Antiphospholipid Syndrome: Clinical and Diagnostic Utility of Laboratory Tests

ABSTRACT

Antiphospholipid antibodies are a wide and heterogeneous group of immunoglobulins that include, among others, lupus anticoagulants and anticardiolipin antibodies. Their presence in patients with arterial and venous thrombosis, and/or obstetrical complications, defines the antiphospholipid syndrome. Antiphospholipid antibodies do not recognize anionic phospholipids, but recognize plasma proteins bound to suitable anionic surfaces: β₂-glycoprotein I and prothrombin are the most common and most frequently investigated antigens. We systematically reviewed published articles on the antiphospholipid syndrome to investigate the association between thrombosis and some antiphospholipid antibodies. Lupus anticoagulants were a clear risk factor for thrombosis, irrespective of the site and type of thrombosis, the presence of systemic lupus erythematosus, and the methods used to detect them. Anticardiolipin and anti-β₂-glycoprotein I antibodies were possible risk factors of thrombosis, at least in some selected situations. The measurement of antiprothrombin antibodies is not helpful to define the patient's risk of thrombosis. These results are mainly due to the still far from optimal standardization of the methods to detect antiphospholipid antibodies; the lack of standardized reference materials; the heterogeneity in reagents, calibrators, and assay conditions; and the methods used to calculate the results. Many efforts are currently being made to improve assay standardization and harmonization, which should help to clarify the clinical relevance of antiphospholipid antibodies.

Antiphospholipid syndrome - antiphospholipid antibodies - lupus anticoagulants - thrombosis

