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Cited by 4Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsHeparin-Induced Thrombocytopenia and Thrombosis

Comparison of different algorithms for lupus anticoagulant detection: a single-center experience

Open access
Apipongrat, Dollapak, Lamool, Rattapan, Arnutti, Pasra, Ruangpratheep, Chetana, Chantkran, Wittawat·2024·Research and Practice in Thrombosis and Haemostasis
DOI 10.1016/j.rpth.2024.102333PMC PMC10885790
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Abstract

Background: The laboratory tests for lupus anticoagulant (LA) detection comprise complex and multistep coagulation testing procedures. There is no established gold standard assay or direct comparison of algorithms as recommended by different guidelines. Objectives: This study aimed to evaluate and compare the LA detection performance of different laboratory algorithms suggested by the existing guidelines. Methods: The routine LA test data of 1801 plasma samples, including 188 LA-positive and 1613 LA-negative samples, were re-evaluated by applying the algorithms recommended by existing guidelines and were interpreted using various methods. Diagnostic performance indices for each LA detection algorithm were compared with those of the other algorithms. The efficacies of the different interpretation methods were analyzed to determine a suitable interpretation methodology for each assay. Results: The diagnostic performance for detecting LA varied by the algorithm and method of interpretation used. All laboratory algorithms displayed exceptional diagnostic performance with all diagnostic parameters of >90.0%. Nearly perfect agreement was observed in all algorithms when compared to the Clinical and Laboratory Standards Institute 2014 guideline interpreted by normalized screen-to-confirm ratio (NSCR) and mixing test-specific cutoff (MTC), as a reference assay (Cohen's kappa coefficient, >0.90 [range, 0.94-1.00]). A combination of the index of circulating anticoagulant and NSCR was optimal for interpreting the activated partial thromboplastin time-based test, whereas a combination of the MTC and NSCR was suitable for the diluted Russell's viper venom time-based test. Conclusion: All laboratory algorithms showed equivalent diagnostic performance. Establishing the best method of interpretation for each assay is recommended to improve LA detection performance.

AI snapshot

Written from the paper’s full text.

TL;DR

This single-center retrospective study re-evaluated routine lupus anticoagulant (LA) testing data from 1801 nonanticoagulated patients against algorithms from ISTH SSC 2009/2020, BCSH 2012, and CLSI 2014 guidelines. All algorithms showed high diagnostic performance (>90% for most parameters) and near-perfect agreement with the CLSI 2014 reference, but the optimal interpretation method differed by assay.

Key findings

  • Among 1801 plasma samples (188 LA-positive, 1613 LA-negative by the reference algorithm), all laboratory algorithms had >90.0% PPA/sensitivity, NPA/specificity, PPV, NPV, and ORA/accuracy; agreement with the CLSI 2014 NSCR+MTC reference was nearly perfect (Cohen’s kappa >0.90; range 0.94–1.00).
  • For aPTT-based assays, the best interpretation combination was ICA plus NSCR (ORA 57.0%; PPA 59.3%; NPA 52.9%), whereas for dRVVT-based assays it was MTC plus NSCR (ORA 91.3%; PPA 86.3%; NPA 95.7%).
  • ISTH SSC 2020 algorithms improved PPA versus ISTH SSC 2009 (median PPA 100.0% vs 93.6%) and identified 4 additional persistently weakly LA-positive patients with a “negative mixing but positive confirmatory tests” pattern.
  • Using 97.5th vs 99.0th percentile cutoffs increased median PPA (97.3% vs 93.6%) but lowered median PPV (95.6% vs 98.9%); dRVVT-based assays had AUCs >0.90, while aPTT-based assays averaged an AUC of 0.83.

Methods

  • Retrospective single-center study at Phramongkutklao Hospital, Bangkok, Thailand (January 2020–December 2022); 1938 samples were screened, 137 excluded, leaving 1801 nonanticoagulant patients clinically investigated for APS, plus 120 healthy subjects for local reference intervals and cutoffs.
  • Routine LA data were re-evaluated using algorithms recommended by ISTH SSC 2009, BCSH 2012, CLSI 2014, and ISTH SSC 2020, with CLSI 2014 interpreted by NSCR and MTC as the reference algorithm.
  • Diagnostic performance was assessed with PPA, NPA, PPV, NPV, ORA, McNemar’s test, Cohen’s kappa, and AUC analysis; optimal interpretation methods combined mixing-test parameters (ICA or MTC) with confirmatory parameters (%Correct, SCR, or NSCR).

