Laboratory Testing for Lupus Anticoagulants: Preexamination Variables, Mixing Studies, and Diagnostic Criteria

ABSTRACT

The latest international guidelines for the laboratory diagnosis of lupus anticoagulants (LA) date back to 1995 and are in need of revision. Various patterns of practice and interpretation by clinical laboratories have altered the intent or usage of the criteria and recommendations made at that time. Moreover, various topics in the preexamination phase of LA testing (such as the role of the clinician in test ordering, the impact of direct thrombin inhibitors or oral anticoagulant therapy, and patient biologic variation) need to be considered in future guidelines. In like fashion, examination issues relating to mixing studies will need critical review. Mixing studies have been applied to a variety of low-phospholipid LA screening assays, and no uniformity or standardization exists as to how these test results should be interpreted or if in fact they are suitable for identifying weak lupus anticoagulants.

KEYWORDS

Lupus anticoagulant(s) - lupus anticoagulant testing - mixing studies - preexamination variables - ISTH SSC guidelines

REFERENCES

• 1 Green D, Hougie C, Kazmier F J et al.. Report of the Working Party on Acquired Inhibitors of Coagulation: studies of the “lupus” anticoagulant.  Thromb Haemost. 1983;  49 144-146
• 2 Exner T, Triplett D A, Taberner D, Machin S J. Guidelines for testing and revised criteria for lupus anticoagulants. SSC Subcommittee for the Standardization of Lupus Anticoagulants.  Thromb Haemost. 1991;  65 320-322
• 3 Brandt J T, Triplett D A, Alving B, Scharrer I. on behalf of the Subcommittee on Lupus Anticoagulant / Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH . Criteria for the diagnosis of lupus anticoagulants: an update.  Thromb Haemost. 1995;  74 1185-1190
• 4 Moffat K A, McKay H, Ledford-Kraemer M R et al.. Variability of clinical laboratory practices in testing for lupus anticoagulant and antiphospholipid antibodies: results of a NASCOLA survey.  [abstract 141] Lab Hematol. 2006;  12 170-171
• 5 http://Available at: www.wordnet.princeton.edu/perl/webwn?s=criterion Accessed August 21, 2007
• 6 Clinical Laboratory Standards Institute .Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture: Approved Standard-Sixth Edition. Wayne, PA; CLSI document H03–A6 2007
• 7 Clinical Laboratory Standards Institute .Procedures for the Handling and Processing of Blood Specimens: Approved Guideline. Third ed. Wayne, PA; Clinical Laboratory Standards Institute 2004 Document H18–A3
• 8 Clinical Laboratory Standards Institute .Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays and Molecular Hemostasis Assays: Approved Guideline. 5th ed. Wayne, PA; Clinical Laboratory Standards Institute 2008 Document H21–A5
• 9 Woodhams B, Girardot O, Blanco M-J, Colesse G, Gourmelin Y. Stability of coagulation proteins in frozen plasma.  Blood Coagul Fibrinolysis. 2001;  12 229-236
• 10 Chantarangkul V, Tripodi A, Clerici M, Bressi C, Mannucci P M. Laboratory diagnosis of lupus anticoagulants—effect of residual platelets in plasma, assessed by Staclot LA and silica clotting time.  Thromb Haemost. 2002;  87 854-858
• 11 Favaloro E J. Preanalytical variables in coagulation testing.  Blood Coagul Fibrinolysis. 2007;  18 86-89
• 12 Exner T, Low J. Detection of procoagulant phospholipid interfering in tests for lupus anticoagulant.  Thromb Res. 2004;  114 547-552
• 13 Narayanan S. Preanalytical aspects of coagulation testing.  Haematologica. 1995;  80(Suppl 2) 1-6
• 14 van den Besselaar A M, Meeuwisse-Braun J. Enzymatic elimination of heparin from plasma for activated partial thromboplastin time and prothrombin time testing.  Blood Coagul Fibrinolysis. 1993;  4 635-638
• 15 Jacobsen E M, Trettenes E J, Wisloff F, Abildgaard U. Detection and quantification of lupus anticoagulants in plasma from heparin treated patients, using addition of polybrene.  http://Available at: www.thrombosisjournal.com/content/4/1/3 Accessed October 22, 2007; 
• 16 Gosselin R C, Dager W E, King J H et al.. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values.  Am J Clin Pathol. 2004;  121 593-599
• 17 Warkentin T E. Heparin-induced thrombocytopenia: pathogenesis and management.  Br J Haematol. 2003;  121 535-555
