Download PDF
Semin Thromb Hemost 2022; 48(06): 643-660
DOI: 10.1055/s-0042-1744363
Review Article

Testing for Lupus Anticoagulants

Gary W. Moore
1   Haemostasis Unit, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2   Department of Natural Sciences, Faculty of Science and Technology, Middlesex University, London, United Kingdom
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Lupus anticoagulant (LA) is one of the three criteria antiphospholipid antibodies (aPLs) employed in classification, and by default diagnosis, of antiphospholipid syndrome (APS). Detection of LA is not via calibrated assays but is based on functional behavior of the antibodies in a medley of coagulation assays. A prolonged clotting time in a screening test is followed by demonstration of phospholipid dependence and inhibitory properties in confirmatory and mixing tests, respectively, which are modifications of the parent screening test. Complications arise because no single screening test is sensitive to every LA, and no test is specific for LA, because they are prone to interference by other causes of elevated clotting times. Several screening tests are available but the pairing of dilute Russell's viper venom time (dRVVT) with LA-sensitive activated partial thromboplastin time (aPTT) is widely used and recommended because it is proven to have good detection rates. Nonetheless, judicious use of other assays can improve diagnostic performance, such as dilute prothrombin time to find LA unreactive with dRVVT and aPTT, and the recently validated Taipan snake venom time with ecarin time confirmatory test that are unaffected by vitamin K antagonist and direct factor Xa inhibitor anticoagulation. Expert body guidelines and their updates have improved harmonization of laboratory practices, although some issues continue to attract debate, such as the place of mixing tests in the medley hierarchy, and areas of data manipulation such as assay cut-offs and ratio generation. This article reviews current practices and challenges in the laboratory detection of LA.

Keywords

activated partial thromboplastin time - antiphospholipid syndrome - antiphospholipid antibodies - dilute prothrombin time - dilute Russell's viper venom time - lupus anticoagulant - Taipan snake venom time


Publication History

Article published online:
01 June 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Meroni PL, Borghi MO. Antiphospholipid antibody assays in 2021: looking for a predictive value in addition to a diagnostic one. Front Immunol 2021; 12: 726820
    CrossrefPubMedGoogle Scholar
  • 2 Barbhaiya M, Zuily S, Ahmadzadeh Y. et al; New APS Classification Criteria Collaborators. Development of a new international antiphospholipid syndrome classification criteria Phase I/II report: generation and reduction of candidate criteria. Arthritis Care Res (Hoboken) 2021; 73 (10) 1490-1501
    CrossrefPubMedGoogle Scholar
  • 3 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
    CrossrefPubMedGoogle Scholar
  • 4 Yin D, de Groot PG, Ninivaggi M, Devreese KMJ, de Laat B. Clinical relevance of isolated lupus anticoagulant positivity in patients with thrombotic antiphospholipid syndrome. Thromb Haemost 2021; 121 (09) 1220-1227
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Moore GW. Current controversies in lupus anticoagulant detection. Antibodies (Basel) 2016; 5 (04) 22
    CrossrefPubMedGoogle Scholar
  • 6 Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost 2014; 40 (02) 163-171
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012; 157 (01) 47-58
    CrossrefPubMedGoogle Scholar
  • 8 CLSI. Laboratory Testing for the Lupus Anticoagulant; approved guideline. CLSI document H60-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2014
    Google Scholar
  • 9 Devreese KMJ, de Groot PG, de Laat B. et al. 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 2020; 18 (11) 2828-2839
    CrossrefPubMedGoogle Scholar
  • 10 Kelsey PR, Stevenson KJ, Poller L. The diagnosis of lupus anticoagulants by the activated partial thromboplastin time—the central role of phosphatidyl serine. Thromb Haemost 1984; 52 (02) 172-175
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Stevenson KJ, Seddon JM. The role of lipids in the detection of lupus anticoagulant by the dilute Russell Viper venom test: are platelets or reagents containing hexagonal HII phases necessary?. Br J Haematol 1994; 86 (03) 583-589
    CrossrefPubMedGoogle Scholar