Limitations

  • The authors state that only one aPTT and one dRVVT reagent were used, that the ellagic acid–based aPTT reagents may be less sensitive to LA, and that anticoagulated patients were excluded, so drug interference was not evaluated.
  • The authors also state that costs and labor associated with each algorithm were not evaluated, and larger studies are needed to assess clinical outcomes.
  • Evident from the text: this was a single-center retrospective study without a true gold standard assay, and the reference algorithm itself was a guideline-based comparator rather than an independent diagnostic standard.

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

Integrity signals

Registry

Crossref · 10.1016/j.rpth.2024.102333

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 58 cited sources checked · 22 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Using mixing tests interpreted with ICA demonstrates superior specificity as there are few false positives of inhibition by non-LA causes in cases of positive LA screening test results.

    “In contrast, using mixing tests interpreted with ICA demonstrates superior specificity as there are few false positives of inhibition by non-LA causes in cases of positive LA screening test results [16].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Kumano, 2019, Ruling out lupus anticoagulants with mixing test-specific cutoff assessment and the index of circulating anticoagulant, Res Pract Thromb Haemost source
  • Findingown data

    When the ISTH SSC 2020 guideline was employed, a maximum of an additional 8 patients classified LA-negative by the reference algorithm were considered LA-positive with a "negative mixing but positive confirmatory tests" pattern.

    “Interestingly, when the ISTH SSC 2020 guideline [20] was employed, a maximum of an additional 8 patients who were classified LA-negative by the reference algorithm were considered LA-positive with a “negative mixing but positive confirmatory tests” pattern.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Devreese, 2020, Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: update of the guidelines for lupus anticoagulant detection and interpretation, J Thromb Haemost source
  • Premisecitation

    Technical and practical issues, including test algorithms, interpretation parameters, cutoff values, and methods of interpretation, are problematic in many laboratories.

    “Technical and practical issues, including test algorithms, interpretation parameters, cutoff values, and methods of interpretation, are problematic in many laboratories [6,8,9,21].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [6] Moore, 2014, Recent guidelines and recommendations for laboratory detection of lupus anticoagulants, Semin Thromb Hemost source
    • cites [8] Moore, 2014, Commonalities and contrasts in recent guidelines for lupus anticoagulant detection, Int J Lab Hematol source
    • cites [9] Moore, 2016, Current controversies in lupus anticoagulant detection, Antibodies (Basel) source
    • cites [21] Cohen, 2019, J Thromb Haemost source
  • Findingown data

    Applying algorithms following the updated ISTH SSC 2020 guideline improved PPA compared with the previous 2009 guideline (median PPA, 93.6% vs 100.0%).

    “It was revealed that the PPA was clearly improved by applying algorithms following the updated ISTH SSC 2020 guideline compared with the previous guideline in 2009 (median PPA, 93.6% vs 100.0%) (Table 1).”
    • Also stated in: § Discussion · hedged
      “Our results indicated that employing the algorithms based on the ISTH SSC 2020 recommendations resulted in significantly improved PPA when compared to their previous version.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Devreese, 2020, Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: update of the guidelines for lupus anticoagulant detection and interpretation, J Thromb Haemost source
  • Findingcitation

    Patients were classified into LA-positive (n = 188) and LA-negative (n = 1613) based on LA test results interpreted by NSCR and MTC under the CLSI 2014 reference algorithm.

    “The patients were classified into 2 groups based on their LA test results interpreted by using NSCR and MTC under the CLSI 2014 guidelines [13] (the reference algorithm): LA-positive (n = 188) and LA-negative (n = 1613).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 2014

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

  • Classified as probably not a substantial claim. 24
  • May combine two claims. 18

  • Classified as probably not a substantial claim.

    Premisecitation

    LA detection laboratory tests comprise complex and multistep coagulation testing procedures, including screening, confirmatory, and mixing tests.

    “Laboratory tests for LA detection comprise complex and multistep coagulation testing procedures, including screening, confirmatory, and mixing tests [[11], [12], [13]], and heterogeneity in these is an important cause of interlaboratory variation.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [11] Pengo, 2009, J Thromb Haemost source
    • cites [12] Keeling, 2012, Guidelines on the investigation and management of antiphospholipid syndrome, Br J Haematol source
    • cites [13] 2014

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

  • May combine two claims.

