Variability of cut‐off values for the detection of lupus anticoagulants: results of an international multicenter multiplatform study
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Essentials Between-lab variations of cut-off values in lupus anticoagulant detection are unknown. Cut-off values were calculated in 11 labs each testing plasma from 120 donors with 3 platforms. Major variation was observed even within the same platform. Cut-off values determined in different labs are not interchangeable.Summary Background Cut-off values for interpretation of lupus anticoagulant (LA) detection are poorly investigated. Aims (i) To assess whether results from healthy donors were normally distributed and (ii) the between-laboratories differences in cut-off values for screening, mixing and LA confirmation when calculated as 99th or 95th centiles, and (iii) to assess their impact on the detection rate for LA. Methods Each of 11 laboratories using one of the three widely used commercial platforms for LA detection was asked to collect plasmas from 120 healthy donors and to perform screening, mixing and LA confirmation with two methods (activated partial thromboplastin time [APTT] and dilute Russell viper venom [dRVV]). A common set of LA-positive or LA-negative freeze-dried plasmas was used to assess the LA detection rate. Results were centralized (Milano) for statistical analysis. Results and conclusions (i) Clotting times or ratios for healthy subjects were not normally distributed in the majority of cases. The take-home message is that cut-off values should be determined preferably by the non-parametric method based on centiles. (ii) There were relatively large inter-laboratory cut-off variations even within the same platform and the variability was marginally attenuated when results were expressed as ratios (test-to-normal pooled plasma). The take-home message is that cut-off values should be determined locally. (iii) There were differences between cut-off values calculated as 99th or 95th centiles that translate into a different LA detection rate (the lower the centile the greater the detection rate). The take-home message is that cut-off values determined as the 95th centile allow a better LA detection rate.
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A study of three commercial LA platforms following ISTH-SSC guidelines found platform-to-platform differences in clotting times and ratios, and differences among participants using the same platform, even after outlier exclusion.
“Differences were observed between platforms for clotting times as well as results expressed as ratio, but also between participants using the same platform.These differences were observed even after detection and exclusion of outliers before cutoff calculation.74”
From Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis (2020) · cites this paper as [73]
The Results and Cut-off values sections describe three commercial platforms and differences in cut-off values between platforms and between laboratories using the same platform, for both clotting times and ratios. But the LA-negative plasma section explicitly says the authors analyzed all results without detecting or rejecting outliers. The claim that the differences persisted after outlier exclusion is therefore not supported by this study. (LLM, conf=0.92)
Experimental — accuracy not yet measuredClotting times or ratios in LA testing are not normally distributed, which supports determining cutoff values by a nonparametric centile method.
“A recent study showed that clotting times or ratios in LA testing were not normally distributed, which confirms that cutoff values should be determined by a nonparametric method based on centiles.73”
Evidence shows that there is great inter-laboratory variability even when using the same analytic platform.
“even if evidence shows that there is a great inter-laboratory variability even when using the same analytic platform [61,63].”
From Lupus Anticoagulant Detection under the Magnifying Glass (2023) · cites this paper as [61]
Some works have shown that the values from the parametric approach do not respect the Gaussian probability model.
