Subscribe to RSS
DOI: 10.1160/TH04-12-0839
Antibody profiles for the diagnosis of antiphospholipid syndrome
Publication History
Received
24 December 2004
Accepted after resubmission
10 March 2005
Publication Date:
11 December 2017 (online)
Summary
Among the so called‘antiphospholipid antibodies’, the presence of Lupus Anticoagulant (LA) is associated with thrombosis-related events and defines the antiphospholipid syndrome. The role of anti-cardiolipin (aCL) antibodies and anti-human β2-glycoprotein I (aβ2GPI) antibodies is less striking. Since the problem of standardization for these tests is far from resolved, we evaluated whether the combination of results (antiphospholipid laboratory profiles) could help to better classify these patients. Over a 6-year period, 618 consecutive subjects (55% of whom had previous documented thrombosis-related events) were referred to our clinic for Antiphospholipid antibody detection. LA was detected according to internationally accepted recommendations. ACL and aβ2GPI antibodies were detected by Enzyme-Linked-Immunosorbent Assay (ELISA). Patients’ records were reviewed for the presence of previous thromboembolic events or obstetric complications according to Sapporo’s clinical criteria for the diagnosis of antiphospholipid syndrome (APS) and each patient underwent a physical examination. When individual tests were considered in a multivariate analysis which took into account age, gender, the presence of SLE or other autoimmune diseases and established risk factors for venous and arterial thromboembolism, LA (Odds Ratio 4.4, Confidence Interval 1.5–13.3) and aβ2GPI antibodies (Odds Ratio 2.9, Confidence Interval 1.1–7.5) but not aCL antibodies (Odds Ratio 1.2, Confidence Interval 0.5–2.7) were found to be independent risk factors for thrombosis-related events. When antiphospholipid antibody profiles instead of individual test positivity were analyzed in the above mentioned model, triple positivity resulted a strong independent risk factor (Odds Ratio 33.3, Confidence Interval 7.0–157.6), retaining its significance when the association with venous or arterial thromboembolism was considered. Double positivity with negative LA was close to significance for thrombosis-related events (Odds Ratio 2.2, Confidence Interval1.0–5.2, p=0.056) and highly significant risk factor for obstetric complications (Odds Ratio 10.8, Confidence Interval 2.9–40.8). Other combinations did not reach statistical significance. The mean level of IgG aβ2GPI antibodies was statistically higher in triple positive profile and might account for positive LA. As compared to a single test, the analysis of a complete antiphospholipid antibody profile can better determine patients at risk.
-
References
- 1 Wilson WA, Gharavi AE, Koike T. et al International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999; 42: 1309-11
- 2 Jennings I, Kitchen S, Woods TAL. et al 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: 934-7
- 3 Arnout J, Meijer P, Vermylen J. Lupus anticoagulant testing in Europe: an analysis of results from the First European Concerted Action on Thrombophilia (ECAT) survey using plasmas spiked with monoclonal antibodies against human β 2-glycoprotein I. Thromb Haemost 1999; 81: 929-34
- 4 Tincani A, Balestrieri G, Allegri F. et al Overview on anticardiolipin ELISA standardization. J Autoimmun 2000; 15: 195-7
- 5 Bevers EM, Galli M, Barbui T. et al Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32
- 6 Galli M, Comfurius P, Maassen C. et al Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7
- 7 Matsuura E, Igarashi Y, Fujimoto M. et al Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8
- 8 Matsuura E, Igarashi Y, Yasuda T. et al Anticardiolipin antibodies recognize β 2 -Glycoprotein-I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62
- 9 Roubey RAS, Eisemberg RA, Harper MF. et al 'Anticardiolipin' autoantibodies recognize β 2 -Glycoprotein- I in the absence of phospholipids. J Immunol 1995; 154: 954-60
- 10 Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a crypti epitope expressed when β 2 -Glycoprotein-I is bound to a suitable surface. Thromb Haemost 1995; 73: 29-34
- 11 Pengo V, Biasiolo A, Brocco T. et al Autoantibodies to phospholipid binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thomb Haemost 1996; 75: 721-4
- 12 Roubey RAS. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996; 39: 1444-54
- 13 Arvieux J, Pernod G, Regnault V. et al Some anticardiolipin antibodies recognize a combination of phospholipids with thrombin-modified antithrombin, complement C4b-binding protein, and lipopolysaccharide binding protein. Blood 1999; 93: 4248-55
- 14 Rampazzo P, Biasiolo A, Garin J. et al Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins. Thromb Haemost 2001; 85: 57-62
- 15 Cabiedes J, Cabral AR, Alarcon-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti- β 2 -Glycoprotein-I than with antiphospholipid antibodies. J Rheumatol 1995; 22: 1899-906
- 16 Balestrieri G, Tincani A, Spatola L. et al Anti- β 2 -Glycoprotein-I antibodies: a marker of antiphospholipid syndrome?. Lupus 1995; 4: 122-30
- 17 Martinuzzo ME, Forastiero RR, Carreras LO. Anti-β2-Glycoprotein-I antibodies detection and association with thrombosis. Br J Haematol 1995; 89: 397-402
- 18 Roubey RAS, Maldonado MA, Byrd SN. Comparison of an enzyme-linked immunosorbent assay for antibodies to β2-Glycoprotein-I and a conventional cardiolipin immunoassay. Arthritis Rheum 1996; 39: 1606-7
- 19 Pengo V, Biasiolo A. The risk of overdiagnosis of antiphospholipid antibody syndrome. Thromb Haemost 2001; 86: 933
- 20 Viard JP, Amoura Z, Bach JF. Association of anti-2-glycoprotein I antibodies with lupus-type c anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-6
- 21 Amengual O, Atsumi T, Khamashta MA. et al Specificity for ELISA for antibody to 2-Glycoprotein-I in patients with antiphospholipid syndrome. Br J Rhematol 1996; 35: 1239-43
- 22 Galli M. Which antiphospholipid antibodies should be measured in the antiphospholipid syndrome?. Haemostasis 2000; 30 (Suppl. 02) 57-62.