    Premisereasoning

    There is currently no established gold standard assay or reference plasma for LA detection.

    “As a result, there are currently no established gold standard assays or reference plasmas for LA detection [[6], [7], [8], [9], [10]].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [6] Moore, 2014, Recent guidelines and recommendations for laboratory detection of lupus anticoagulants, Semin Thromb Hemost source

      The Abstract says that an absence of gold standards complicates LA detection, and “Which Screening Tests to Use and How Many to Use?” explicitly notes the lack of a gold-standard LA detection method. The paper does not establish the more specific claim that no reference plasma exists; its “Ratios” section discusses variation among normal pooled plasmas instead. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [7] Moore, 2017, Application of different lupus anticoagulant diagnostic algorithms to the same assay data leads to interpretive discrepancies in some samples, Res Pract Thromb Haemost source
    • cites [8] Moore, 2014, Commonalities and contrasts in recent guidelines for lupus anticoagulant detection, Int J Lab Hematol source
    • cites [9] Moore, 2016, Current controversies in lupus anticoagulant detection, Antibodies (Basel) source
    • cites [10] Devreese, 2012, Standardization of antiphospholipid antibody assays. Where do we stand?, Lupus source

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

    Premisecitation

    Mixing tests are performed to improve the specificity of LA detection and rule out other causes of prolonged clotting time, including coagulation factor deficiency, anticoagulant use, and coagulation factor inhibitors.

    “Mixing tests are performed to improve the specificity of LA detection and rule out other causes of prolonged clotting time (CT), including coagulation factor deficiency, anticoagulant use, and coagulation factor inhibitors [15,16].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] Moore, 2020, Mixing studies for lupus anticoagulant: mostly no, sometimes yes, Clin Chem Lab Med source
    • cites [16] Kumano, 2019, Ruling out lupus anticoagulants with mixing test-specific cutoff assessment and the index of circulating anticoagulant, Res Pract Thromb Haemost source

      The Introduction says mixing tests help distinguish inhibitors from factor deficiencies, and the Discussion reports that ICA improves specificity when investigating non-LA causes of prolonged clotting time. But the Discussion also says mixing tests are not specific for LA-induced inhibition: factor inhibitors and direct anticoagulants can affect their results, and confirmatory tests are needed. Thus the source does not support saying mixing tests rule out all the listed causes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In tests with absence of a gold standard assay, PPA, NPA, and ORA are recommended in place of sensitivity, specificity, and %accuracy.

    “However, in tests with absence of a gold standard assay, the terms positive percent agreement (PPA), negative percent agreement (NPA), and overall rate of agreement (ORA) were recommended in place of sensitivity, specificity, and %accuracy, respectively.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Obermeier, 2016, Enabling precision medicine with digital case classification at the point-of-care, EBioMedicine source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    Because no single assay is sensitive to all LA antibodies, at least 2 coagulation tests based on different assay principles are recommended for LA detection.

    “Because there is no single assay sensitive to all LA antibodies, at least 2 coagulation tests based on different assay principles are recommended for LA detection [[11], [12], [13]].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [11] Pengo, 2009, J Thromb Haemost source
    • cites [12] Keeling, 2012, Guidelines on the investigation and management of antiphospholipid syndrome, Br J Haematol source
    • cites [13] 2014

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Various interpretation indices, including %Correct, SCR, and NSCR, are suggested to determine the presence of LA in phospholipid-dependent assays.

    “Various interpretation indices, including percentage of correction (%Correct), screen-to-confirm ratio (SCR), and normalized SCR (NSCR), are suggested to determine the presence of LA in these phospholipid-dependent assays [[11], [12], [13]].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [11] Pengo, 2009, J Thromb Haemost source
    • cites [12] Keeling, 2012, Guidelines on the investigation and management of antiphospholipid syndrome, Br J Haematol source

      The ‘Lupus anticoagulant testing’ section recommends percentage correction or a normalized screen-to-confirm ratio for interpreting LA tests. It does not recommend an unnormalized screen-to-confirm ratio (SCR) as a separate index; it specifies that screen and confirm results should first be expressed as ratios against a normal plasma pool. No page number is available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [13] 2014

      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

    ISTH SSC 2020 guideline recommends performing the mixing and confirmatory tests simultaneously if the screening test shows the presence of LA.

