Abstract
Background:
Lupus anticoagulant (LAC) detection represents diagnostic challenges among which the multitude of available reagents and interference by anticoagulant treatment. One of the two advised tests is the dilute Russell’s viper venom time (dRVVT). However, it is currently not clear whether all dRVVT reagents may be considered equivalent. The objective of the study was to evaluate the diagnostic performance of two dRVVT reagents, with special attention to the influence of anticoagulant therapy.
Methods:
STA®-Staclot® dRVV Screen/Confirm (Stago, Asnières-sur-Seine, France) and dRVT-LS/dRVTL-LR (Haematex, Hornsby, Australia) were evaluated on 443 patient samples [358 consecutive patients with LAC request including six antiphospholipid syndrome (APS) patients, 18 non-consecutively selected APS patients and 37 vitamin K antagonists (VKA)-treated and 30 direct oral anticoagulants (DOAC)-treated non-APS patients]. Additionally, pooled normal plasma (PNP) was spiked with factor deficient plasma (n=33) and DOAC calibrators (n=21) to evaluate sensitivity for factor deficiencies and false-positivity rates, respectively.
Results:
A higher number of samples were defined as LAC positive by Stago vs. Haematex [11.5% (41/358) vs. 3.63% (13/358)]. Most discordances were in the VKA and DOAC group. Haematex was less prone to VKA-related factor deficiencies, explaining the absence of false-positive LAC results in VKA-treated non-APS patients compared to 10.8% with Stago. We observed no false-positive LAC ratios with Haematex in DOAC-spiked PNP and a lower number in DOAC-treated non-APS patients. However, increased specificity seemed to be at cost of a reduced sensitivity as Haematex showed less positive APS patient samples (45.8% vs. 87.5%).
Conclusions:
dRVVT reagents differ in LAC sensitivity and for VKA and DOAC interference.
Acknowledgments:
We wish to thank Michael Luypaert and Fien Matthys for their technical support and all lab technicians of the Coagulation Laboratory for their practical help. The authors thank Stago Diagnostica and T. Exner for providing us the dRVVT reagents for this study.
Author contributions: B. Depreter interpreted data, performed statistical analyses and wrote the manuscript. K. Devreese designed the study, interpreted data and wrote and reviewed the manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Court EL. Lupus anticoagulants: pathogenesis and laboratory diagnosis. Br J Biomed Sci 1997;54:287–98.Search in Google Scholar
2. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants – an update. Thromb Haemost 1995;74:1185–90.10.1055/s-0038-1649901Search in Google Scholar
3. Machin SJ, Giddings JC, Greaves M, Hutton RA, Mackie IJ, Malia RG, et al. Guidelines on testing for the lupus anticoagulant. J clin pathol 1991;44:885–9.Search in Google Scholar
4. Clinical and Laboratory Standards Institute. Laboratory testing for the lupus anticoagulant; Approved guideline, Wayne: CLSI Document H60-A, 2014. 2014.Search in Google Scholar
5. Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. British committee for standards in H. guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012;157:47–58.10.1111/j.1365-2141.2012.09037.xSearch in Google Scholar PubMed
6. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardisation committee of the international society on thrombosis and haemostasis. J Thromb Haemost 2009;7:1737–40.10.1111/j.1538-7836.2009.03555.xSearch in Google Scholar PubMed
7. Devreese KM. Antiphospholipid antibody testing and standardization. Int J Lab Hem 2014;36:352–63.10.1111/ijlh.12234Search in Google Scholar PubMed
8. Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem 2010;56:930–40.10.1373/clinchem.2009.133678Search in Google Scholar PubMed
9. Devreese K, Hoylaerts MF. Laboratory diagnosis of the antiphospholipid syndrome: a plethora of obstacles to overcome. Eur J Hematol 2009;83:1–16.10.1111/j.1600-0609.2009.01243.xSearch in Google Scholar PubMed
10. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.10.1111/j.1538-7836.2006.01753.xSearch in Google Scholar PubMed
11. McGlasson DL, Fritsma GA. Comparison of six dilute russell viper venom time lupus anticoagulant screen/confirm assay kits. Sem Thromb Hemost 2013;39:315–9.10.1055/s-0033-1334865Search in Google Scholar PubMed
12. Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Sem Thromb Hemost 2014;40:163–71.10.1055/s-0033-1364185Search in Google Scholar PubMed
13. 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;81:758–62.10.1055/s-0037-1614567Search in Google Scholar
14. Chantarangkul V, Biguzzi E, Asti D, Palmucci C, Tripodi A. Laboratory diagnostic outcome applying detection criteria recommended by the scientific and standardization committee of the ISTH on lupus anticoagulant. Thromb Haemost 2013;110:46–52.10.1160/TH12-11-0850Search in Google Scholar PubMed
15. Haematex dRVT insert. Available at: http://haematex.com/images/haematex_dRVTinsert.pdf. Accessed on 6 Feb, 2016.Search in Google Scholar
16. 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;167:704–7.10.1111/bjh.13030Search in Google Scholar PubMed PubMed Central