  • 12 Okuda M, Yamamoto Y. Usefulness of synthetic phospholipid in measurement of activated partial thromboplastin time: a new preparation procedure to reduce batch difference. Clin Lab Haematol 2004; 26 (03) 215-223
    CrossrefPubMedGoogle Scholar
  • 13 Ledford-Kraemer MR. Laboratory testing for lupus anticoagulants: pre-examination variables, mixing studies, and diagnostic criteria. Semin Thromb Hemost 2008; 34 (04) 380-388
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Li R, Swaelens C, Vandermijnsbrugge F, Cantinieaux B. Applying a direct aPTT ratio (PlatelinLS/ActinFS) permits to identify rapidly and reliably a bleeding-related factor deficiency or a lupus anticoagulant sequential to an isolated prolongation of aPTT in paediatric pre-operative screening. Eur J Haematol 2016; 96 (06) 578-585
    CrossrefPubMedGoogle Scholar
  • 15 Kumano O, Amiral J, Dunois C, Peyrafitte M, Moore GW. Paired APTTs of low and high lupus anticoagulant sensitivity permit distinction from other abnormalities and achieve good lupus anticoagulant detection rates in conjunction with dRVVT. Int J Lab Hematol 2019; 41 (01) 60-68
    CrossrefPubMedGoogle Scholar
  • 16 Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993; 70 (05) 787-793
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Saxena R, Saraya AK, Kotte VK, Singh YN, Prasad L, Malviya AN. Evaluation of four coagulation tests to detect plasma lupus anticoagulants. Am J Clin Pathol 1991; 96 (06) 755-758
    CrossrefPubMedGoogle Scholar
  • 18 Cappucci G, Grandone E, Giuliani N, Margaglione M, Di Minno G. The use of frozen-thawed platelet-derived phospholipids as a confirmatory test for the diagnosis of lupus anticoagulants. Comparison with two commercial confirmatory system tests. Thromb Res 1999; 94 (06) 373-380
    CrossrefPubMedGoogle Scholar
  • 19 Smock KJ, Rodgers GM. Laboratory identification of lupus anticoagulants. Am J Hematol 2009; 84 (07) 440-442
    CrossrefPubMedGoogle Scholar
  • 20 Carroll P, Ray M, Just S, Hawson G. A lupus anticoagulant neutralization procedure using the patient's own platelets. Blood Coagul Fibrinolysis 1994; 5 (04) 523-527
    PubMedGoogle Scholar
  • 21 Exner T, Low J. Detection of procoagulant phospholipid interfering in tests for lupus anticoagulant. Thromb Res 2004; 114 (5-6): 547-552
    CrossrefPubMedGoogle Scholar
  • 22 Kristoffersen AH, Hammer IJ, Vannes S, Åsberg A, Aakre KM. Impact of different preanalytical conditions on results of lupus anticoagulant tests. Int J Lab Hematol 2019; 41 (06) 745-753
    CrossrefPubMedGoogle Scholar
  • 23 Sletnes KE, Gravem K, Wisløff F. Preparation of plasma for the detection of lupus anticoagulants and antiphospholipid antibodies. Thromb Res 1992; 66 (01) 43-53
    CrossrefPubMedGoogle Scholar
  • 24 Gosselin RC, Honeychurch K, Kang HJ, Dwyre DM. Effect of multiple freeze-thaw cycles on coagulation testing. Semin Thromb Hemost 2020; 46 (04) 515-520
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Froom P, Barak M. Testing for lupus anticoagulants—fresh or frozen?. Clin Chem Lab Med 2012; 50 (09) 1607-1609
    CrossrefPubMedGoogle Scholar
  • 26 Gosselin RC, Dwyre DW. Determining the effect of freezing on coagulation testing: comparison of results between fresh and once frozen-thawed plasma. Blood Coagul Fibrinolysis 2015; 26 (01) 69-74
    CrossrefPubMedGoogle Scholar
  • 27 Gosselin RC, Honeychurch K, Kang HJ, Dwyre DM. Effects of storage and thawing conditions on coagulation testing. Int J Lab Hematol 2015; 37 (04) 551-559
    CrossrefPubMedGoogle Scholar
  • 28 Aringer M, Costenbader K, Daikh D. et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019; 78 (09) 1151-1159
    CrossrefPubMedGoogle Scholar
  • 29 Moore GW, Rangarajan S, Holland LJ, Henley A, Savidge GF. Low frequency of elevated prothrombin times in patients with lupus anticoagulants when using a recombinant thromboplastin reagent: implications for dosing and monitoring of oral anticoagulant therapy. Br J Biomed Sci 2005; 62 (01) 15-18 , quiz 47
    CrossrefPubMedGoogle Scholar
  • 30 Pengo V, Ruffatti A, Legnani C. et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011; 118 (17) 4714-4718
    CrossrefPubMedGoogle Scholar
  • 31 Mustonen P, Lehtonen KV, Javela K, Puurunen M. Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study. Lupus 2014; 23 (14) 1468-1476
    CrossrefPubMedGoogle Scholar
  • 32 Ten Boekel E, Böck M, Vrielink GJ, Liem R, Hendriks H, de Kieviet W. Detection of shortened activated partial thromboplastin times: an evaluation of different commercial reagents. Thromb Res 2007; 121 (03) 361-367