    “In contrast, the ISTH SSC 2020 guideline recommends performing the mixing and confirmatory tests simultaneously if the screening test shows the presence of LA [20].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Devreese, 2020, Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: update of the guidelines for lupus anticoagulant detection and interpretation, J Thromb Haemost source

      Section 3.4, “Three step procedure” (page not provided), says that performing the mixing and confirmatory steps at the same time after a suggestive screening test can be helpful. It does not explicitly recommend simultaneous testing, so the claim states the guidance more strongly than the source does. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    MTC and ICA can be calculated and employed as interpretation indices for mixing tests.

    “In addition, the mixing test–specific cutoff (MTC) and index of circulating anticoagulant (ICA) can be calculated and employed as interpretation indices for the mixing tests [[15], [16], [17], [18], [19]].”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [15] Moore, 2020, Mixing studies for lupus anticoagulant: mostly no, sometimes yes, Clin Chem Lab Med source
    • cites [16] Kumano, 2019, Ruling out lupus anticoagulants with mixing test-specific cutoff assessment and the index of circulating anticoagulant, Res Pract Thromb Haemost source
    • cites [17] Depreter, 2016, Differences in lupus anticoagulant final conclusion through clotting time or Rosner index for mixing test interpretation, Clin Chem Lab Med source
    • cites [18] Kumano, 2018, Lupus anticoagulant mixing tests for multiple reagents are more sensitive if interpreted with a mixing test-specific cut-off than index of circulating anticoagulant, Res Pract Thromb Haemost source
    • cites [19] Moore, 2016, Mixing test specific cut-off is more sensitive at detecting lupus anticoagulants than index of circulating anticoagulant, Thromb Res source

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

    Premisecitation

    The LA-sensitive aPTT assay can be used as a secondary test for LA detection.

    “The diluted Russell’s viper venom time (dRVVT) assay is the first recommended test for detecting LA due to its high sensitivity and specificity [14], while the LA-sensitive activated partial thromboplastin time (aPTT) assay can be used as a secondary test [[11], [12], [13], [14]].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [11] Pengo, 2009, J Thromb Haemost source
    • cites [12] Keeling, 2012, Guidelines on the investigation and management of antiphospholipid syndrome, Br J Haematol source
    • cites [13] 2014

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

    • cites [14] Favaloro, 2019, The Russell viper venom time (RVVT) test for investigation of lupus anticoagulant (LA), Am J Hematol source

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

    Premisecitation

    Several studies have recommended the use of MTC over ICA as it offers greater sensitivity in detecting in vitro inhibition of LA.

    “For the interpretation of the LA mixing test result, several studies have recommended the use of MTC over ICA as it offers greater sensitivity in detecting in vitro inhibition of LA [[17], [18], [19]].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [17] Depreter, 2016, Differences in lupus anticoagulant final conclusion through clotting time or Rosner index for mixing test interpretation, Clin Chem Lab Med source
    • cites [18] Kumano, 2018, Lupus anticoagulant mixing tests for multiple reagents are more sensitive if interpreted with a mixing test-specific cut-off than index of circulating anticoagulant, Res Pract Thromb Haemost source
    • cites [19] Moore, 2016, Mixing test specific cut-off is more sensitive at detecting lupus anticoagulants than index of circulating anticoagulant, Thromb Res source

  • May combine two claims.

    Premisecitation

    Although MTC provides greater sensitivity for the detection of LA, especially when weak LA is present, it has a greater tendency to produce false-positive results than ICA.

    “Although MTC provides greater sensitivity for the detection of LA, especially when weak LA is present, it has a greater tendency to produce false-positive results than ICA [16,18,19].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [16] Kumano, 2019, Ruling out lupus anticoagulants with mixing test-specific cutoff assessment and the index of circulating anticoagulant, Res Pract Thromb Haemost source
    • cites [18] Kumano, 2018, Lupus anticoagulant mixing tests for multiple reagents are more sensitive if interpreted with a mixing test-specific cut-off than index of circulating anticoagulant, Res Pract Thromb Haemost source

      The Results and Discussion report higher MTC sensitivity than ICA for detecting LA, including cases that mixing-test dilution could otherwise cause to appear negative. But the reported comparison uses samples positive for LA in undiluted plasma; it does not establish that MTC produces more false-positive results than ICA. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [19] Moore, 2016, Mixing test specific cut-off is more sensitive at detecting lupus anticoagulants than index of circulating anticoagulant, Thromb Res source

  • May combine two claims.

