Clinical Utility of Laboratory Tests Used to Identify Antiphospholipid Antibodies and to Diagnose the Antiphospholipid Syndrome

 

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ABSTRACT

The antiphospholipid syndrome (APS) is defined by thrombotic and/or obstetric events together with the presence of antiphospholipid antibodies in plasma of patients. The original laboratory criteria of APS included lupus anticoagulants (LA) and/or IgG/IgM anticardiolipin antibodies (aCL). They were recently updated with the addition of IgG/IgM anti-β2 glycoprotein I antibodies (anti-β2GPI), a better definition of “medium to high antibody titer,” and the extension to 12 weeks of the “persistence in time.” The revised criteria represent an improvement; however, the potential overdiagnosis of APS remains possible, thus putting patients at risk of overtreatment. To reduce this possibility, proposals have been made to implement strict guidelines for the performance of the LA assay, to exclude aCL measurements in their current application from the criteria, and to limit the measurement of anti-β2GPI to the G isotype. This should also help in simplifying the laboratory workup of patients being investigated for APS.

REFERENCES

• 1 Wilson W A, Gharavi A E, Koike T et al.. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome.  Arthritis Rheum. 1999;  42 1309-1311
  CrossrefPubMedGoogle Scholar
• 2 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 295-306
  CrossrefPubMedGoogle Scholar
• 3 Brandt J T, Triplett D A, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update.  Thromb Haemost. 1995;  74 1185-1190
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Galli M, Luciani D, Bertolini G, Barbui T. Antiβ2-glycoprotein I, antiprothrombin antibodies and the risk of thrombosis in the antiphospholipid syndrome.  Blood. 2003;  102 2717-2723
  CrossrefPubMedGoogle Scholar
• 5 Reber G, Arvieux J, Comby E et al.. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. The Working Group on Methodologies in Haemostasis from the GEHT (Groupe d'Etudes sur l'Hemostase et la Thrombose).  Thromb Haemost. 1995;  73 444-452
  PubMedGoogle Scholar
• 6 Tincani A, Allegri F, Sanmarco M et al.. Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations – a cooperative project of the European Antiphospholipid Forum.  Thromb Haemost. 2001;  86 575-583
  PubMedGoogle Scholar
• 7 Favaloro E J, Silvestrini R. Assessing the usefulness of anticardiolipin antibody assays: a cautious approach is suggested by high variation and limited consensus in multilaboratory testing.  Am J Clin Pathol. 2002;  118 548-557
  CrossrefPubMedGoogle Scholar
• 8 Tincani A, Allegri F, Balestrieri G et al.. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies.  Thromb Res. 2004;  114 553-558
  CrossrefPubMedGoogle Scholar
• 9 Reber G, Shousboe I, Tincani A et al.. Inter-laboratory variability of anti-beta2-glycoprotein I measurement. A collaborative study in the frame of the European Forum on Antiphospholipid Antibodies Standardization Group.  Thromb Haemost. 2002;  88 66-73
  PubMedGoogle Scholar
• 10 Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa M C. for the European Forum on Antiphospholipid Antibodies Standardization Group . Variability of anti-beta2-glycoprotein I measurement by commercial assays.  Thromb Haemost. 2005;  94 665-672
  PubMedGoogle Scholar
• 11 Favaloro E J, Wong R C, Jovanovich S, Roberts-Thomson P. A review of beta2-glycoprotein I antibody testing results from a peer-driven multilaboratory quality assurance program.  Am J Clin Pathol. 2007;  127 441-448
  CrossrefPubMedGoogle Scholar
• 12 Pierangeli S S, Goldsmith G H, Krnic S, Harris E N. Difference in functional activity of anticardiolipin antibodies from patients with syphilis and those with the antiphospholipid syndrome.  Infect Immun. 1994;  62 4081-4084
  PubMedGoogle Scholar