“(even if some works have shown that these values do not respect the Gaussian probability model [61,62])”
From Lupus Anticoagulant Detection under the Magnifying Glass (2023) · cites this paper as [61]
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Cites
MIYAKIS, S., LOCKSHIN, M. D., ATSUMI, T., BRANCH, D. W., BREY, R. L., CERVERA, R., DERKSEN, R. H. W. M., DE GROOT, P. G., KOIKE, T., MERONI, P. L., et al. (2006) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2006.01753.x · Cited by 7,203 · see citing works
Update of the guidelines for lupus anticoagulant detection
PENGO, V., TRIPODI, A., REBER, G., RAND, J. H., ORTEL, T. L., GALLI, M., & DE GROOT, P. G. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03555.x · Cited by 1,197 · see citing works
Self-citationDetection and Quantitative Evaluation of Lupus Circulating Anticoagulant Activity
Rosner, E., Pauzner, R., Lusky, A., Modan, M., & Many, A. (1987) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1651083 · Cited by 188 · see citing works
Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment
Tripodi, A., de Groot, P. G., & Pengo, V. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02362.x · Cited by 113 · see citing works
Self-citationJennings, I., Kitchen, S., Woods, T. A. L., Preston, F. E., & Greaves, M. (1997) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1656080 · Cited by 103 · see citing works
Meijer, P., Vermylen, J., & Arnout, J. (1999) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614601 · Cited by 96 · see citing works
Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples
Pengo, V., Biasiolo, A., Gresele, P., Marongiu, F., Erba, N., Veschi, F., Ghirarduzzi, A., Candia, E. D., Montaruli, B., Testa, S., et al. (2007) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2007.02454.x · Cited by 95 · see citing works
Self-citationLaboratory Testing for Lupus Anticoagulants: A Review of Issues Affecting Results
Tripodi, A. (2007) · Clinical Chemistry · doi:10.1373/clinchem.2007.089524 · Cited by 81 · see citing works
Self-citationTripodi, A., Biasiolo, A., Chantarangkul, V., & Pengo, V. (2003) · Clinical Chemistry · doi:10.1373/49.10.1608 · Cited by 65 · see citing works
Self-citationTripodi, A., Chantarangkul, V., Clerici, M., & Mannucci, P. M. (2002) · PubMed · Cited by 62 · see citing works
Self-citationGardiner, C., Mackie, I. J., Malía, R. G., Jones, D. W., Winter, M. R., Leeming, D., Taberner, D. A., Machin, S. J., & Greaves, M. (2000) · British Journal of Haematology · doi:10.1046/j.1365-2141.2000.02466.x · Cited by 55 · see citing works
Pengo, V., Biasiolo, A., Gresele, P., Marongiu, F., Erba, N., Veschi, F., Ghirarduzzi, A., Barcellona, D., & Tripodi, A. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.153536 · Cited by 49 · see citing works
Self-citationIdentification of factor inhibitors by diagnostic haemostasis laboratories
Bonar, R., Duncan, E. M., Earl, G., et al. (2006) · Thrombosis and Haemostasis · doi:10.1160/th06-01-0004 · Cited by 48 · see citing works
Laboratory Diagnosis of Lupus Anticoagulants for Patients on Oral Anticoagulant Treatment
Chantarangkul, V., Clerici, M., Mannucci, P. M., & Tripodi, A. (2002) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1613259 · Cited by 43 · see citing works
Self-citationFavaloro, E. J., Bonar, R. A., Sioufi, J., Wheeler, M., Low, J., Aboud, M., Duncan, E., Smith, J. A., Exner, T., Lloyd, J. V., et al. (2005) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-2005-863805 · Cited by 41 · see citing works
Brandt, J. T., Triplett, D. A., Rock, W., BOVILL, E. G., & Arkin, C. F. (1991) · PubMed · Cited by 34 · see citing works
Lupus Anticoagulants:First French Interlaboratory Etalonorme Survey
Roussi, J., Jp, R., & Goguel, A. (1996) · American Journal of Clinical Pathology · doi:10.1093/ajcp/105.6.788 · Cited by 29 · see citing works
Pradella, P., Azzarini, G., Santarossa, L., Caberlotto, L., Bardin, C., Poz, A., D’Aurizio, F., & Giacomello, R. (2013) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2012-0382 · Cited by 26 · see citing works
Self-citationGardiner, C., Mackie, I. J., Malía, R. G., et al. (2000) · British Journal of Haematology · doi:10.1111/j.1365-2141.2000.02466.x · Cited by 18 · see citing works
Tripodi, A., Chantarangkul, V., Clerici, M., Palmucci, C., Bison, E., Banzato, A., Biguzzi, E., & Pengo, V. (2011) · Thrombosis Research · doi:10.1016/j.thromres.2011.01.015 · Cited by 8 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Horowitz GL, Altaie S, Boyd JC, Ceriotti F, Garg U, Horn P, Pesce A, Sine HE, Zakowski J. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline- third edition. CLSI Document C28-A3; Clinical and Laboratory Standards Institute, Wayne PA, Vol 28, Number 30, 2008.