    Findingown data

    Among the 188 LA-positive cases, 67.0% were LA-positive by dRVVT alone, 7.5% by aPTT alone, and 25.5% by both dRVVT and aPTT.

    “Among the 188 LA-positive cases, 67.0% (126 of 188), 7.5% (14 of 188), and 25.5% (48 of 188) were considered LA-positive by dRVVT alone, aPTT alone, and both dRVVT and aPTT, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the present study, only 20.7% of APS patients were triple-positive APS, whereas 79.3% were non-triple-positive APS.

    “In the present study, we found that only 20.7% (57 of 275) of these patients were triple-positive APS, whereas the remaining 79.3% (218 of 275) were considered non–triple-positive APS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number of cases requiring complete 3-step testing was less when using the 99.0th percentile cutoff than when using the 97.5th percentile cutoff, though not statistically significant (P = .448; average number of cases requiring complete 3-step testing, 185 vs 199 cases).

    “Although it did not reach statistical significance, the number of cases requiring complete 3-step testing was less when using the 99.0th percentile cutoff than when using the 97.5th percentile cutoff (P = .448; average number of cases requiring complete 3-step testing, 185 vs 199 cases) (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Approximately 56.4% of LA-positive patients experienced arterial or venous thrombosis, and 16.0% presented with obstetrical and gynecological comorbidities.

    “Approximately 56.4% of LA-positive patients (106 of 188) experienced arterial or venous thrombosis, whereas 16.0% (30 of 188) of the patients presented with obstetrical and gynecological comorbidities.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only 3 patients had positive LA mixing test results but negative confirmatory test results; they demonstrated clearly negative results when the tests were repeated after 12 weeks.

    “Only 3 patients who had positive LA mixing test results but negative confirmatory test results were observed; however, they demonstrated clearly negative results when the tests were repeated after 12 weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Although different positive patterns of aPTT and dRVVT tests were observed in some samples, all cases demonstrated consistent positive results whether the 97.5th or 99.0th percentile cutoffs were used.

    “Although the different positive pattern of aPTT and dRVVT tests was observed in some samples, all cases demonstrated consistent positive results whether the 97.5th or 99.0th percentile cutoffs were used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among LA-positive patients, 52.7% had positive aβ2-GPI and 31.4% had positive aCL results.

    “As expected, among the LA-positive patients, 52.7% (99 of 188) and 31.4% (59 of 188) had positive aβ2-GPI and aCL results, respectively.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CLSI 2014 guideline reprioritizes the test order to screen-confirm-mix to reduce false negatives by mixing tests.

    “While the ISTH SSC 2009 and the BCSH 2012 guidelines suggest that the screening test should be followed by the mixing study and then the confirmatory test (screen-mix-confirm), the CLSI 2014 guideline reprioritizes the test order to screen-confirm-mix to reduce false negatives by mixing tests [[11], [12], [13],20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11], [12], [13],20

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

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The remaining 1801 plasma samples from nonanticoagulant patients clinically suspected of APS were analyzed.

    “The remaining 1801 plasma samples obtained from nonanticoagulant patients clinically suspected of being investigated for APS were analyzed (Figure 1).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    ISTH SSC 2009 and BCSH 2012 guidelines suggest that the screening test should be followed by the mixing study and then the confirmatory test (screen-mix-confirm).

    “While the ISTH SSC 2009 and the BCSH 2012 guidelines suggest that the screening test should be followed by the mixing study and then the confirmatory test (screen-mix-confirm), the CLSI 2014 guideline reprioritizes the test order to screen-confirm-mix to reduce false negatives by mixing tests [[11], [12], [13],20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11], [12], [13],20

      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

    The dRVVT assay is the first recommended test for detecting LA due to its high sensitivity and specificity.

    “The diluted Russell’s viper venom time (dRVVT) assay is the first recommended test for detecting LA due to its high sensitivity and specificity [14], while the LA-sensitive activated partial thromboplastin time (aPTT) assay can be used as a secondary test [[11], [12], [13], [14]].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Favaloro, 2019, The Russell viper venom time (RVVT) test for investigation of lupus anticoagulant (LA), Am J Hematol source

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

    Premisecitation

    ISTH SSC 2009 and 2020 guidelines advise using 99.0th percentile cutoffs, whereas BCSH 2012 and CLSI 2014 guidelines advise using 97.5th percentile cutoffs.