• 13 Hunt J E, McNeil H P, Morgan G J, Crameri R M, Krilis S A. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection.  Lupus. 1992;  1 75-81
  CrossrefPubMedGoogle Scholar
• 14 Greaves M, Cohen H, Machin S I, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome.  Br J Haematol. 2000;  109 704-715
  CrossrefPubMedGoogle Scholar
• 15 Bevers E M, Galli M, Barbui T, Comfurius P, Zwaal R FA. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin.  Thromb Haemost. 1991;  66 629-632
  PubMedGoogle Scholar
• 16 Galli M, Comfurius P, Barbui T, Zwaal R FA, Bevers E M. Anticoagulant activity of β2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies.  Thromb Haemost. 1992;  68 297-300
  PubMedGoogle Scholar
• 17 Horbach D A, van Oort E, Derksen R HWM, de Groot P G. The contribution of anti-prothrombin antibodies to the lupus anticoagulant activity – Discrimination between functional and non-function anti-prothrombin antibodies.  Thromb Haemost. 1998;  79 790-795
  PubMedGoogle Scholar
• 18 Pengo V, Biasiolo A, Pegoraro C, Iliceto S. A two-step coagulation test to identify aβ2-glycoprotein I lupus antcoagulants.  J Thromb Haemost. 2004;  2 702-727
  CrossrefPubMedGoogle Scholar
• 19 Simmelink M J, Derksen R HWM, Arnout J, de Groot P G. A simple method to discriminate between β2-glycoprotein I and prothrombin-dependent lupus anticoagulants.  J Thromb Haemost. 2003;  1 740-747
  CrossrefPubMedGoogle Scholar
• 20 De Laat H B, Derksen R HWM, Urbanus R T, Roest M, de Groot P G. β2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome.  Blood. 2004;  104 3598-3602
  CrossrefPubMedGoogle Scholar
• 21 De Laat B, Derksen R HWM, Urbanus R T, de Groot P G. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of β2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis.  Blood. 2005;  105 1540-1545
  CrossrefPubMedGoogle Scholar
• 22 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors of thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature.  Blood. 2003;  101 1827-1832
  CrossrefPubMedGoogle Scholar
• 23 Opatrny L, David M, Kahn S R, Shrier I, Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a meta-analysis.  J Rheumatol. 2006;  33 2214-2221
  PubMedGoogle Scholar
• 24 Male C, Foulon D, Hoogendoom H et al.. Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus.  Blood. 2005;  106 4152-4158
  CrossrefPubMedGoogle Scholar
• 25 Galli M, Borrelli G, Jacobsen E M et al.. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study.  Blood. 2007;  110 1178-1183
  CrossrefPubMedGoogle Scholar
• 26 Naess I A, Christiansen S C, Cannegieter S C, Rosendaal F R, Hammerstroem J. A prospective study of anticardiolipin antibodies as a risk factor for venous thrombosis in a general population (the HUNT study).  J Thromb Haemost. 2006;  4 44-49
  PubMedGoogle Scholar
• 27 Runchey S S, Folsom A R, Tsai M Y, Cushman M, McGovern P D. Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study.  Br J Haematol. 2002;  119 1005-1010
  CrossrefPubMedGoogle Scholar
• 28 Iverson G M, Victoria E J, Marquis D M. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI.  Proc Natl Acad Sci U S A. 1998;  95 15542-15546
  CrossrefPubMedGoogle Scholar
• 29 McNeeley P A, Dlott J S, Furie R A et al.. β2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of β2-glycoprotein I.  Thromb Haemost. 2001;  86 590-595
  PubMedGoogle Scholar
• 30 Koike T, Ichikawa K, Kasahara H, Atsumi T, Tsutsumi A, Matsuura E. Epitopes on β2-GPI recognized by anticardiolipin antibodies.  Lupus. 1998;  7(Suppl 2) S14-S17
  CrossrefPubMedGoogle Scholar
• 31 Hunt J, Krilis S A. The fifth domain of β2-glycoprotein I contains a phospholipids binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies.  J Immunol. 1994;  152 653-659
  PubMedGoogle Scholar
• 32 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F. Antibody profiles for the diagnosis of antiphospholipid syndrome.  Thromb Haemost. 2005;  93 1147-1152