    CrossrefPubMedGoogle Scholar
  • 33 Schouwers SM, Delanghe JR, Devreese KM. Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C-reactive protein interfere with LAC test results?. Thromb Res 2010; 125 (01) 102-104
    CrossrefPubMedGoogle Scholar
  • 34 Ruinemans-Koerts J, Ahmed-Ousenkova YM, Kaasjager HA, Hendriks-van Wijhe C, Hovens MM. When to screen for lupus anticoagulant? Influence of testing during acute phase and consequences for clinical practise. Lupus 2015; 24 (11) 1233-1235
    CrossrefPubMedGoogle Scholar
  • 35 Topping J, Quenby S, Farquharson R, Malia R, Greaves M. Marked variation in antiphospholipid antibodies during pregnancy: relationships to pregnancy outcome. Hum Reprod 1999; 14 (01) 224-228
    CrossrefPubMedGoogle Scholar
  • 36 Pengo V, Tripodi A, Reber G. et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7 (10) 1737-1740
    CrossrefPubMedGoogle Scholar
  • 37 Triplett DA, Stocker KF, Unger GA, Barna LK. The Textarin/Ecarin ratio: a confirmatory test for lupus anticoagulants. Thromb Haemost 1993; 70 (06) 925-931
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Liestøl S, Jacobsen EM, Wisløff F. Dilute prothrombin time-based lupus ratio test. Integrated LA testing with recombinant tissue thromboplastin. Thromb Res 2002; 105 (02) 177-182
    CrossrefPubMedGoogle Scholar
  • 39 Moore GW. Alternative assays to dRVVT and aPTT for lupus anticoagulant detection. Am J Hematol 2020; 95 (08) 992-998
    CrossrefPubMedGoogle Scholar
  • 40 Cunliffe A, Dobson J, Swallow G, Ravenscroft J, Tang TS. Taipan snake venom time for antiphospholipid syndrome solves a 20-year diagnostic challenge. Clin Exp Dermatol 2020; 45 (06) 805-808
    CrossrefPubMedGoogle Scholar
  • 41 Hillarp A, Strandberg K, Gustafsson KM, Lindahl TL. Unveiling the complex effects of direct oral anticoagulants on dilute Russell's viper venom time assays. J Thromb Haemost 2020; 18 (08) 1866-1873
    CrossrefPubMedGoogle Scholar
  • 42 Favaloro EJ, Posen J, Ramakrishna R. et al. Factor V inhibitors: rare or not so uncommon? A multi-laboratory investigation. Blood Coagul Fibrinolysis 2004; 15 (08) 637-647
    CrossrefPubMedGoogle Scholar
  • 43 Forastiero R. Bleeding in the antiphospholipid syndrome. Hematology 2012; 17 (Suppl. 01) S153-S155
    CrossrefPubMedGoogle Scholar
  • 44 Pengo V, Biasiolo A, Rampazzo P, Brocco T. dRVVT is more sensitive than KCT or TTI for detecting lupus anticoagulant activity of anti-beta2-glycoprotein I autoantibodies. Thromb Haemost 1999; 81 (02) 256-258
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Galli M, Dlott J, Norbis F. et al. Lupus anticoagulants and thrombosis: clinical association of different coagulation and immunologic tests. Thromb Haemost 2000; 84 (06) 1012-1016
    PubMedGoogle Scholar
  • 46 de Laat HB, Derksen RH, Urbanus RT, Roest M, de Groot PG. beta2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 2004; 104 (12) 3598-3602
    CrossrefPubMedGoogle Scholar
  • 47 Jennings I, Greaves M, Mackie IJ, Kitchen S, Woods TA, Preston FE. UK National External Quality Assessment Scheme for Blood Coagulation. Lupus anticoagulant testing: improvements in performance in a UK NEQAS proficiency testing exercise after dissemination of national guidelines on laboratory methods. Br J Haematol 2002; 119 (02) 364-369
    CrossrefPubMedGoogle Scholar
  • 48 Dembitzer FR, Ledford Kraemer MR, Meijer P, Peerschke EI. Lupus anticoagulant testing: performance and practices by North American clinical laboratories. Am J Clin Pathol 2010; 134 (05) 764-773
    CrossrefPubMedGoogle Scholar
  • 49 Adams M. Measurement of lupus anticoagulants: an update on quality in laboratory testing. Semin Thromb Hemost 2013; 39 (03) 267-271
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Lawrie AS, Mackie IJ, Purdy G, Machin SJ. The sensitivity and specificity of commercial reagents for the detection of lupus anticoagulant show marked differences in performance between photo-optical and mechanical coagulometers. Thromb Haemost 1999; 81 (05) 758-762
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Moore GW, Savidge GF. Heterogeneity of Russell's viper venom affects the sensitivity of the dilute Russell's viper venom time to lupus anticoagulants. Blood Coagul Fibrinolysis 2004; 15 (03) 279-282
    CrossrefPubMedGoogle Scholar
  • 52 Moore GW. Snake venoms in diagnostic hemostasis and thrombosis. Semin Thromb Hemost 2022; 48: 145-160
