Ruling out lupus anticoagulants with mixing test-specific cutoff assessment and the index of circulating anticoagulant
Open accessAbstract
BACKGROUND: Lupus anticoagulant (LA) is classified in the antibody family that is recognized in antiphospholipid syndrome. Mixing tests are recommended for LA detection, and either a mixing test-specific cutoff (MTC) or index of circulating anticoagulant (ICA) is used for the interpretation. Although we previously showed MTC had higher sensitivity for LA than ICA, there are few studies investigating specificity. OBJECTIVES: To investigate specificity of multiple activated partial thromboplastin time (APTT) and diluted Russell's viper venom time (dRVVT) reagents for inhibitors using plasmas with non-LA causes of prolonged clotting times, interpreted with MTC and ICA. METHODS: Seventy-six factor-deficient samples (either artificially prepared, hereditary deficiency, or warfarin), and 12 inhibitors (either coagulation factor inhibitors, rivaroxaban, or apixaban) were used. Samples were tested with 4 APTTs, 1 dilute APTT (dAPTT), and 2 dRVVT reagents, and all elevated screen ratios were followed up with mixing tests. Frequencies of corrected and not-corrected results were calculated. RESULTS: The frequency of MTC and ICA corrected results, suggesting factor deficiency, were 5% to 43% and 79% to 100%, respectively, except for dAPTT, where MTC and ICA performed similarly. Frequencies of MTC and ICA not-corrected results, suggesting inhibition, were 29% to 100% and 25% to 67%, respectively. CONCLUSIONS: The data indicate that MTC has a tendency to generate not-corrected mixing tests in factor-deficient, warfarin, and other inhibitor samples, while ICA exhibited higher specificity. When we perform the mixing test and interpret the data, it is important to understand the characteristics of the indexes for maximizing the diagnostic potential of mixing test.
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The mixing test normalized ratio is most sensitive to inhibitors.
“The mixing test normalized ratio showed non-correction in all LA samples, indicating that this index is most sensitive to inhibitors”
From Performance characteristics of 5 numerical indexes in mixing test interpretation under coexistence of lupus anticoagulant and coagulation factor deficiency (2023) · cites this paper as [7]
The Introduction reports that the mixing test–specific cutoff (based on the mix ratio) was more sensitive to lupus anticoagulants than the index of circulating anticoagulant. The Results also found more frequent inhibitor detection with that cutoff for most, but not all, reagents. This paper does not report non-correction in all lupus anticoagulant samples or establish that the ratio is the most sensitive index overall. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMixing 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 [16]
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 measuredICA has a high specificity to factor deficiency, whereas the mixing test ratio has a high sensitivity to inhibitors.
“For instance, ICA has a high specificity to factor deficiency, whereas the mixing test ratio has a high sensitivity to inhibitors [6,7], although both indexes are recommended for LA diagnosis [8,9].”
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 [16]
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].”
From Comparison of different algorithms for lupus anticoagulant detection: a single-center experience (2024) · cites this paper as [16]
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].”
From Comparison of different algorithms for lupus anticoagulant detection: a single-center experience (2024) · cites this paper as [16]
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“For instance, ICA has a high specificity to factor deficiency, whereas the mixing test ratio has a high sensitivity to inhibitors [6,7], although both indexes are recommended for LA diagnosis [8,9].”
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Self-citation
- Authors
- Kumano, O., & Moore, G. W.
- Affiliations
- Sysmex (Japan) (JP)
- St Thomas' Hospital (GB)
- Corresponding author
- Kumano, Osamu
- Venue
- Research and Practice in Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 3
- Issue
- 4
- Pages
- 695-703
- ISSN
- 2475-0379 (ISSN-L)
- PMC
- PMC6781930
- OpenAlex
- W2966541221
- Cited by
- 24
- References
- 30
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 7 · 2023: 4 · 2022: 2 · 2021: 3 · 2019: 3 · 2017: 1
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Research and Practice in Thrombosis and Haemostasis (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Keywords
- lupus anticoagulant, mixing test, antiphospholipid syndrome, activated partial thromboplastin time, factor deficiency, warfarin, coagulation factor inhibitors, rivaroxaban, apixaban, prolonged clotting time, specificity
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