    “The ISTH SSC 2009 and 2020 guidelines advise using 99.0th percentile cutoffs, whereas the BCSH 2012 and the CLSI 2014 guidelines advise using 97.5th percentile cutoffs [[11], [12], [13],20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11], [12], [13],20

      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

    The sensitivity of ellagic acid-based reagents to LA is comparable with that of other silica-based reagents.

    “Although the sensitivity of ellagic acid-based reagents to LA is comparable with that of other silica-based reagents, the commercial reagents employed in this study are potentially less sensitive to LA [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Kumano, 2012, APTT reagent with ellagic acid as activator shows adequate lupus anticoagulant sensitivity in comparison to silica-based reagent, J Thromb Haemost source

  • May combine two claims.

    Interpretationown data

    Applying the updated ISTH SSC 2020 guideline not only improves sensitivity but also increases the chance of detecting patients with weak LA presence by reducing the chance of a false negative result involving the mixing step.

    “These findings suggest that applying this updated guideline not only improves sensitivity but also increases the chance of detecting patients with weak LA presence by reducing the chance of a false negative result involving the mixing step.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Differences in reagent composition and concentration of phospholipids between various types of reagents are considered to be the cause of interreagent variation in LA sensitivity.

    “Differences in reagent composition and concentration of phospholipids between various types of reagents are considered to be the cause of interreagent variation in LA sensitivity [30,31].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Brandt, 1987, The sensitivity of different coagulation reagents to the presence of lupus anticoagulants, Arch Pathol Lab Med

      Not checked in the free run.

    • cites [31] Kumano, 2012, APTT reagent with ellagic acid as activator shows adequate lupus anticoagulant sensitivity in comparison to silica-based reagent, J Thromb Haemost source

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

    Premisecitation

    A previous study recommended the use of MTC for the dRVVT-based mixing test and ICA for the aPTT-based mixing test to achieve the highest sensitivity.

    “a previous study recommended the use of MTC for the dRVVT-based mixing test and ICA for the aPTT-based mixing test to achieve the highest sensitivity [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Martinuzzo, 2012, New guidelines for lupus anticoagulant: sensitivity and specificity of cut-off values calculated with plasmas from healthy controls in mixing and confirmatory tests, Int J Lab Hematol source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study did not evaluate the costs and labor associated with each algorithm and guideline.

    “Nevertheless, we did not evaluate the costs and labor associated with each algorithm and guideline in our study, so further research comparing the cost-effectiveness of these guidelines is needed to draw a firm conclusion.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The NSCR is recommended by the existing guidelines as a parameter for interpreting phospholipid-dependent assays because it can reduce both interlaboratory and interreagent variations.

    “The NSCR is recommended by the existing guidelines as a parameter for interpreting phospholipid-dependent assays [[11], [12], [13],20] because it can reduce both interlaboratory and interreagent variations [25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11], [12], [13],20

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

    • cites [25] Ling, 2022, Interpretation of clot-based lupus anticoagulant assays—normalizing clotting time against different denominators, Int J Lab Hematol source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The analyzed data were only applied to the results of clinical samples with 1 aPTT and 1 dRVVT reagent.

    “First, the analyzed data were only applied to the results of clinical samples with 1 aPTT and 1 dRVVT reagent.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The aPTT reagent pair used in this study (Actin FSL for screening and Actin FS for confirmation) is one of only a few paired aPTT reagents offered by commercial manufacturers, with most manufacturers of silica-based aPTT assays offering an LA-sensitive reagent, but not providing an LA insensitive silica-based paired reagent.

    “On the other hand, the aPTT reagent pair used in this study (Actin FSL for screening and Actin FS for confirmation) is one of only a few paired aPTT reagents offered by commercial manufacturers, with most manufacturers of silica-based aPTT assays offering an LA-sensitive reagent, but not providing an LA insensitive silica-based paired reagent [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Favaloro EJ, Dean E, Arunachalam S. Variable performance of lupus anticoagulant testing: the Australasian/Asia-Pacific experience. Semin Thromb Hemost 2023; in press. https://doi.org/10.1055/s-0043-1776406 source

  • May combine two claims.

    Study design and conductreasoning

    The samples of patients who received anticoagulants were excluded, so the interfering effect of drugs on the diagnostic performance of LA testing was not evaluated.

