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Cited by 36Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVasculitis and related conditions

Clinical Relevance of Isolated Lupus Anticoagulant Positivity in Patients with Thrombotic Antiphospholipid Syndrome

Yin, Dongmei, de Groot, Philip G., Ninivaggi, Marisa, Devreese, Katrien M. J., de Laat, Bas·2021·Thrombosis and Haemostasis
DOI 10.1055/a-1344-4271
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Abstract

Background Patients positive for all three types of antiphospholipid antibodies (aPLs; triple positivity) have been identified for having a high risk for thrombotic events. However, the clinical significance of isolated lupus anticoagulant (LAC) positivity is debated. Objectives To investigate the clinical relevance of isolated LAC. Methods A total of 456 patients were enrolled in this study; 66 antiphospholipid syndrome patients and 390 control patients. The control group consisted of autoimmune patients (n = 91), patients with thrombosis but without aPLs (n = 127), and normal controls (n = 172). LAC, anticardiolipin (anti-CL), and anti-β2 glycoprotein I (anti-β2GPI) immunoglobulin G (IgG) and immunoglobulin M (IgM) were determined according to the International Society on Thrombosis and Haemostasis (ISTH) guidelines. Anti-CL and anti-β2GPI were measured by four different solid-phase platforms to overcome variability between test systems. The noncriteria IgA anti-CL and anti-β2GPI, antidomain I of β2GPI IgG, and antiphosphatidylserine/prothrombin antibodies (anti-PS/PT) IgG and IgM were detected according to the ISTH guidelines for solid-phase assays. Results In total, 70 patients were positive for LAC, of which 44 were negative for both anti-β2GPI and anti-CL antibodies. We found that isolated LAC proved to be strongly associated with vascular thrombosis (odds ratio [OR]: 7.3; 95% confidence interval [CI]: 3.3–16.1), even better than triple-positive samples (OR: 4.3; 95% CI: 1.6–12.2). The titers of the anti-PS/PT IgG and IgM were significantly higher in triple-positivity samples compared with samples with isolated LAC positivity. The majority of single LAC positives were anti-PS/PT-negative. We observed that LAC positivity was weaker in isolated LAC-positive patients compared with LAC activity in triple-positive patients. Conclusion Isolated LAC was highly associated with thrombosis. The presence of anti-PS/PT antibodies could not explain LAC positivity in isolated LAC. Isolated LAC showed a weaker LAC activity compared with triple-positive patients.

AI snapshot

Written from the paper’s full text.

TL;DR

In a cohort of 456 patients, isolated lupus anticoagulant (LAC) positivity was strongly associated with thrombosis, with a higher odds ratio than triple positivity. Isolated LAC also showed weaker LAC activity and was mostly negative for anti-PS/PT antibodies, suggesting an unidentified target antigen.

Key findings

  • Among 70 LAC-positive patients, 44 were negative for anti-CL and anti-β2GPI IgG/IgM on all four solid-phase platforms; isolated LAC was associated with thrombosis (OR: 7.3; 95% CI: 3.3–16.1), higher than triple positivity (OR: 4.3; 95% CI: 1.6–12.2). After excluding triple-positive samples, isolated LAC remained higher (OR: 7.9; 95% CI: 3.6–17.5) than triple positivity after excluding isolated LAC (OR: 5.3; 95% CI: 1.9–14.8).
  • Anti-PS/PT IgG and IgM titers were significantly higher in triple-positive samples than in isolated LAC samples: median anti-PS/PT IgG 13.0 U/mL (IQR: 6.2–77.9) vs. 6.8 U/mL (IQR: 5.9–8.6), p = 0.006; median anti-PS/PT IgM 77.3 U/mL (IQR: 34.4–324.5) vs. 13.0 U/mL (IQR: 8.3–20.5), p < 0.0001.
  • Most isolated LAC samples were anti-PS/PT-negative: only 8 of 44 were positive for anti-PS/PT antibodies, leaving 36 with LAC activity independent of β2GPI or prothrombin as cofactor; none of the isolated LAC samples were positive for anti-domain I antibodies.
  • Isolated LAC showed weaker LAC activity than triple positivity: dRVVT confirmation ratio 1.39 (1.33–1.50) vs. 1.60 (1.38–1.96), p = 0.007; aPTT screen ratio 1.38 (1.21–1.55) vs. 1.80 (1.34–2.62), p = 0.004; dRVVT mix ratio 1.17 (1.13–1.27) vs. 1.35 (1.21–1.66), p = 0.0005; aPTT mix ratio 1.07 (1.00–1.16) vs. 1.27 (1.17–1.89), p < 0.0001. In the isolated LAC group, 98% were dRVVT-positive and only one patient was positive in the aPTT system only.