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 McGlasson DL, Fritsma GA. Comparison of six dilute Russell viper venom time lupus anticoagulant screen/confirm assay kits. Semin Thromb Hemost 2013; 39 (03) 315-319
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Simmelink MJA, Derksen RHWM, Arnout J, De Groot PG. A simple method to discriminate between beta2-glycoprotein I- and prothrombin-dependent lupus anticoagulants. J Thromb Haemost 2003; 1 (04) 740-747
    CrossrefPubMedGoogle Scholar
  • 55 Pengo V, Biasiolo A, Pegoraro C, Iliceto S. A two-step coagulation test to identify antibeta-glycoprotein I lupus anticoagulants. J Thromb Haemost 2004; 2 (05) 702-707
    CrossrefPubMedGoogle Scholar
  • 56 Molhoek JE, de Groot PG, Urbanus RT. The lupus anticoagulant paradox. Semin Thromb Hemost 2018; 44 (05) 445-452
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Fritsma GA, Dembitzer FR, Randhawa A. et al. Recommendations for appropriate activated partial thromboplastin time reagent selection and utilization. Am J Clin Pathol 2012; 137 (06) 904-908
    CrossrefPubMedGoogle Scholar
  • 58 Charles LA, McGlasson DL, Hawksworth BA, Ashcraft JH, Ortel TL. Evaluation of a modified procedure for Staclot LA for the confirmation of lupus anticoagulants. Blood Coagul Fibrinolysis 1994; 5 (04) 601-604
    PubMedGoogle Scholar
  • 59 Devreese KM. Evaluation of a new silica clotting time in the diagnosis of lupus anticoagulants. Thromb Res 2007; 120 (03) 427-438
    CrossrefPubMedGoogle Scholar
  • 60 Moore GW. Commonalities and contrasts in recent guidelines for lupus anticoagulant detection. Int J Lab Hematol 2014; 36 (03) 364-373
    CrossrefPubMedGoogle Scholar
  • 61 Bailly J, Louw S, de Koker A. et al. Guidelines for lupus anticoagulant testing in South Africa. JMLSTSA 2020; 2: 6-12
    PubMedGoogle Scholar
  • 62 Moore GW, Maloney JC, de Jager N. et al. Application of different lupus anticoagulant diagnostic algorithms to the same assay data leads to interpretive discrepancies in some samples. Res Pract Thromb Haemost 2017; 1 (01) 62-68
    CrossrefPubMedGoogle Scholar
  • 63 Dragoni F, Minotti C, Palumbo G. et al. As compared to kaolin clotting time, silica clotting time is a specific and sensitive automated method for detecting lupus anticoagulant. Thromb Res 2001; 101 (02) 45-51
    CrossrefPubMedGoogle Scholar
  • 64 Chantarangkul V, Tripodi A, Arbini A, Mannucci PM. Silica clotting time (SCT) as a screening and confirmatory test for detection of the lupus anticoagulants. Thromb Res 1992; 67 (04) 355-365
    CrossrefPubMedGoogle Scholar
  • 65 Grypiotis P, Ruffatti A, Pengo V. et al. Use of a new silica clotting time for diagnosing lupus anticoagulant in patients who meet the clinical criteria for antiphospholipid syndrome. J Clin Lab Anal 2006; 20 (01) 15-18
    CrossrefPubMedGoogle Scholar
  • 66 Kumano O, Ieko M, Naito S, Yoshida M, Takahashi N. APTT reagent with ellagic acid as activator shows adequate lupus anticoagulant sensitivity in comparison to silica-based reagent. J Thromb Haemost 2012; 10 (11) 2338-2343
    CrossrefPubMedGoogle Scholar
  • 67 Arnout J, Vanrusselt M, Huybrechts E, Vermylen J. Optimization of the dilute prothrombin time for the detection of the lupus anticoagulant by use of a recombinant tissue thromboplastin. Br J Haematol 1994; 87 (01) 94-99
    CrossrefPubMedGoogle Scholar
  • 68 Mackie IJ, Lawrie AS, Greenfield RS, Guinto ER, Machin SJ. A new lupus anticoagulant test based on dilute prothrombin time. Thromb Res 2004; 114: 673-674
    PubMedGoogle Scholar
  • 69 Swadzba J, Iwaniec T, Pulka M, De Laat B, De Groot PG, Musial J. Lupus anticoagulant: performance of the tests as recommended by the latest ISTH guidelines. J Thromb Haemost 2011; 9 (09) 1776-1783
    CrossrefPubMedGoogle Scholar
  • 70 Moore GW, Smith MP, Patel Y, Savidge GF. The Activated Seven Lupus Anticoagulant (ASLA) assay: a new test for lupus anticoagulants (LAs). Evidence that some LAs are detectable only in extrinsic pathway-based assays. Blood Coagul Fibrinolysis 2002; 13 (03) 261-269
    CrossrefPubMedGoogle Scholar
  • 71 Marinuzzo M, Adamczuk Y, Varela ML, Pombo G, Forastiero R. The Activated Seven Lupus Anticoagulant (ASLA) test has comparable sensitivity to classical assays for screening of lupus anticoagulant. Thromb Haemost 2005; 93 (05) 1007-1009
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Moore GW, Rangarajan S, Savidge GF. The activated seven lupus anticoagulant assay detects clinically significant antibodies. Clin Appl Thromb Hemost 2008; 14 (03) 332-337