- 23 Roubey RAS, Maldonado MA, Byrd S. Comparison of an enzyme-linked immunoassay for antibodies to 2-Glycoprotein-I and a conventional anticardiolipin immunoassay. Arthritis Rheum 1996; 39: 1606-7
- 24 Reber G, Schousboe I, Tincani A. et al Inter-laboratory variability of anti- β 2-glycoprotein I measurement. A collaborative study in the frame of the European Forum on Antiphospholipid Antibodies Standardization Group. Thromb Haemost 2002; 88: 66-73
- 25 Pengo V, Biasiolo A, Pegoraro C. et al A two-step coagulation test to identify antibeta-glycoprotein I lupus anticoagulants. J Thromb Haemost 2004; 2: 702-7
- 26 Brandt JT, Triplett DA, Alvin B. et al Criteria for the diagnosis of lupus anticoagulant. Thromb Haemost 1995; 74: 1185
- 27 Pengo V, Biasiolo A, Rampazzo P. et al dRVVT is more sensitive than KCT or TTI for detecting Lupus Anticoagulant activity of anti- β 2 -Glycoprotein-I autoantibodies. Thromb Haemost 1999; 81: 256-8
- 28 Biasiolo A, Pengo V. Antiphospholipid antibodies are not present in the membrane of gel-filtered platelets of patients with IgG anticardiolipin antibodies, lupus anticoagulant and thrombosis. Blood Coagul Fibrinolysis 1993; 4: 425-8
- 29 Pengo V, Filippi B, Biasiolo A. et al Association of the G20210A mutation in the factor II gene with systemic embolism in nonvalvular atrial fibrillation. Am J Cardiol 2002; 90: 545-7
- 30 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1745
- 31 Triplett DA. Lupus anticoagulant. In: Jespersen J, Bertina RM, Haverkate F, eds. Laboratory technique in thrombosis – a manual: 2nd revised edition of the ECAT assay procedures. Dordrecht, the Nederlands: Kluver Academic; 1999: 183-7.
- 32 Wahl DG, Guillermin F, de Maistre E. et al Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus – a metaanalysis. Lupus 1997; 6: 467-73
- 33 Galli M, Luciani D, Bertolini G. et al Lupus Anticoagulants are stronger risk factors of thrombosis than anticardiolipin antibodies: a systematic review of the literature. Blood 2003; 101: 1827-32
- 34 Vaarala O, Manttari M, Manninen V. et al Anticardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91: 23-7
- 35 Finazzi G, Brancaccio V, Moia M. et al Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four year prospective study from the Italian Registry. Am J Med 1996; 100: 530-6
- 36 Blank M, Faden D, Tincani A. et al Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice. J Autoimmun 1994; 7: 441-55
- 37 Pengo V, Balestrieri G, Tincani A. et al Utilization of dilute Russell’s Viper Venom Time to detect autoantibodies against β 2-Glycoprotein I which express anticoagulant activity in the presence but not in the absence of exogenous phospholipids. Thromb Haemost 1997; 77: 123-6
- 38 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid sindrome. Blood 1999; 93: 2149-57
- 39 Atsumi T, Koike T. Clinical relevance of antiprothrombin antibodies. Autoimm Rew 2002; 1: 49-53
- 40 Simmelink MJA, De Groot PG, Derksen RHWM. A study on association between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis. J Thromb Haemost 2003; 1: 735-9
- 41 Galli M, Luciani D, Bertolini G. et al Anti-β2-Glycoprotein I antibodies, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid sindrome. Blood 2003; 102: 2717-23