Methods

  • Cohort of 456 patients: 66 APS patients, 91 autoimmune disease controls, 127 non-APS thrombosis patients, and 172 normal controls. Mean age 44 years (SD 13); 73% female.
  • LAC determined by STA-R Evolution according to ISTH guidelines using dRVVT and a sensitive aPTT; anti-CL and anti-β2GPI IgG/IgM measured by four solid-phase platforms (HemosIL AcuStar, BioPlex 2200, Phadia, QUANTA Lite ELISA); noncriteria IgA anti-CL/anti-β2GPI, anti-domain I IgG, and anti-PS/PT IgG/IgM also measured.
  • Associations calculated as odds ratios with 95% confidence intervals; Chi-squared test for prevalence comparisons and Mann–Whitney U-test for continuous variables; p < 0.05 considered significant.

Limitations

  • The paper does not state a formal limitations section.
  • Evident from the text: the study reports associations with a history of thrombosis, so causality cannot be established; samples came from a single center (Ghent University Hospital), and the target antigen responsible for isolated LAC remains unidentified, with further studies needed.
  • The authors note that weak LAC positives may fluctuate and low-positive results might not be persistently positive, so positive results must be repeated after 12 weeks; in this cohort all single LAC-positive samples were confirmed after 12 weeks. They also note no established LAC standard exists in sufficient quantity, and no evidence links “stronger” LAC to clinical symptoms.

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

Integrity signals

Registry

Crossref · 10.1055/a-1344-4271

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

16 of 34 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation
    § Antibody Profile and Patient Characteristics · p. 3

    LAC-positive patients were tested positive on two separate occasions according to ISTH guidelines.

    “The LAC-positive patients were tested positive on two separate occasions according to the ISTH guidelines. 5”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] K MJ Devreese, 2018, Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH, J Thromb Haemost source
  • Findingown data
    § Discussion · p. 6

    In our study, triple positivity was strongly associated with thrombosis.

    “In our study, triple positivity was strongly associated with thrombosis, which is consistent with previous studies. 19,23”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [19] W Chayoua, 2018, Identification of high thrombotic risk triple-positive antiphospholipid syndrome patients is dependent on anti-cardiolipin and anti-β2glycoprotein I antibody detection assays, J Thromb Haemost source
    • cites [23] V Pengo, 2013, Correct laboratory approach to APS diagnosis and monitoring, Autoimmun Rev source
  • Premisecitation
    § Discussion · p. 7

    International External Quality Assessment programs have shown significant inter-laboratory variation, especially for weaker LAC samples.

    “International External Quality Assessment programs have shown significant inter-laboratory variation, especially for weaker LAC samples. 2,4,7”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [2] K M Devreese, 2012, Standardization of antiphospholipid antibody assays. Where do we stand?, Lupus source
    • cites [4] K M Devreese, 2014, Antiphospholipid antibody testing and standardization, Int J Lab Hematol source
    • cites [7] M L Bertolaccini, 2014, 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends, Autoimmun Rev source
  • Findingown data
    § Keywords · p. 1

    Triple positivity is associated with vascular thrombosis (OR 4.3, 95% CI 1.6-12.2).

    “even better than triple-positive samples (OR: 4.3; 95% CI: 1.6 -12.2).”
    • Also stated in: § Association of Isolated LAC and Triple Positivity with Thrombosis · p. 4 · plain
      “The association between isolated LAC or triple positivity with thrombosis resulted in an OR (95% CI) of 7.3 (3.3 -16.1) and 4.3 (1.6 -12.2), respectively ( ► Table 4A ).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Keywords · p. 1

    Isolated LAC is strongly associated with vascular thrombosis (OR 7.3, 95% CI 3.3-16.1).