Cited by
Sorted by citations
Devreese, K. M. J., de Groot, P. G., de Laat, B., Erkan, D., Favaloro, E. J., Mackie, I., Martinuzzo, M., Ortel, T. L., Pengo, V., Rand, J. H., et al. (2020) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.15047 · Cited by 439 · see citing works
Self-citationDevreese, K. M. J., Bertolaccini, M. L., Branch, D. W., de Laat, B., Erkan, D., Favaloro, E. J., Pengo, V., Ortel, T. L., Wahl, D., & Cohen, H. (2025) · Journal of Thrombosis and Haemostasis · doi:10.1016/j.jtha.2024.10.022 · Cited by 92 · see citing works
Self-citationMoore, G. W., Jones, P. O., Platton, S., Hussain, N., White, D., Thomas, W., Rigano, J., Pouplard, C., Gray, E., & Devreese, K. M. J. (2021) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.15438 · Cited by 47 · see citing works
Self-citationVanoverschelde, L., Kelchtermans, H., Musial, J., de Laat, B., & Devreese, K. M. J. (2019) · Research and Practice in Thrombosis and Haemostasis · doi:10.1002/rth2.12207 · Cited by 33 · see citing works
Moore, G. W., & Kumano, O. (2020) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14669 · Cited by 18 · see citing works
Diagnostic Challenges on the Laboratory Detection of Lupus Anticoagulant
Tripodi, A. (2021) · Biomedicines · doi:10.3390/biomedicines9070844 · Cited by 14 · see citing works
Self-citationLupus Anticoagulant Detection under the Magnifying Glass
Molinari, A. C., Martini, T., Banov, L., Ierardi, A., Leotta, M., Strangio, A., & Santoro, R. C. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12206654 · Cited by 9 · see citing works
“…BSH guidelines [15,36], on the other hand, employ a “parametric” approach assuming a Gaussian distribution of LA results, using a reference range of ± 2 standard deviations from the mean value (even if some works have shown that these values do not respect the Gaussian probability model [61,62]).”
BackgroundMethodChantarangkul, V., Peyvandi, F., & Tripodi, A. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.03.018 · Cited by 8 · see citing works
Self-citationAnalytical dilemmas in lupus anticoagulant detection
Moore, G. W. (2023) · Exploration of Immunology · doi:10.37349/ei.2023.00104 · Cited by 5 · see citing works
Lupus Anticoagulant Testing in Challenging Situations: Navigating Complexities
Devreese, K. M. J. (2026) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.14490 · Cited by 2 · see citing works
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- Authors
- Tripodi, A., Chantarangkul, V., Cini, M., Devreese, K., Dlott, J. S., Giacomello, R., Gray, E., Legnani, C., Martinuzzo, M. E., Pradella, P., Siegemund, A., Subramanian, S., Suchon, P., & Testa, S.
- Affiliations
- University of Milan (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Ghent University Hospital (BE)
- Quest Diagnostics (United States) (US)
- University of Udine (IT)
- National Institute for Biological Standards and Control (GB)
- Hospital Italiano de Buenos Aires (AR)
- Ospedale di Cattinara (IT)
- St.John's Medical College Hospital (IN)
- Inserm (FR)
- Istituti Ospitalieri di Cremona (IT)
- Corresponding author
- Tripodi, A.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 15
- Issue
- 6
- Pages
- 1180-1190
- ISSN
- 1538-7836 (ISSN-L)
- OpenAlex
- W2595302723
- Cited by
- 35
- References
- 20
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 3
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Institutional Research Information System (University of Udine) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- lupus anticoagulant, cut-off values, inter-laboratory variability, healthy donors, activated partial thromboplastin time, anticoagulant screening
- MeSH terms
- Adolescent, Adult, Aged, Blood Coagulation Tests, Female, Humans, Male, Middle Aged, Partial Thromboplastin Time, Plasma, Prothrombin Time, Reference Values, Reproducibility of Results, Normal Distribution, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome, Young Adult, Healthy Volunteers
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