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Forastiero R, Martinuzzo M, Pombo G et al.. A prospective study of antibodies to β2-GPI and prothrombin and risk of thrombosis.  J Thromb Haemost. 2005;  3 1231-1238
  CrossrefPubMedGoogle Scholar
• 34 Bizzaro N, Ghirardello A, Zampieri S et al.. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study.  J Thromb Haemost. 2007;  5 1158-1164
  CrossrefPubMedGoogle Scholar
• 35 Loeliger A. Prothrombin as co-factor for the circulating anticoagulant in systemic lupus erythematosus?.  Thromb Diath Haemorrh. 1959;  3 327-356
  PubMedGoogle Scholar
• 36 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome.  Blood. 1999;  93 2149-2157
  PubMedGoogle Scholar
• 37 Arvieux J, Darnige L, Reber G, Bensa J C, Colomb M G. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants.  Thromb Haemost. 1995;  74 1120-1125
  PubMedGoogle Scholar
• 38 Galli M, Beretta G, Daldossi M, Bevers E M, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies.  Thromb Haemost. 1997;  77 486-491
  PubMedGoogle Scholar
• 39 Atsumi T, Ieko M, Bertolaccini M L et al.. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and the presence of lupus anticoagulant.  Arthritis Rheum. 2000;  43 1982-1993
  CrossrefPubMedGoogle Scholar
• 40 Donohoe S, Mackie I J, Isenberg D, Machin S I. Anti-prothrombin antibodies: assay conditions and clinical associations in the anti-phospholipid syndrome.  Br J Haematol. 2001;  113 544-549
  CrossrefPubMedGoogle Scholar
• 41 Galli M, Willems G M, Rosing J et al.. Anti-prothrombin IgG from patients with anti-phospholipid antibodies inhibits the inactivation of factor Va by activated protein C.  Br J Haematol. 2005;  129 240-247
  CrossrefPubMedGoogle Scholar
• 42 Field S L, Hogg P J, Daly E B et al.. Lupus anticoagulants form immune complexes with prothrombin and phospholipid that can augment thrombin production in flow.  Blood. 1999;  94 3421-3431
  PubMedGoogle Scholar
• 43 Lanir N, Aharon A, Brenner B. Procoagulant and anticoagulant mechanisms in human placenta.  Semin Thromb Hemost. 2003;  29 175-184
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 van Ommen C H, van Wijnen M, de Groot P G, van der Horst C M, Peters J. Postvaricella purpura fulminans caused by acquired protein S deficiency resulting from antiprotein S antibodies: search for the epitopes.  J Pediatr Hematol Oncol. 2002;  24 413-416
  CrossrefPubMedGoogle Scholar
• 45 Kurugol Z, Vardar F, Ozkinay F, Kavakli K, Ozkinay C. Lupus anticoagulant and protein S deficiency in otherwise healthy children with acute varicella infection.  Acta Paediatr. 2000;  89 1186-1189
  CrossrefPubMedGoogle Scholar
• 46 Büller H R, Agnelli G, Hull R D, Hyers T M, Prins M H, Raskob G E. Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP Conference on antithrombotic and thrombolytic therapy.  Chest. 2004;  126 S401-S28
  CrossrefPubMedGoogle Scholar
• 47 Crowther M A, Ginsberg J S, Julian J et al.. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.  N Engl J Med. 2003;  349 1133-1138
  CrossrefPubMedGoogle Scholar
• 48 Finazzi G, Marchioli R, Brancaccio V et al.. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with antiphospholipid syndrome (WAPS).  J Thromb Haemost. 2005;  3 848-853
  CrossrefPubMedGoogle Scholar
• 49 Khamashta M A, Hunt B J. Moderate dose oral anticoagulant therapy in patients with the antiphospholipid syndrome? No.  J Thromb Haemost. 2005;  3 844-845
  CrossrefPubMedGoogle Scholar
• 50 Galli M, Reber G, De Moerloose P, deGroot P G. Invitation to a debate on the serological criteria that define the antiphospholipid syndrome.  J Thromb Haemost. 2008;  6 399-401
  CrossrefPubMedGoogle Scholar

Monica GalliM.D. Ph.D. 

Department of Hematology, Largo Barozzi

1, 24128 Bergamo, Italy

Email: monicagalli@ospedaliriuniti.bergamo.it