    “We found that isolated LAC proved to be strongly associated with vascular thrombosis (odds ratio [OR]: 7.3; 95% confidence interval [CI]: 3.3 -16.1)”
    • Also stated in: § Association of Isolated LAC and Triple Positivity with Thrombosis · p. 4 · plain
      “The association between isolated LAC or triple positivity with thrombosis resulted in an OR (95% CI) of 7.3 (3.3 -16.1) and 4.3 (1.6 -12.2), respectively ( ► Table 4A ).”
    • Also stated in: § Keywords · p. 1 · boosted
      “Isolated LAC was highly associated with thrombosis.”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation
    § Introduction · p. 2

    Triple-positive patients have a high risk for developing a first thrombotic event and recurrence of thrombosis.

    “Patients positive for the combination of LAC, antiβ 2GPI, and anti-CL antibodies,theso-called triple-positive patients, exhibit a high risk for developing a first thrombotic event and recurrence of thrombosis. 8,9”
    • Also stated in: § Keywords · p. 1 · plain
      “Patients positive for all three types of antiphospholipid antibodies (aPLs; triple positivity) have been identified for having a high risk for thrombotic events.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] V Pengo, 2010, Clinical course of high-risk patients diagnosed with antiphospholipid syndrome, J Thromb Haemost source

      The Discussion (page unavailable) says patients positive on all three tests are at higher risk of thrombosis and have a substantial risk of recurrent thromboembolic events. However, this study followed patients already diagnosed with APS and does not establish the risk of a first thrombotic event in triple-positive patients generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] V Pengo, 2011, Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study, Blood source

      The Results report a considerable risk of a first thromboembolic event among 104 triple-positive carriers (25 events; 5.3% per year). The study followed people without prior thromboembolic events, so it does not establish the claimed risk of thrombosis recurrence. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation
    § Solid-Phase Assays · p. 2

    Cut-off values from manufacturers were transferred after confirmation in 20 healthy individuals according to guidelines.

    “The cut-off values from the manufacturers were transferred after confirmation in 20 healthy individuals according to the guidelines. 17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] K M Devreese, 2014, Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH, J Thromb Haemost source

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Lupus Anticoagulant and Antiphospholipid Syndrome · p. 2

    LAC was determined according to ISTH guidelines using dRVVT and aPTT.

    “LAC was determined using the STA-R Evolution Coagulation Analyzer (Diagnostica Stago, Asnières-sur-Seine, France) according to ISTH guidelines 1 applying dilute Russell ' s viper venomtime (dRVVT Screen and dRVVT Confirm, Diagnostica Stago, Asnières-sur-Seine, France) and a sensitive activated partial thromboplastin time (aPTT) with silica as an activator (PTT-LA, Diagnostica Stago, Asnières-sur-”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] V Pengo, 2009, Update of the guidelines for lupus anticoagulant detection, J Thromb Haemost source

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

    Premisecitation
    § Discussion · p. 7

    Cofactor-independent antibodies have been shown to be relevant, although clinical data are rare.

    “Also cofactor-independent antibodies have been shown to be relevant, although clinical data are rare. 31,32”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [31] S M Schouwers, 2010, Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?, Thromb Res source
    • cites [32] K MJ Devreese, 2015, Interference of C-reactive protein with clotting times, Clin Chem Lab Med source

      The paper’s opening passage and spiking-experiment results discuss C-reactive protein interference with clotting assays, not the clinical relevance of cofactor-independent antibodies. Searches for 'cofactor-independent antibodies' and their clinical relevance found no passage addressing either part of the claim; page numbers were not available in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation
    § Discussion · p. 7

    In single LAC-positive samples negative for antiβ2GPI and anti-PS/PT antibodies, the antibody is not directed toward the known antigens but might be directed against other plasma proteins.