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
• 2 Asherson R A, Khamashta M A, Ordi-Ros J et al.. The “primary” antiphospholipid syndrome; major clinical and serological features.  Medicine (Baltimore). 1989;  68 366-374
• 3 Alarcon-Segovia D, Deleze M, Oria C V, Sanchez-Guerrero J, Gomez-Pacheco L. Antiphospholipid antibodies and the antiphospholipid syndrome in SLE. A prospective analysis of 500 consecutive patients.  Medicine (Baltimore). 1989;  68 353-365
• 4 Triplett D A, Boffa M C. Lupus anticoagulant: detection, standardization and heterogeneity. In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y The Antiphospholipid Syndrome II. Autoimmune Thrombosis. Amsterdam; Elsevier 2002: 23-28
• 5 Pierangeli S S, Harris E N. Antibodies to cardiolipin and other phospholipids. In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y The Antiphospholipid Syndrome II. Autoimmune Thrombosis. Amsterdam; Elsevier 2002: 29-43
• 6 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
• 7 Galli M, Comfurius P, Maassen C et al.. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor.  Lancet. 1990;  335 1544-1547
• 8 McNeil H P, Simpson R J, Chesterman C N, Krilis S A. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H).  Proc Natl Acad Sci USA. 1990;  87 4120-4127
• 9 Matsuura E, Igarashi Y, Fujimoto M et al.. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease.  Lancet. 1990;  336 177-178
• 10 Bevers E M, Galli M, Barbui T, Comfurius P, Zwaal RF A. 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
• 11 Galli M, Comfurius P, Barbui T, Zwaal RF A, Bevers E M. Anticoagulant activity of β₂-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies.  Thromb Haemost. 1992;  68 297-300
• 12 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
• 13 Willems G M, Janssen M P, Pelsers M M et al.. Role of divalency in the high-affinity binding of anticardiolipin antibody-β₂-glycoprotein I complexes to lipid membranes.  Biochemistry. 1996;  35 13833-13842
• 14 Willems G M, Janssen M P, Comfurius P et al.. Kinetics of prothrombin-mediated binding of lupus anticoagulant antibodies to phosphatidylserine-containing phospholipid membranes: an ellipsometric study.  Biochemistry. 2002;  41 14357-14363
• 15 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 79-86
• 16 Field S L, Chesterman C N, Dai Y P, Hogg P J. Lupus antibody bivalency is required to enhance prothrombin binding to phospholipid.  J Immunol. 2001;  166 6118-6125
• 17 Shi W, Chong B H, Hogg P J et al.. Anticardiolipin antibodies block the inhibition by β₂-glycoprotein I of the factor Xa generating activity.  Thromb Haemost. 1993;  70 342-345
• 18 Permpkul P, Rao LV M, Rapaport S I. Functional and binding studies of the roles of prothrombin and β₂-glycoprotein I in the expression of lupus anticoagulant activity.  Blood. 1994;  83 2878-2892
• 19 Horbach D A, van Oort E, Derksen R HWM et al.. The contribution of anti-prothrombin antibodies to lupus anticoagulant activity: discrimination between functional and non-functional anti-prothrombin antibodies.  Thromb Haemost. 1998;  79 790-795
• 20 Simmelink M JA, 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
• 21 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
• 22 Roussi J, Roisin J P, Goguel A. Lupus anticoagulants. First French interlaboratory etalanorme survey.  Am J Clin Pathol. 1996;  105 788-793
• 23 Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulants.  Thromb Haemost. 2001;  86 83-91
• 24 Jennings I, Kitchen S, Woods TA L, Preston F E, Greaves M. Clinically important inaccuracies in testing for the lupus anticoagulant: an analysis of results from three surveys of the UK national external quality assessment scheme (NEQAS) for blood coagulation.  Thromb Haemost. 1997;  77 934-937
• 25 Jennings I, Greaves M, Mackie I J, Kitchen S, Woods TA L, Preston F E. 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;  119 364-369
• 26 Le Querrec A, Arnout J, Arnoux D et al.. Quantification of lupus anticoagulants in clinical samples using anti-β₂-glycoprotein I and anti-prothrombin monoclonal antibodies.  Thromb Haemost. 2001;  86 584-589
• 27 Arnout J, Meijer P, Vermylen J. Lupus anticoagulant testing in Europe: an analysis of results from the first European concerted action of thrombophilia (ECAT) survey using plasma spiked with monoclonal antibodies against human β₂-glycoprotein I.  Thromb Haemost. 1999;  81 929-934
• 28 Reber G, Arvieux J, Comby E et al.. Multicenter evaluation of nine commercial kits for the quantification of anticardiolipin antibodies.  Thromb Haemost. 1995;  73 444-452
• 29 Harris E N, Gharavi A E, Patel S, Hughes GR V. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held April 4 1986.  Clin Exp Immunol. 1987;  68 215-222
• 30 Harris E N. The second international anticardiolipin standardization workshop/the Kingston Antiphospholipid Antibody study (KAPS) group.  Am J Clin Pathol. 1990;  94 476-484
• 31 Harris E N, Pierangeli S, Birch D. Anticardiolipin wet workshop: 5th International Symposium on antiphospholipid antibodies.  Am J Clin Pathol. 1994;  101 616-624
• 32 Pierangeli S S, Stewart M, Silva L K, Harris E N. Report of an anticardiolipin wet workshop during the VIIth International Symposium on antiphospholipid antibodies.  J Rheumatol. 1998;  25 156-162
• 33 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
• 34 Favaloro E J, Silvestrini R. Assessing the usefulness of anticardiolipin antibody assays.  Am J Clin Pathol. 2002;  118 548-557
• 35 Reber G, Schousboe I, Tincani A et al.. Inter-laboratory variability of anti-β₂-glycoprotein I measurement. A collaborative study in the frame of the European Forum on antiphospholipid antibodies standardization group.  Thromb Haemost. 2002;  88 66-73
• 36 Donohoe S, Mackie J I, Isenberg D, Machin S J. Anti-prothrombin antibodies: assay conditions and clinical associations in the anti-phospholipid syndrome.  Br J Haematol. 2001;  113 544-549
• 37 Vaarala O, Palosuo T, Kleemola M, Aho K. Anticardiolipin response in acute infection.  Clin Immunol Immunopathol. 1986;  41 8-15
• 38 Sammaritano L R. Drug-induced antiphospholipid antibodies. In: Khamashta MA Hughes Syndrome. The Antiphospholipid Syndrome London; Springer 2000: 144-154
• 39 Asherson R A. Antiphospholipid antibodies, malignancies and paraproteinemias.  J Autoimmun. 2000;  15 117-122
• 40 Santiago M, Martinelli R, Ko A et al.. Anti-beta2 glycoprotein I and anticardiolipin antibodies in leptospirosis, syphilis and Kala-azar.  Clin Exp Rheumatol. 2001;  19 425-430
• 41 Guerin J, Smith O, White B, Sweetman G, Feighery C, Jackson J. Antibodies to prothrombin in antiphospholipid syndrome and inflammatory disorders.  Br J Haematol. 1998;  102 896-902
• 42 Giordano P, Galli M, Del Vecchio G et al.. Lupus anticoagulant, anticardiolipin antibodies and hepatitis C virus infection in thalassemia.  Br J Haematol. 1998;  102 903-906
• 43 El-roey A, Gleicher N. Definition of normal autoantibody levels in apparently healthy population.  Obstet Gynecol. 1988;  72 596-602
• 44 Vila P, Hernandez M C, Lopez-Fernandez M F, Batle J. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects.  Thromb Haemost. 1994;  72 209-213
• 45 Manoussakis M N, Tzioufas A G, Silis M P et al.. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population.  Clin Exp Immunol. 1987;  69 557-565
• 46 Fields R A, Toubbeh H, Searles R P, Bankhurst A D. The prevalence of anticardiolipin antibodies in a healthy elderly population and its association with antinuclear antibodies.  J Rheumatol. 1989;  16 623-625
• 47 Shi W, Krilis S A, Chong B H, Gordon S, Chesterman C N. Prevalence of lupus anticoagulant and anticardiolipin antibodies in a healthy population.  Aust N Z J Med. 1990;  20 231-236
• 48 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
• 49 Galli M, Finazzi G, Norbis F, Marziali S, Marchioli R, Barbui T. The risk of thrombosis in patients with lupus anticoagulants is predicted by their specific coagulation profile.  Thromb Haemost. 1999;  81 695-700
• 50 Galli M, Dlott J, Norbis F et al.. Lupus anticoagulants and thrombosis: clinical association of different coagulation and immunologic tests.  Thromb Haemost. 2000;  84 1012-1016
• 51 Forastiero R R, Martinuzzo M E, Cerrato G S, Kordich L C, Carreras L O. Relationship of antiß2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies.  Thromb Haemost. 1997;  78 1008-1014
• 52 Simmelink MJ A, Horbach D A, van Oort E, Derksen R HWM, de Groot P G. DRVVT is a much better predictor than KCT for the risk of thrombosis.  Lupus. 1998;  7(suppl 2) S219
• 53 Galli M, Luciani D, Bertolini G, Barbui T. Anti-β₂-glycoprotein I, antiprothrombin antibodies and the risk of thrombosis in the antiphospholipid syndrome.  Blood. 2003;  102 2717-2723
• 54 Galli M, Ruggeri L, Barbui T. Differential effects of anti-β₂-glycoprotein I and anti-prothrombin antibodies on the anticoagulant activity of activated protein C.  Blood. 1998;  91 1999-2004
• 55 Field S L, Chesterman C N, Hogg P J. Dependence on prothrombin for inhibition of activated protein C activity by lupus antibodies.  Thromb Haemost. 2000;  84 1132-1133