    “Second, as the samples of patients who received anticoagulants were excluded, the interfering effect of the drugs on the diagnostic performance of LA testing was not evaluated in our study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MTC was optimal for interpreting the dRVVT-based test results, while using ICA for interpreting the aPTT-based mixing tests yielded the most precise results as it offered better positive agreement rates with the highest rate of overall agreements when compared with the reference assay.

    “Similarly, our results demonstrated that MTC was optimal for interpreting the dRVVT-based test results, while using ICA for interpreting the aPTT-based mixing tests yielded the most precise results as it offered better positive agreement rates with the highest rate of overall agreements when compared with the reference assay.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The ICA was considered the most robust approach to express the LA mixing test results.

    “The ICA was considered the most robust approach to express the LA mixing test results [26]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Tripodi, 2007, Laboratory testing for lupus anticoagulants: a review of issues affecting results, Clin Chem source

  • May combine two claims.

    Premisecitation

    Compared with dRVVT, aPTT is a more complex assay involving multiple enzymatic steps and may be influenced by physiologic and pathologic factors unrelated to the inhibition of LA.

    “Compared with dRVVT, aPTT is a more complex assay involving multiple enzymatic steps and may be influenced by physiologic and pathologic factors unrelated to the inhibition of LA [14,29].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Favaloro, 2019, The Russell viper venom time (RVVT) test for investigation of lupus anticoagulant (LA), Am J Hematol source
    • cites [29] Winter, 2017, Coagulation testing in the core laboratory, Lab Med source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    120 normal plasma samples were used to establish and validate the specific local RIs and cutoff values.

    “Additionally, 120 normal plasma samples were used to establish and validate the specific local RIs and cutoff values.”
    Quote in the paperSubstantial claim
36 of 36

  • The paper relies on this without support.

    No study has compared the testing algorithms recommended by the ISTH SSC 2009, BCSH 2012, CLSI 2014, and ISTH SSC 2020 guidelines in terms of LA diagnostic performance.

    “Furthermore, no study has compared the testing algorithms recommended by each of the abovementioned guidelines in terms of their LA diagnostic performance.”

  • The paper relies on this without support.

    There is no gold standard assay available for LA detection.

    “Although the current guidelines have helped standardize the LA testing process and interpretation, there is no gold standard assay available for LA detection.”

  • The paper relies on this without support.

    There is a lack of empirical data to support any strong evidence-based recommendations.

    “Furthermore, there is a lack of empirical data to support any strong evidence-based recommendations.”
3 of 3

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.

  • The stated ORA formula does not produce the reported ORA

    Minor

    The stated formula gives (95.7 + 99.9) / 1801 × 100 = 10.9%, not the 99.4% ORA reported for the first algorithm in Table 1. The table appears to use overall agreement based on case counts instead.

  • Identical classifications have different kappa coefficients

    Minor

    The two CLSI 2014 rows each report 188 positive cases, comprising the same 184 reference-positive and four reference-negative cases. Against the same reference results, their Cohen's kappa coefficients must be identical, but the table reports 0.98 and 0.95.

  • Specificity increases despite an additional false positive

    Minor

    Both ISTH SSC 2009 rows have 172 reference-positive cases among their positive results. With the same 1613 reference-negative samples, the row with three reference-negative positives cannot have higher specificity than the row with two; the reported values are reversed.

3 of 3

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Related

Authors
Apipongrat, D., Lamool, R., Arnutti, P., Ruangpratheep, C., & Chantkran, W.
Affiliations
  • Phramongkutklao Hospital (TH)
  • Phramongkutklao College of Medicine
Corresponding author
Chantkran, Wittawat
ORCID
Venue
Research and Practice in Thrombosis and Haemostasis
Publisher
Elsevier BV
Published
2024-01
Volume
8
Issue
1
Pages
102333
ISSN
2475-0379 (ISSN-L)
DOI
10.1016/j.rpth.2024.102333
PMC
PMC10885790
OpenAlex
W4391344566
Semantic Scholar
55e52d27bf50b1791b68c473413a5b0602ffd544
Cited by
4
References
31
Citations by year
2026: 2 · 2025: 2
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Research and Practice in Thrombosis and Haemostasis (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Surgery › Heparin-Induced Thrombocytopenia and Thrombosis
Keywords
lupus anticoagulant, diagnostic performance, activated partial thromboplastin time, Russell's viper venom time, assay interpretation, antiphospholipid syndrome

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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Statistics and arithmetic are recomputed, not judged.

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