    “In single LAC-positive samples,negativeforantiβ 2GPIandanti-PS/PTantibodies,the antibody is not directed toward the known antigens but might be directed against other plasma proteins. 24,25”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [24] P Rampazzo, 2001, Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins, Thromb Haemost source
    • cites [25] D Yin, 2019, Commentary on: circulating plasmablasts contribute to antiphospholipid antibody production, associated with type I interferon upregulation, J Thromb Haemost source

      The commentary discusses heterogeneous antiphospholipid antibodies and lists APS laboratory tests, but it does not address isolated LAC-positive samples negative for anti-β2GPI and anti-PS/PT. Searches for that combination and for alternative plasma-protein targets found no passage establishing the proposed target. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Discussion · p. 7

    Cut-off values in our study were calculated by the 99th percentile on 120 healthy donors.

    “Cut-off values in our study were calculated by the 99th percentile on 120 healthy donors 5”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] K MJ Devreese, 2018, Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH, J Thromb Haemost source

      The paper’s recommended laboratory testing table specifies a threshold above the 99th percentile of normal controls, and its section on anticardiolipin and β2-glycoprotein I antibodies discusses a cut-off calculated from the 99th percentile. It does not specify 120 healthy donors or verify the citing authors’ study-specific calculation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Discussion · p. 5

    Patients positive for all three aPLs are identified as individuals at high risk for a first clinical event and for recurrence.

    “andpatientspositiveforallthree aPLs are identified as individuals at high risk for a first clinical event and for recurrence. 8,9”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] V Pengo, 2010, Clinical course of high-risk patients diagnosed with antiphospholipid syndrome, J Thromb Haemost source

      The Discussion and Abstract identify triple-positive patients with APS as being at high risk of recurrent thromboembolic events. The study enrolled patients who already had definite APS and a qualifying clinical event, so it does not establish their risk of a first clinical event. Page numbers are not available in the supplied passages. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [9] V Pengo, 2011, Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study, Blood source

      The Results (page not available in our copy) report 25 first thromboembolic events among 104 triple-positive carriers, supporting the claim about a first clinical event. The study followed people without prior clinical APS events and did not establish their risk of recurrence; its Introduction calls triple-positive patients with APS high-risk but does not quantify recurrence risk. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Discussion · p. 7

    This study supports the dRVVT as the preferred assay to detect LAC.

    “This study supports the dRVVT as the preferred assay to detect LAC. 1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] V Pengo, 2009, Update of the guidelines for lupus anticoagulant detection, J Thromb Haemost source

  • May combine two claims.

    Interpretationcitation
    § Discussion · p. 7

    The single patient positive for aPTT only had a higher CRP level and could be a false-positive result.

    “this patient had a higher CRP level and could be a false-positive result, as described in the literature. 31,32”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [31] S M Schouwers, 2010, Lupus anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?, Thromb Res source
    • cites [32] K MJ Devreese, 2015, Interference of C-reactive protein with clotting times, Clin Chem Lab Med source

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Discussion · p. 7

    LAC was performed according to the ISTH guidelines.

    “and LAC was performed according to the ISTH guidelines. 1,34”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] V Pengo, 2009, Update of the guidelines for lupus anticoagulant detection, J Thromb Haemost source
    • cites [34] K MJ Devreese, 2020, Update of the guidelines for lupus anticoagulant detection and interpretation. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis, J Thromb Haemost source

  • May combine two claims.

    Findingown data
    § Antibody Profile and Patient Characteristics · p. 3

    Fifty-five out of 70 LAC-positive patients were diagnosed with APS, 13 were AID patients, and two were normal controls.

    “Fifty-five out of these 70 patients were diagnosed with APS, 13 were AID patients, and two were normal controls.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Discussion · p. 6

    In our study, isolated LAC was strongly correlated with a history of thrombosis with an even higher OR than triple positivity.

    “Interestingly, our study showed that an isolated LAC was also strongly correlated with a history of thrombosis with an even higher OR.”
    • Also stated in: § What does this paper add? · p. 7 · boosted
      “Isolated lupus anticoagulant (LAC) is highly associated with thrombosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The four solid-phase assays used are sufficient to exclude anti-CL and anti-β2GPI antibodies, so that patients classified as isolated LAC truly lack these antibodies.

  • May combine two claims.