17. Moore GW. Commonalities and contrasts in recent guidelines for lupus anticoagulant detection. Int J Lab Hem 2014;36:364–73.10.1111/ijlh.12227Search in Google Scholar PubMed
18. Barnes GD, Ageno W, Ansell J, Kaatz S. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:1539.Search in Google Scholar
19. Antovic J, Antovic A, Norberg EM, Berndtsson M, Skeppholm M. Effects of new (direct) oral anticoagulants on lupus anticoagulant assays. J Thromb Haemost 2015;13:166– Meeting Abstract: OR87.10.1136/annrheumdis-2015-eular.5847Search in Google Scholar
20. van Os GM, de Laat B, Kamphuisen PW, Meijers JC, de Groot PG. Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time. J Thromb Haemost 2011;9:1657–9.10.1111/j.1538-7836.2011.04395.xSearch in Google Scholar PubMed
21. Martinuzzo ME, Barrera LH, MA Da, 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 Hem 2014;36:144–50.10.1111/ijlh.12138Search in Google Scholar PubMed
22. 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;13:1264–73.10.1111/jth.12917Search in Google Scholar PubMed
23. Merriman E, Kaplan Z, Butler J, Malan E, Gan E, Tran H. Rivaroxaban and false positive lupus anticoagulant testing. Thromb Haemost 2011;105:385–6.10.1160/TH10-08-0511Search in Google Scholar PubMed
24. Goralczyk T, Iwaniec T, Wypasek E, Undas A. False-positive lupus anticoagulant in patients receiving rivaroxaban: 24 h since the last dose are needed to exclude antiphospholipid syndrome. Blood Coagul Fibrin 2015;26:473–5.10.1097/MBC.0000000000000235Search in Google Scholar PubMed
25. Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993;70:787–93.10.1055/s-0038-1649671Search in Google Scholar
26. Triplett DA. Assays for detection of antiphospholipid antibodies. Lupus 1994;3:281–7.10.1177/096120339400300415Search in Google Scholar PubMed
27. 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;139:98–101.10.1016/j.thromres.2016.01.019Search in Google Scholar PubMed
28. 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;54:1511–6.10.1515/cclm-2015-0978Search in Google Scholar PubMed
29. Devreese KM. No more mixing tests required for integrated assay systems in the laboratory diagnosis of lupus anticoagulants? J Thromb Haemost 2010;8:1120–2.10.1111/j.1538-7836.2010.03807.xSearch in Google Scholar PubMed
30. Favaloro EJ, Bonar R, Zebeljan D, Kershaw G, Marsden K. Laboratory investigation of lupus anticoagulants: mixing studies are sometimes required. J Thromb Haemost 2010;8:2828–31.10.1111/j.1538-7836.2010.04090.xSearch in Google Scholar PubMed
31. Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogne JM. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res 2012;130: 956–66.10.1016/j.thromres.2012.09.004Search in Google Scholar PubMed
32. Becker RC, Yang H, Barrett Y, Mohan P, Wang J, Wallentin L, et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban--an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011;32:183–7.10.1007/s11239-011-0591-8Search in Google Scholar PubMed
33. Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus? Clin Chem Lab Med 2015;53: 185–97.10.1515/cclm-2014-0767Search in Google Scholar PubMed
34. Van Blerk M, Bailleul E, Chatelain B, Demulder A, Devreese K, Douxfils J, et al. Influence of dabigatran and rivaroxaban on routine coagulation assays a nationwide Belgian survey. Thromb Haemost 2015;113:154–64.10.1160/TH14-02-0161Search in Google Scholar PubMed
35. Dumoulin EN, Fiers L, Devreese KM. Investigation of sensitivity for coagulation factor deficiency in APTT and PT: how to perform it? Clin Chem Lab Med 2016;54:169–72.10.1515/cclm-2015-0670Search in Google Scholar PubMed
36. Practical guide dabigatran, guidance for use in particular situations. Thrombosis guidelines group of the Belgian society of Thrombosis and Haemostasis (Version 2.0, January 2013, http://www.thrombosisguidelinesgroup.be/sites/default/files/Dabigatran%20practical%20guide_Version%202%200_January%202013.pdf).Search in Google Scholar
37. Fabris M, Giacomello R, Poz A, Pantarotto L, Tanzi N, Curcio F, et al. The introduction of anti-phosphatidylserine/prothrombin autoantibodies in the laboratory diagnostic process of anti-phospholipid antibody syndrome: 6 months of observation. Auto Immun Highlights 2014;5:63–7.10.1007/s13317-014-0061-3Search in Google Scholar PubMed PubMed Central
38. Exner T, Ellwood L, Rubie J, Barancewicz A. Testing for new oral anticoagulants with LA-resistant Russells viper venom reagents. An in vitro study. Thromb Haemost 2013;109:762–5.10.1160/TH12-11-0842Search in Google Scholar PubMed
39. Halbmayer WM, Weigel G, Quehenberger P, Tomasits J, Haushofer AC, Aspoeck G, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med 2012;50:1601–5.10.1515/cclm-2011-0888Search in Google Scholar PubMed
40. Smith SA, Comp PC, Morrissey JH. Phospholipid composition controls thromboplastin sensitivity to individual clotting factors. J Thromb Haemost 2006;4:820–7.10.1111/j.1538-7836.2006.01848.xSearch in Google Scholar PubMed
41. Isert M, Miesbach W, Schuttfort G, Weil Y, Tirneci V, Kasper A, et al. Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome. Ann Hematol 2015;94:1291–9.10.1007/s00277-015-2374-3Search in Google Scholar PubMed
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