    CrossrefPubMedGoogle Scholar
  • 73 Goldford MD. Lupus anticoagulant screen and confirm reagents utilizing the FX activating venom from Vipera lebetina. J Thromb Haemost 2013; 11 (Suppl. 03) 61 (Abstract LSPE34)
    PubMedGoogle Scholar
  • 74 Rooney AM, McNally T, Mackie IJ, Machin SJ. The Taipan snake venom time: a new test for lupus anticoagulant. J Clin Pathol 1994; 47 (06) 497-501
    CrossrefPubMedGoogle Scholar
  • 75 Moore GW, Smith MP, Savidge GF. The Ecarin time is an improved confirmatory test for the Taipan snake venom time in warfarinized patients with lupus anticoagulants. Blood Coagul Fibrinolysis 2003; 14 (03) 307-312
    CrossrefPubMedGoogle Scholar
  • 76 Moore GW, Jones PO, Platton S. et al. International multicenter, multiplatform study to validate Taipan snake venom time as a lupus anticoagulant screening test with ecarin time as the confirmatory test: Communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2021; 19 (12) 3177-3192
    CrossrefPubMedGoogle Scholar
  • 77 Moore GW, Culhane AP, Maloney JC, Archer RA, Breen KA, Hunt BJ. Taipan snake venom time coupled with ecarin time enhances lupus anticoagulant detection in nonanticoagulated patients. Blood Coagul Fibrinolysis 2016; 27 (04) 477-480
    CrossrefPubMedGoogle Scholar
  • 78 Arnout J, Wittevrongel C, Vanrusselt M, Hoylaerts M, Vermylen J. Beta-2-glycoprotein I dependent lupus anticoagulants form stable bivalent antibody beta-2-glycoprotein I complexes on phospholipid surfaces. Thromb Haemost 1998; 79 (01) 79-86
    Article in Thieme ConnectPubMedGoogle Scholar
  • 79 Field SL, Chesterman CN, Dai Y-P, Hogg PJ. Lupus antibody bivalency is required to enhance prothrombin binding to phospholipid. J Immunol 2001; 166 (10) 6118-6125
    CrossrefPubMedGoogle Scholar
  • 80 Simmelink MJ, Horbach DA, Derksen RH. et al. Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulant activity by competing with the binding of clotting factors for catalytic phospholipid surfaces. Br J Haematol 2001; 113 (03) 621-629
    CrossrefPubMedGoogle Scholar
  • 81 Noordermeer T, Molhoek JE, Schutgens REG. et al. Anti-β2-glycoprotein I and anti-prothrombin antibodies cause lupus anticoagulant through different mechanisms of action. J Thromb Haemost 2021; 19 (04) 1018-1028
    CrossrefPubMedGoogle Scholar
  • 82 Amagai H, Kanda T, Shizuka R, Fukumura Y, Kobayashi I. Ratio of factor V activities in PT and APTT assays as a new diagnostic marker of lupus anticoagulant. Clin Lab Haematol 1999; 21 (01) 45-49
    CrossrefPubMedGoogle Scholar
  • 83 Moore GW, Savidge GF. The dilution effect of equal volume mixing studies compromises confirmation of inhibition by lupus anticoagulants even when mixture specific reference ranges are applied. Thromb Res 2006; 118 (04) 523-528
    CrossrefPubMedGoogle Scholar
  • 84 Devreese KM. No more mixing tests required for integrated assay systems in the laboratory diagnosis of lupus anticoagulants?. J Thromb Haemost 2010; 8 (05) 1120-1122
    CrossrefPubMedGoogle Scholar
  • 85 Reber G, Meijer P. In ECAT veritas?. Lupus 2012; 21 (07) 722-724
    CrossrefPubMedGoogle Scholar
  • 86 Hong SK, Hwang SM, Kim JE, Kim HK. Clinical significance of the mixing test in laboratory diagnoses of lupus anticoagulant: the fate of the mixing test in integrated lupus anticoagulant test systems. Blood Coagul Fibrinolysis 2012; 23 (08) 739-744
    CrossrefPubMedGoogle Scholar
  • 87 Pennings MT, De Groot PG, Meijers JC, Huisman A, Derksen RH, Urbanus RT. Optimisation of lupus anticoagulant tests: should test samples always be mixed with normal plasma?. Thromb Haemost 2014; 112 (04) 736-742
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Devreese KM, de Laat B. Mixing studies in lupus anticoagulant testing are required at least in some type of samples. J Thromb Haemost 2015; 13 (08) 1475-1478
    CrossrefPubMedGoogle Scholar
  • 89 Moore GW. Mixing studies for lupus anticoagulant: mostly no, sometimes yes. Clin Chem Lab Med 2020; 58 (04) 492-495
    CrossrefPubMedGoogle Scholar
  • 90 Kaczor DA, Bickford NN, Triplett DA. Evaluation of different mixing study reagents and dilution effect in lupus anticoagulant testing. Am J Clin Pathol 1991; 95 (03) 408-411
    CrossrefPubMedGoogle Scholar
  • 91 Moore GW, Brown KL, Bromidge ES, Drew AJ, Ledford-Kraemer MR. Lupus anticoagulant detection: out of control?. Int J Lab Hematol 2013; 35 (02) 128-136
    CrossrefPubMedGoogle Scholar