    Findingown data
    § Association of Isolated LAC and Triple Positivity with Thrombosis · p. 4

    The association between isolated LAC or triple positivity and APS showed overall higher ORs, also higher in the isolated LAC group compared with the triple-positive group.

    “The association between isolated LAC or triple positivity and APS showed overall higher ORs ( ► Table 4B ), also higher in the isolated LAC group compared with the triple-positive group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Strength of LAC Activity: Isolated LAC versus LAC in Triple-Positive Patients · p. 5

    25% of patients with isolated LAC and 33% of patients with triple positivity were positive for both assays.

    “In addition, 25% of the patients with isolated LAC and 33% of patients with triple positivity were positive for both assays.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Strength of LAC Activity: Isolated LAC versus LAC in Triple-Positive Patients · p. 4

    Isolated positive LAC patients showed weaker LAC activity compared with triple-positive patients, although there were differences between the aPTT and dRVVT.

    “Isolated positive LAC patients showed weaker LAC activity compared with triple-positive patients, although there were differences between the aPTT and the dRVVT ( ► Fig. 2 ).”
    • Also stated in: § Discussion · p. 7 · boosted
      “We did observe that patients with isolated LAC showed significantly less prolongation in the dRVVT and aPTT screening tests compared with patients with triple positivity, as previously reported. 35”
    • Also stated in: § What does this paper add? · p. 7 · plain
      “Isolated LAC displays weaker activity than LAC in triple-positive patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Antibody Profile and Patient Characteristics · p. 3

    Six out of 70 LAC-positive patients were LAC-positive with anti-CL or anti-β2GPI antibodies, and four (67%) of them were APS patients.

    “Six out of 70 LAC-positive patients were LAC-positive with anti-CL or antiβ 2GPI antibodies and four (67%) of them were APS patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Antibody Profile and Patient Characteristics · p. 3

    Of the 36 APS patients with isolated LAC, 28 had a history of venous thrombosis, 6 had a history of arterial thrombosis, and 2 had a combination of venous thrombosis and arterial thrombosis or pregnancy morbidity.

    “Of these 36 APS patients, 28 had a history of venous thrombosis, 6 had a history of arterial thrombosis, and 2 had a combination of venous thrombosis and arterial thrombosis or pregnancy morbidity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Antibody Profile and Patient Characteristics · p. 4

    For IgA, there was a lower prevalence of anti-CL and anti-β2GPI IgA in the isolated LAC group compared with the triple-positive patient group (anti-CL: 0-5 vs 30-55%; anti-β2GPI: 0 vs 30-55%).

    “For IgA we found a lower prevalence of anti-CL and antiβ 2GPI IgA in the isolated LAC group compared with the triple-positive patient group (anti-CL: 0 -5 vs. 30 -55% and antiβ 2GPI: 0 vs. 30 -55%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Strength of LAC Activity: Isolated LAC versus LAC in Triple-Positive Patients · p. 5

    In the isolated LAC group, the majority of patients were dRVVT-positive (98%) and only one patient was positive in the aPTT system only.

    “In the isolated LAC group, the majority of patients were dRVVT-positive (98%) and only one patient was positive in the aPTTsystem only.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Strength of LAC Activity: Isolated LAC versus LAC in Triple-Positive Patients · p. 5

    The one isolated LAC patient positive in the aPTT system only had a high level of C-reactive protein (CRP) (100 mg/L).

    “This patient had a high level of C-reactive protein (CRP) (100mg/L).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Strength of LAC Activity: Isolated LAC versus LAC in Triple-Positive Patients · p. 5

    In the triple-positive group, 100% were positive in the dRVVT and no patient was positive in the aPTT system only.

    “Similar results for the triple-positive group were found as 100% was positive in the dRVVT and no patient was positive in the aPTTsystem only.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction · p. 2

    A positive LAC is a strong risk factor for thrombosis in APS.

    “Although a positive LAC is considered to be a strong risk factor for thrombosis in APS, 10,11”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] M Galli, 2003, Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature, Blood source
    • cites [11] Q Reynaud, 2014, Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis, Autoimmun Rev source

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

    Study design and conductnone given
    § Keywords · p. 1

    Anti-CL and anti-β2GPI were measured by four different solid-phase platforms to overcome variability between test systems.