• 18 Smogorzewska A, Brandt J T, Chandler W L et al.. Effect of fondaparinux on coagulation assays: results of College of American Pathologists proficiency testing.  Arch Pathol Lab Med. 2006;  130 1605-1611
• 19 Gosselin R C, King J H, Janatpur K A, Dager W H, Larkin E C, Owings J T. Effects of pentasaccharide (fondaparinux) and direct thrombin inhibitors on coagulation testing.  Arch Pathol Lab Med. 2004;  128 1142-1145
• 20 Genzen J R, Miller J L. Presence of direct thrombin inhibitors can affect the results and interpretation of lupus anticoagulant testing.  Am J Clin Pathol. 2005;  124 586-593
• 21 Tripodi A, Chantarangkul V, Clerici M, Mannucci P M. Laboratory diagnosis of lupus anticoagulants for patients on oral anticoagulant treatment. Performance of dilute Russell viper venom test and silica clotting time in comparison with Staclot LA.  Thromb Haemost. 2002;  88 583-586
• 22 Rauch J, Tannenbaum M, Janoff A S. Distinguishing plasma lupus anticoagulants from anti-factor antibodies using hexagonal (II) phase phospholipids.  Thromb Haemost. 1989;  62 892-896
• 23 Triplett D A, Stocker K F, Unger G A, Barna L K. The textarin/ecarin ratio: a confirmatory test for lupus anticoagulants.  Thromb Haemost. 1993;  70 925-931
• 24 Greaves M, Cohen H, Machin S J, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome.  Br J Haematol. 2000;  109 704-715
• 25 Clinical Laboratory Standards Institute .How to Define and Determine Reference Intervals in the Clinical Laboratory: Approved Guideline. Second ed. Wayne, PA; Clinical Laboratory Standards Institute 2000 Document C28–A2
• 26 Brandt J T, Triplett D A, Musgrave K, Orr C. The sensitivity of different coagulation reagents to the presence of lupus anticoagulants.  Arch Pathol Lab Med. 1987;  111 120-124
• 27 Denis-Magdelaine A, Flahault A, Verdy E. Sensitivity of sixteen APTT reagents for the presence of lupus anticoagulants.  Haemostasis. 1995;  25 98-105
• 28 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 94-99
• 29 Thiagarajan P, Pengo V, Shapiro S S. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants.  Blood. 1986;  68 869-874
• 30 Exner T, Rickard K A, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns.  Br J Haematol. 1978;  40 143-151
• 31 Chantarangkul V, Tripodi A, Arbini A, Mannucci P M. Silica clotting time (SCT) as a screening and confirmatory test for detection of the lupus anticoagulants.  Thromb Res. 1992;  67 355-365
• 32 Kaczor D A, Bickford N N, Triplett D A. Evaluation of different mixing study reagents and dilution effect in lupus anticoagulant testing.  Am J Clin Pathol. 1991;  95 408-411
• 33 Thom J, Ivey L, Eikelboom J. Normal plasma mixing studies in the laboratory diagnosis of lupus anticoagulant.  J Thromb Haemost. 2003;  1 2689-2691
• 34 Villa P, Mira Y, Ferrando F, Vaya A, Aznar J. Detection of low levels of lupus anticoagulant antibodies.  Thromb Res. 2005;  116 447-449
• 35 Moore G W, Savidge G F. 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;  118 523-528
• 36 Exner T. Conceptions and misconceptions in testing for lupus anticoagulants.  J Autoimmun. 2000;  15 179-183
• 37 Loeliger A. Prothrombin as a co-factor of the circulating anticoagulant in systemic lupus erythematosus.  Thromb Diath Haemorrh. 1959;  3 237-256
• 38 Lo S C, Oldmeadow M J, Howard M A, Firkin B G. Comparison of laboratory tests used for identification of the lupus anticoagulant.  Am J Hematol. 1989;  30 213-220
• 39 Eschwege V, Lutters B, Hugel B, Freyssinet J M, Robert A, de Groot P G. Importance of beta-2 glycoprotein I in the lupus anticoagulant cofactor effect; a case report.  J Thromb Haemost. 2003;  1(Suppl 1) , abstract 1526
• 40 Dlott J S, Taylor J M, Dixon J L, Willen D R, Triplett D A. The high frequency and specificity of the lupus cofactor effect in a dPT screen.  J Thromb Haemost. 2003;  1(Suppl 1) , abstract 1561
• 41 Rosner E, Pauzner R, Lusky A, Modan M, Many A. Detection and quantitative evaluation of lupus circulating anticoagulant activity.  Thromb Haemost. 1987;  57 144-147
• 42 Chang S H, Tillema V, Scherr D A. “Percent correction” formula for evaluation of mixing studies.  Am J Clin Pathol. 2002;  117 62-73
• 43 Brandt J T, Barna L K, Triplett D A. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the ISTH.  Thromb Haemost. 1995;  74 1597-1603
• 44 Devreese K M. Interpretation of normal plasma mixing studies in the laboratory diagnosis of lupus anticoagulants.  Thromb Res. 2007;  119 369-376