  • 92 Moore GW. Reference interval mean clotting times should not be used to calculate lupus anticoagulant mixing test ratios unless they match the normal pooled plasma clotting time. Thromb Res 2017; 159: 16-18
    CrossrefPubMedGoogle Scholar
  • 93 Chandrashekar V. Dilute Russell's viper venom and activated partial thromboplastin time in lupus anticoagulant diagnosis: is mixing essential?. Blood Coagul Fibrinolysis 2016; 27 (04) 408-411
    CrossrefPubMedGoogle Scholar
  • 94 Asakrah S, Davis R, Bhargava P. Practical considerations and testing nuances for the detection of lupus anticoagulant: do low phospholipid screen results, assay type, and test ratio matter?. Am J Clin Pathol 2021; 156 (06) 1073-1082
    CrossrefPubMedGoogle Scholar
  • 95 Favaloro EJ, Bonar R, Zebeljan D, Kershaw G, Marsden K. Laboratory investigation of lupus anticoagulants: mixing studies are sometimes required. J Thromb Haemost 2010; 8 (12) 2828-2831
    CrossrefPubMedGoogle Scholar
  • 96 Moore GW, Savidge GF, Smith MP. Improved detection of lupus anticoagulants by the dilute Russell's Viper venom time. Blood Coagul Fibrinolysis 2000; 11 (08) 767-774
    CrossrefPubMedGoogle Scholar
  • 97 Favaloro E. Mixing studies for lupus anticoagulant: mostly yes, sometimes no. Clin Chem Lab Med 2020; 58 (04) 487-491
    CrossrefPubMedGoogle Scholar
  • 98 Pengo V, Zardo L, Cattini MG. et al. Prothrombin Is responsible for the lupus cofactor phenomenon in a patient with lupus anticoagulant/hypoprothrombinemia syndrome. TH Open 2020; 4 (01) e40-e44
    Article in Thieme ConnectPubMedGoogle Scholar
  • 99 Oosting JD, Derksen RH, Entjes HT, Bouma BN, de Groot PG. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost 1992; 67 (05) 499-502
    Article in Thieme ConnectPubMedGoogle Scholar
  • 100 Murphy CH, Jin J, Zehnder JL. Antiphospholipid antibodies in patients with lupus anticoagulant prozone effect. Am J Clin Pathol 2020; 153 (02) 229-234
    CrossrefPubMedGoogle Scholar
  • 101 Limper M, de Leeuw K, Lely AT. et al. Diagnosing and treating antiphospholipid syndrome: a consensus paper. Neth J Med 2019; 77 (03) 98-108
    PubMedGoogle Scholar
  • 102 Cohen H, Mackie IJ, Devreese KMJ. International Society for Thrombosis and Haemostasis Scientific and Standardization Committee for Lupus Anticoagulant/Antiphospholipid Antibodies. Clinical and laboratory practice for lupus anticoagulant testing: An International Society of Thrombosis and Haemostasis Scientific and Standardization Committee survey. J Thromb Haemost 2019; 17 (10) 1715-1732
    CrossrefPubMedGoogle Scholar
  • 103 Gardiner C, MacKie IJ, Malia RG. et al. The importance of locally derived reference ranges and standardized calculation of dilute Russell's viper venom time results in screening for lupus anticoagulant. Br J Haematol 2000; 111 (04) 1230-1235
    CrossrefPubMedGoogle Scholar
  • 104 Gerbutavicius R, Fareed J, Messmore Jr HL. et al. Reference intervals of the dilute tissue thromboplastin inhibition and dilute Russell's viper venom tests revisited. Clin Appl Thromb Hemost 2002; 8 (02) 115-124
    CrossrefPubMedGoogle Scholar
  • 105 Pradella P, Azzarini G, Santarossa L. et al. Cooperation experience in a multicentre study to define the upper limits in a normal population for the diagnostic assessment of the functional lupus anticoagulant assays. Clin Chem Lab Med 2013; 51 (02) 379-385
    CrossrefPubMedGoogle Scholar
  • 106 Moore GW, Kumano O. Lupus anticoagulant assay cut-offs vary between reagents even when derived from a common set of normal donor plasmas. J Thromb Haemost 2020; 18 (02) 439-444
    CrossrefPubMedGoogle Scholar
  • 107 Tripodi A, Chantarangkul V, Cini M. et al. Variability of cut-off values for the detection of lupus anticoagulants: results of an international multicenter multiplatform study. J Thromb Haemost 2017; 15 (06) 1180-1190
    CrossrefPubMedGoogle Scholar
  • 108 Chantarangkul V, Peyvandi F, Tripodi A. Investigating Group. Effect of different methods for outlier detection and rejection when calculating cut off values for diagnosis of lupus anticoagulants. Thromb Res 2020; 190: 20-25
    CrossrefPubMedGoogle Scholar
  • 109 Jennings I, Mackie I, Arnout J, Preston FE. UK National External Quality Assessment Scheme for Blood Coagulation. Lupus anticoagulant testing using plasma spiked with monoclonal antibodies: performance in the UK NEQAS proficiency testing programme. J Thromb Haemost 2004; 2 (12) 2178-2184
    CrossrefPubMedGoogle Scholar