    “Anti-CL and antiβ 2GPI were measured by four different solid-phase platforms to overcome variability between test systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion · p. 7

    In international external quality programs, the dRVVT performs better and with less variation than an aPTT in identifying APS-positive samples.

    “In international external quality programs the dRVVT performs better and with less variation than an aPTT in identifying APS-positive samples. 33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] V Pengo, 1999, dRVVT is more sensitive than KCT or TTI for detecting lupus anticoagulant activity of anti-β2-glycoprotein I autoantibodies, Thromb Haemost source

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

    Premisecitation
    § Discussion · p. 6

    Others found no significant lower persistence in single-positive patients (93.3%) compared with double- and triple-positive patients (96.8 and 97.9%, respectively).

    “Others found no significant lower persistence in the single-positive patients (93.3%) compared with the doubleand triple-positive patients(96.8and97.9%,respectively). 22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] J Devignes, 2019, Extended persistence of antiphospholipid antibodies beyond the 12-week time interval: association with baseline antiphospholipid antibodies titres, Int J Lab Hematol source

  • May combine two claims.

    Study design and conductown data
    § Antibody Profile and Patient Characteristics · p. 3

    Age and male/female ratios were balanced between the isolated LAC and triple-positive groups (p=0.11 and p=0.74).

    “When the isolated LAC patients were compared with the triple-positive patient group, the age and male/female ratios werebalanced ( p ¼ 0.11 and p ¼ 0.74, respectively), as well as their clinical characteristics ( ► Table 2 ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion · p. 6

    An isolated LAC is an independent risk factor for myocardial infarction and ischemic stroke.

    “Moreover,anisolated LAC is an independent risk factor for myocardial infarction and ischemic stroke. 14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] R T Urbanus, 2009, Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study, Lancet Neurol source

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

    Premisecitation
    § Discussion · p. 7

    Other antibodies against protein C/S and annexin V have been shown to interfere with coagulation.

    “Indeed, other antibodies against protein C/S and annexin V have also been shown to interfere with coagulation. 26,27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] B de Laat, 2008, Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C, Blood Coagul Fibrinolysis source
    • cites [27] B de Laat, 2007, Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5, Blood source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion · p. 5

    It is generally accepted that patients with isolated LAC have a lower risk profile in APS.

    “It is generally accepted that patients with isolated LAC have alowerriskprofileinAPS 12,20”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] V Pengo, 2015, Incidence of a first thromboembolic event in carriers of isolated lupus anticoagulant, Thromb Res source
    • cites [20] K M Devreese, 2012, Antiphospholipid antibodies: evaluation of the thrombotic risk, Thromb Res source

  • May combine two claims.

    Premisecitation
    § Discussion · p. 6

    Persistence of LAC in triple-positive patients is very high (up to 100% of patients), and single LAC positives remain positive after 12 weeks in 40% of patients.

    “persistence of LAC in triple-positive patients is very high (up to 100%ofpatients,alsosingleLACpositivesremainpositiveafter 12 weeks in 40% of patients). 21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] V Pengo, 2013, Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile, J Thromb Haemost source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning
    § Discussion · p. 7

    In our cohort, the final conclusion of LAC positivity was made only if the three steps of the test procedure (screening, mixing, and confirmation) were positive.

    “the final conclusion of LAC positivity can only be made if the three steps of the test procedure (screening, mixing, and confirmation) are positive, which was the case in our cohort.”
    Quote in the paperSubstantial claim
31 of 31

  • The paper relies on this without support.

    The normal control group is representative of individuals without APS-related thrombosis or antiphospholipid antibodies.

    “The normal controls were patients who were referred for aPL antibody testing for reasons other than the clinical criteria of APS, including subfertility ( n ¼ 115) and prolonged aPTT ( n ¼ 7).”

  • The paper relies on this without support.

    LAC activity measurements are comparable across patients and test systems.

    “We observed that LAC positivity was weaker in isolated LAC-positive patients compared with LAC activity in triple-positive patients.”

