the local center, according to the ISTH-SSC (International Society of Thrombosis and Haemostasis-Scientific Standardisation Subcommittee) guideline [15]”
    “In addition, we did not assess the variation of triple-positivity detection introduced by LAC assays.”

  • The paper relies on this without support.

    Samples stored for less than 5 years preserve aPL antibodies.

    “Patients were enrolled within a time-span of 1 year, with patient samples stored for less than 5 years.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • LAC odds ratio differs between Results and Table 5

    Major

    The Results report an odds ratio of 3.63 for LAC positivity, whereas Table 5 reports 3.4 for LAC across every platform; the confidence intervals also differ.

  • Non-thrombotic denominator conflicts with group counts

    Major

    The named non-thrombotic groups contain 196 + 193 = 389 patients, not 582 or 583. Using 389, the reported 17-28 triple-positive patients represent approximately 4.4-7.2%, rather than 2.9-4.8%.

  • Claimed BioPlex-only count exceeds pairwise count

    Minor

    The text claims 32 thrombotic APS patients were BioPlex-positive and negative on every other platform. Table 3 shows only 13 BioPlex-positive, ACL AcuStar-negative patients in the entire population, so the claimed group cannot contain 32.

  • Study population totals differ

    Minor

    The text says 851 patients were included, but Table 1 reports 853. Its group counts also sum to 853.

4 of 4

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Authors
Chayoua, W., Kelchtermans, H., Moore, G. W., Musiał, J., Wahl, D., de Laat, B., & Devreese, K. M. J.
Affiliations
  • Maastricht University Medical Centre (NL)
  • St Thomas' Hospital (GB)
  • Jagiellonian University (PL)
  • Inserm (FR)
  • Ghent University Hospital (BE)
Corresponding author
Devreese, K.M.J.
ORCID
Venue
Journal of Thrombosis and Haemostasis
Publisher
Elsevier BV
Published
2018-10
Volume
16
Issue
10
Pages
2016-2023
ISSN
1538-7836 (ISSN-L)
DOI
10.1111/jth.14261
OpenAlex
W2885614240
Semantic Scholar
fdcd0a8d376816c97a9705952f090d04d9d9dc09
Cited by
71
References
32
Citations by year
2026: 6 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 6 · 2019: 8 · 2018: 1
FWCI
5.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thrombosis and Haemostasis (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
  • Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • Bio-Rad Laboratories
  • ThermoFisher/Phadia
  • Werfen/Instrumentation Laboratory
  • Inova Diagnostics
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
Keywords
antiphospholipid syndrome, triple positivity, lupus anticoagulant, anticardiolipin antibodies, anti-beta2-glycoprotein I antibodies, thrombosis risk, thrombosis risk stratification
MeSH terms
Adult, Aged, Aged, 80 and over, Enzyme-Linked Immunosorbent Assay, Europe, Female, Humans, Immunoglobulin G, Immunoglobulin M, Immunoassay, Male, Middle Aged, Predictive Value of Tests, Prognosis, Retrospective Studies, Risk Factors, Thrombosis, Biomarkers, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome, Antibodies, Antiphospholipid, Antibodies, Anticardiolipin, Risk Assessment, beta 2-Glycoprotein I, Young Adult

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