  • 110 Favaloro EJ, Bonar R, Marsden K. Internal quality control and external quality assurance in testing for antiphospholipid antibodies: Part II–Lupus anticoagulant. Semin Thromb Hemost 2012; 38 (04) 404-411
    Article in Thieme ConnectPubMedGoogle Scholar
  • 111 CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline. 3rd ed. CLSI Document C28–A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008
    Google Scholar
  • 112 Depreter B, Devreese KM. Differences in lupus anticoagulant final conclusion through clotting time or Rosner index for mixing test interpretation. Clin Chem Lab Med 2016; 54 (09) 1511-1516
    PubMedGoogle Scholar
  • 113 Moore GW, Culhane AP, Daw CR, Noronha CP, Kumano O. Mixing test specific cut-off is more sensitive at detecting lupus anticoagulants than index of circulating anticoagulant. Thromb Res 2016; 139: 98-101
    CrossrefPubMedGoogle Scholar
  • 114 Kumano O, Moore GW. 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 2017; 2 (01) 105-113
    CrossrefPubMedGoogle Scholar
  • 115 Tripodi A, Cohen H, Devreese KMJ. Lupus anticoagulant detection in anticoagulated patients. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020; 18 (07) 1569-1575
    CrossrefPubMedGoogle Scholar
  • 116 Jouhikainen T. Detection of lupus anticoagulant by means of dilute Russell's viper venom time is affected by oral anticoagulant therapy. Blood Coagul Fibrinolysis 1990; 1 (06) 627-632
    PubMedGoogle Scholar
  • 117 Olteanu H, Downes KA, Patel J, Praprotnik D, Sarode R. Warfarin does not interfere with lupus anticoagulant detection by dilute Russell's viper venom time. Clin Lab 2009; 55 (3-4): 138-142
    PubMedGoogle Scholar
  • 118 Chandler JB, Torres R, Rinder HM, Tormey CA. Lupus anticoagulant testing and anticoagulation do not mix: quantitation of discrepant results and potential approaches to reduce false positives. Br J Haematol 2014; 167 (05) 704-707
    CrossrefPubMedGoogle Scholar
  • 119 Isert M, Miesbach W, Stoever G, Lindhoff-Last E, Linnemann B. Screening for lupus anticoagulants in patients treated with vitamin K antagonists. Int J Lab Hematol 2015; 37 (06) 758-765
    CrossrefPubMedGoogle Scholar
  • 120 Seheult JN, Meyer MP, Bontempo FA, Chibisov I. The effects of indirect- and direct-acting anticoagulants on lupus anticoagulant assays: a large, retrospective study at a coagulation reference laboratory. Am J Clin Pathol 2017; 147 (06) 632-640
    CrossrefPubMedGoogle Scholar
  • 121 Kanouchi K, Narimatsu H, Ohnuma O, Morikane K, Fukao A. Clinical usefulness of the dilute Russell viper venom time test for patients taking warfarin. Int J Hematol 2017; 106 (02) 206-211
    CrossrefPubMedGoogle Scholar
  • 122 Moore GW. Combining Taipan snake venom time/Ecarin time screening with the mixing studies of conventional assays increases detection rates of lupus anticoagulants in orally anticoagulated patients. Thromb J 2007; 5: 12
    CrossrefPubMedGoogle Scholar
  • 123 Moore GW, Kamat AV, Gurney DA. et al. Alteration in the laboratory profile of a lupus anticoagulant in a patient with non-Hodgkin's lymphoma. Clin Lab Haematol 2004; 26 (06) 429-434
    CrossrefPubMedGoogle Scholar
  • 124 Cattini MG, Bison E, Pontara E, Cheng C, Denas G, Pengo V. Tetra positive thrombotic antiphospholipid syndrome: major contribution of anti-phosphatidyl-serine/prothrombin antibodies to lupus anticoagulant activity. J Thromb Haemost 2020; 18 (05) 1124-1132
    CrossrefPubMedGoogle Scholar
  • 125 Tonello M, Bison E, Cattini MG. et al. Anti-phosphatidyl-serine/prothrombin antibodies (aPS/PT) in isolated lupus anticoagulant (LA): is their presence linked to dual test positivity?. Clin Chem Lab Med 2021; 59 (12) 1950-1953
    CrossrefPubMedGoogle Scholar
  • 126 Reda S, Brügelmann A, Müller J, Oldenburg J, Pötzsch B, Rühl H. Functional lupus anticoagulant testing in a large retrospective cohort of thrombosis patients with direct oral anticoagulants. Sci Rep 2020; 10 (01) 12221
    CrossrefPubMedGoogle Scholar
  • 127 De Kesel PMM, Devreese KMJ. The effect of unfractionated heparin, enoxaparin, and danaparoid on lupus anticoagulant testing: can activated carbon eliminate false-positive results?. Res Pract Thromb Haemost 2019; 4 (01) 161-168
    CrossrefPubMedGoogle Scholar
  • 128 Martinuzzo ME, Barrera LH, D'adamo MA, Otaso JC, Gimenez MI, Oyhamburu J. Frequent false-positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin. Int J Lab Hematol 2014; 36 (02) 144-150
    CrossrefPubMedGoogle Scholar