  • The paper relies on this without support.

    The four solid-phase assays used are sufficient to exclude anti-CL and anti-β2GPI antibodies, so that patients classified as isolated LAC truly lack these antibodies.

    “We defined a plasma sample as isolated LAC when tested positive in a dRVVT- and/or an aPTT-based assay, and tested negative for anti-CL and antiβ 2GPI IgG and IgM antibodies applying four different solidphase platforms. This was done to overcome the variability between solid-phase assays. 18,19”
3 of 3

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?

  • Single aPL positivity does not seem to be associated with an elevated risk of thrombosis, except for isolated LA positivity, which has been highly associated with thrombosis.

    “whereas single positivity does not seem to be associated with an elevated risk of thrombosis except for isolated LA positivity that has been highly associated with thrombosis. 18”

    From Single or triple positivity for antiphospholipid antibodies in “carriers” or symptomatic patients: Untangling the knot (2021) · cites this paper as [18]

    The Results (p. 1) and the section on association with thrombosis (p. 4) strongly associate isolated lupus anticoagulant positivity with thrombosis (OR 7.3, 95% CI 3.3–16.1). The Introduction (p. 2) reports little or no association for other aPLs in studies of myocardial infarction and stroke, but the paper does not establish the broader claim that all other forms of single aPL positivity lack elevated thrombosis risk. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Single LA assay repertoires are still in use and risk missing not only single-positive APS where isolated persistent LA is a risk factor, but also identification of triple-positive patients who require different management.

    “Single LA assay repertoires are still in use and risk missing not only single-positive APS where isolated persistent LA is a risk factor [11,30], but also identification of triple-positive patients who require different management.”

    From Triple-positive antiphospholipid syndrome does not guarantee positivity in each lupus anticoagulant assay (2023) · cites this paper as [11]

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.

  • dRVVT screening difference described as significant despite p = 0.118

    Minor

    The discussion calls the dRVVT screening difference significant, but the results report p = 0.118 for that comparison, above the paper's 0.05 threshold.

  • Triple-positive APS count differs between text and table

    Minor

    The text reports 14 APS patients among the 20 triple-positive patients, whereas Table 2 reports 15. The text's breakdown of 14 APS, 4 autoimmune-disease controls, and 1 normal control also totals only 19.

  • Age and sex p-values conflict with Table 2

    Minor

    The text assigns p = 0.11 to age and p = 0.74 to the male/female ratio. Table 2 instead gives 0.798 for age and 0.113 for female prevalence.

  • Reported 33% cannot represent patients in the 20-person triple-positive group

    Minor

    With 20 triple-positive patients, an integer number positive for both assays would yield a percentage in increments of 5%; it cannot yield 33% when rounded to a whole percent.

4 of 4

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Authors
Yin, D., de Groot, P. G., Ninivaggi, M., Devreese, K. M. J., & de Laat, B.
Affiliations
  • Maastricht University Medical Centre (NL)
  • Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
  • Synapse (Netherlands) (NL)
  • Ghent University Hospital (BE)
  • Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
ORCID
Venue
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Published
2020-12-31
Volume
121
Issue
09
Pages
1220-1227
ISSN
  • 0340-6245 (ISSN-L)
  • 2567-689X
DOI
10.1055/a-1344-4271
OpenAlex
W3114188559
Semantic Scholar
5053174dc93d8f6c0e088a9dff290dc1f784ba4b
Cited by
36
References
35
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 11 · 2021: 5
FWCI
3.97
Type
journal article
Language
en
Open access
closed
Locations
  • Thrombosis and Haemostasis (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion)
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
lupus anticoagulant, antiphospholipid syndrome, thrombotic antiphospholipid syndrome, anticardiolipin antibodies, anti-beta2-glycoprotein I antibodies, anti-phosphatidylserine/prothrombin antibodies, vascular thrombosis
MeSH terms
Adult, Female, Humans, Immunoglobulin M, Male, Middle Aged, Predictive Value of Tests, Thrombosis, Biomarkers, Case-Control Studies, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome, Antibodies, Anticardiolipin

About these checks

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 2026-10-25.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-25.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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