Mixing studies for lupus anticoagulant: mostly no, sometimes yes
Abstract
Mixing tests have long been a mainstay in the lupus anticoagulant (LA) testing armoury of screen, mix and confirm assays. If a sample with an elevated screening test does not evidence inhibition in the mixing test, the search for an LA is halted and a different diagnostic pathway embarked upon. Recent years have seen studies evidencing sometimes high frequencies of false-negative mixing tests with perhaps sinister implications for missed diagnoses and skewed patient management. Issues such as the dilution effect, between-reagent sensitivity and specificity differences, variability of normal pooled plasma (NPP) quality and suitability and interpretive inconsistencies all contribute to questioning the reliability of mixing tests and their pivotal place in the LA assay hierarchy. The advent of integrated testing, where phospholipid-dependence is demonstrated or excluded prior to any attempt to evidence inhibitory properties with a fallible analytical principle, provides an alternative path to LA detection. In the absence of other causes of elevated clotting times, LA assay screen and confirm discordance is sufficient to secure a laboratory diagnosis of the presence of an LA, leaving the mixing test in a supplementary yet valuable role when further diagnostic discrimination is required.
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A majority of ISTH-SSC survey respondents, 84.1%, affirmed the need for mixing tests.
“The need for mixing tests is reflected in the affirmative response of majority of the ISTH-SSC survey respondents (84.1%) and recent literature.15,61,62”
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].”
From Comparison of different algorithms for lupus anticoagulant detection: a single-center experience (2024) · cites this paper as [15]
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]].”
From Comparison of different algorithms for lupus anticoagulant detection: a single-center experience (2024) · cites this paper as [15]
The unavoidable dilution effect of mixing tests on antibody titer can make LA undetectable, leading to false-negative results.
“The principal limitation regarding mixing is the unavoidable dilution effect on the antibody titer, which in some cases can make the LA undetectable, leading to false-negative results [104].”
From Lupus Anticoagulant Detection under the Magnifying Glass (2023) · cites this paper as [104]
Cites
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“A variety of formulae have been proposed and employed for interpreting mixing tests and current guidelines recommend either the index of circulating anticoagulant (ICA) calculation, or a mixing test-specific cut-off (MTC) derived from the upper limit of a population distribution [11, 17].”
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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
“The principal limitation regarding mixing is the unavoidable dilution effect on the antibody titer, which in some cases can make the LA undetectable, leading to false-negative results [104].”
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Self-citationLupus Anticoagulant Testing: Taipan Snake Venom Time with Ecarin Time as Confirmatory Test
Moore, G. W. (2023) · Methods in Molecular Biology · doi:10.1007/978-1-0716-3175-1_16 · Cited by 5 · see citing works
Self-citationComparison of different algorithms for lupus anticoagulant detection: a single-center experience
Apipongrat, D., Lamool, R., Arnutti, P., Ruangpratheep, C., & Chantkran, W. (2024) · Research and Practice in Thrombosis and Haemostasis · doi:10.1016/j.rpth.2024.102333 · Cited by 4 · see citing works
- Authors
- Moore, G. W.
- Affiliations
- Addenbrooke's Hospital (GB)
- Corresponding author
- Moore, Gary W.
- ORCID
- Moore, Gary W.
- Venue
- Clinical Chemistry and Laboratory Medicine (CCLM)
- Publisher
- Walter de Gruyter GmbH
- Published
- 2019-12-24
- Volume
- 58
- Issue
- 4
- Pages
- 492-495
- ISSN
- 1434-6621 (ISSN-L)
- 1437-4331
- OpenAlex
- W2997725712
- Cited by
- 19
- References
- 20
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 1 · 2020: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Chemistry and Laboratory Medicine (CCLM) (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Keywords
- lupus anticoagulant, mixing test, false-negative results, dilution effect, phospholipid dependence, integrated testing, anticoagulant screening, assay sensitivity and specificity
- MeSH terms
- Anticoagulants, False Negative Reactions, Humans, Partial Thromboplastin Time, Plasma, Prothrombin Time, Reproducibility of Results, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome
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