  • 129 Olah Z, Szarvas M, Bereczky Z, Kerenyi A, Kappelmayer J, Boda Z. Direct thrombin inhibitors and factor Xa inhibitors can influence the diluted prothrombin time used as the initial screen for lupus anticoagulant. Arch Pathol Lab Med 2013; 137 (07) 967-973
    CrossrefPubMedGoogle Scholar
  • 130 Arachchillage DR, Mackie IJ, Efthymiou M, Isenberg DA, Machin SJ, Cohen H. Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome. J Thromb Haemost 2015; 13 (07) 1264-1273
    CrossrefPubMedGoogle Scholar
  • 131 Flieder T, Weiser M, Eller T. et al. Interference of DOACs in different DRVVT assays for diagnosis of lupus anticoagulants. Thromb Res 2018; 165: 101-106
    CrossrefPubMedGoogle Scholar
  • 132 Depreter B, Devreese KM. Dilute Russell's viper venom time reagents in lupus anticoagulant testing: a well-considered choice. Clin Chem Lab Med 2017; 55 (01) 91-101
    CrossrefPubMedGoogle Scholar
  • 133 Moore GW, Peyrafitte M, Dunois C, Amiral J. Newly developed dilute Russell's viper venom reagents for lupus anticoagulant detection with improved specificity. Lupus 2018; 27 (01) 95-104
    CrossrefPubMedGoogle Scholar
  • 134 Ratzinger F, Lang M, Belik S. et al. Lupus-anticoagulant testing at NOAC trough levels. Thromb Haemost 2016; 116 (02) 235-240
    PubMedGoogle Scholar
  • 135 Gay J, Duchemin J, Imarazene M, Fontenay M, Jourdi G. Lupus anticoagulant diagnosis in patients receiving direct oral FXa inhibitors at trough levels: a real-life study. Int J Lab Hematol 2019; 41 (06) 738-744
    CrossrefPubMedGoogle Scholar
  • 136 Hillarp A, Gustafsson KM, Faxälv L. et al. Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays. J Thromb Haemost 2014; 12 (09) 1545-1553
    CrossrefPubMedGoogle Scholar
  • 137 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
    CrossrefPubMedGoogle Scholar
  • 138 Bonar R, Favaloro EJ, Mohammed S. et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex-vivo samples. Pathology 2016; 48 (01) 60-71
    CrossrefPubMedGoogle Scholar
  • 139 Antovic A, Norberg EM, Berndtsson M. et al. Effects of direct oral anticoagulants on lupus anticoagulant assays in a real-life setting. Thromb Haemost 2017; 117 (09) 1700-1704
    Article in Thieme ConnectPubMedGoogle Scholar
  • 140 Villalba JA, Van Cott EM. High frequency of false-positive results of aPTT-based lupus anticoagulant tests in patients receiving argatroban. Am J Hematol 2019; 94 (06) E166-E169
    CrossrefPubMedGoogle Scholar
  • 141 De Kesel PM, Devreese KMJ. Direct oral anticoagulant adsorption: impact on lupus anticoagulant testing-review of the literature and evaluation on spiked and patient samples. J Thromb Haemost 2020; 18 (08) 2003-2017
    CrossrefPubMedGoogle Scholar
  • 142 Exner T, Ahuja M, Ellwood L. Effect of an activated charcoal product (DOAC Stop™) intended for extracting DOACs on various other APTT-prolonging anticoagulants. Clin Chem Lab Med 2019; 57 (05) 690-696
    CrossrefPubMedGoogle Scholar
  • 143 Riva N, Vella K, Hickey K. et al. The effect of DOAC-Stop® on several oral and parenteral anticoagulants. Int J Lab Hematol 2021; 43 (04) O171-O175
    CrossrefPubMedGoogle Scholar
  • 144 Baker SA, Jin J, Pfaffroth C, Vu T, Zehnder JL. DOAC-Stop in lupus anticoagulant testing: direct oral anticoagulant interference removed in most samples. Res Pract Thromb Haemost 2021; 5 (02) 314-325
    CrossrefPubMedGoogle Scholar
  • 145 Cox-Morton S, MacDonald S, Thomas W. A diagnostic solution for haemostasis laboratories for patients taking direct oral anticoagulants using DOAC-Remove. Br J Haematol 2019; 187 (03) 377-385
    CrossrefPubMedGoogle Scholar
  • 146 Farkh C, Ellouze S, Gounelle L. et al. A diagnostic solution for lupus anticoagulant testing in patients taking direct oral FXa inhibitors using DOAC filter. Front Med (Lausanne) 2021; 8: 683357
    CrossrefPubMedGoogle Scholar
  • 147 Skaugen JM, Sayre C, Hassett AC. et al. Performance characteristics of DOAC-Remove for neutralization of the effects of apixaban and rivaroxaban in lupus anticoagulant assays. Am J Clin Pathol 2021; x: 149
    PubMedGoogle Scholar
  • 148 Platton S, Hunt C. Influence of DOAC Stop on coagulation assays in samples from patients on rivaroxaban or apixaban. Int J Lab Hematol 2019; 41 (02) 227-233
    CrossrefPubMedGoogle Scholar
  • 149 Szabó G, Antal-Szalmás P, Kerényi A, Pénzes K, Bécsi B, Kappelmayer J. Laboratory approaches to test the function of antiphospholipid antibodies. Semin Thromb Hemost 2022; 48 (02) 132-144
    Article in Thieme ConnectPubMedGoogle Scholar