Relationship of Anti β2-giycoprotein I and Anti Prothrombin Antibodies to Thrombosis and Pregnancy Loss in Patients with Antiphospholipid Antibodies

Ricardo R Forastiero; Marta E Martinuzzo; Graciela S Cerrato; Lucía C Kordich; Luis O Carreras

doi:10.1055/s-0038-1657678

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 78(03): 1008-1014
DOI: 10.1055/s-0038-1657678

Rapid Communication

Schattauer GmbH Stuttgart

Relationship of Anti β₂-giycoprotein I and Anti Prothrombin Antibodies to Thrombosis and Pregnancy Loss in Patients with Antiphospholipid Antibodies

Authors

Ricardo R Forastiero

The University Institute of Biomedical Sciences and Institute of Cardiology and Cardiovascular Surgery, Favaloro Foundation, Buenos Aires, Argentina
Marta E Martinuzzo

The University Institute of Biomedical Sciences and Institute of Cardiology and Cardiovascular Surgery, Favaloro Foundation, Buenos Aires, Argentina
Graciela S Cerrato

The University Institute of Biomedical Sciences and Institute of Cardiology and Cardiovascular Surgery, Favaloro Foundation, Buenos Aires, Argentina
Lucía C Kordich

¹The Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
Luis O Carreras

The University Institute of Biomedical Sciences and Institute of Cardiology and Cardiovascular Surgery, Favaloro Foundation, Buenos Aires, Argentina

Abstract

PDF Download

Summary

The lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) are clinically relevant because of their association with thrombosis and pregnancy loss. The group of antiphospholipid antibodies (aPL) includes antibodies primarily directed against various phospholipid-binding proteins, mainly β₂-glycoprotein I (β₂GPI) and prothrombin. Some studies suggest that there is an association between the presence of anti β₂GPI antibodies (a(β₂GPI) of IgG isotype and thrombosis. Therefore, aPL defined according to the plasma protein to which they are directed appear to be more appropriate for the evaluation of their clinical importance. Using home-made ELISAs we evaluated the presence of a(β₂GPI and antiprothrombin antibodies (anti-II) of both isotypes (IgG and IgM) in a group of 233 patients with LA and/or aCL. Forty-four women had a history of pregnancy loss, 45 patients had a history of venous thrombosis (VT) and 32 of arterial thrombosis (AT). Patients from the autoimmune group (systemic lupus erythematosus and antiphospholipid syndrome) had a higher prevalence of aβ₂GPI and/or anti-II than those from the miscellaneous group. In the univariate analysis, a significant association was shown between the presence of aβ₂GPI-IgG (OR 3.2; 95% Cl 1.5-6.6) and previous VT, but not AT. Anti-II were related to VT but the multivariate analysis showed that aβ₂GPI-IgG are the only independent risk factor for VT (OR 3.0; 95% Cl 1.3-6.2). The presence of aβ₂GPI-IgM correlates well with a history of pregnancy loss (OR 2.6; 95% Cl 1.1-6.1). The coagulation tests profile showed that the clotting assays were more prolonged in patients having aCL, a(β₂GPI or anti-II. But a higher prevalence of abnormal results was only found for the dilute Russell viper venom time in patients with VT, as compared to those without thrombosis (94.4% vs. 58.7%, p <0.02). The measurement of aβ₂GPI of both isotypes could help to identify aPL-positive patients with a higher risk for thrombosis and pregnancy loss, although this association should be confirmed by prospective studies.

PDF (1624 kb)

References

References
1 Exner T. Diagnostic methodologies for circulating anticoagulants. Thromb Haemost 1995; 74: 338-344
2 Harris EN. The Second International Anticardiolipin Standardization Workshop/The Kingston Antiphospholipid Antibody (KAPS) Study Group. Am J Clin Pathol 1990; 94: 476-484
3 Harris EN. The antiphospholipid syndrome – an introduction. In: Phospholipid-Binding Antibodies. Harris EN, Exner T, Hughes GRV, Asherson RA. eds. Boca Raton Florida (USA): CRC Press; 1991: 373-386
4 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-698
5 Vila P, Hernandez MC, López-Femández MF, Batlle J. Prevalence, followup and clinical significance of the anticardiolipin antibodies in normal subjects. Thromb Haemost 1994; 72: 209-213
6 Finazzi G, Brancaccio V, Moia M, Ciavarella N, Mazzucconi G, Schinco P, Ruggeri M, Pogliani EM, Gamba G, Rossi E, Baudo F, Manotti C, D’Angelo A, Palareti G, De StefanoV, Berrettini M, Barbui T. 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: 530-536
7 Thiagarajan P, Shapiro SS, De Marco L. Monoclonal immunoglobulin M X coagulation inhibitor with phospholipid specificity: Mechanism of a lupus anticoagulant. J Clin Invest 1980; 66: 397-405
8 Pengo V, Thiagarajan P, Shapiro SS, Heine MJ. Immunologic specificity and mechanism of action of IgG lupus anticoagulant. Blood 1987; 70: 69-76
9 Rauch J, Tannenbaum H, Janoff AS. Distinguishing plasma lupus anticoagulants from antifactor antibodies using hexagonal (II) phase phospholipids. Thromb Haemost 1989; 62: 892-896
10 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipidbinding inhibitor of coagulation: (β₂-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
11 Galli M, Comfurius P, Maassen C, Hemker HC, de BaetsMH, van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
12 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of antiphospholipid antibodies by ELISA using β₂-glycoprotein I as an antigen. J Immunol Methods 1991; 143: 223-229
13 Viard JP, Amoura Z, Bach JF. Association of anti β₂-glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-186
14 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Suzuki T, Sumida T, Yasuda T, Koike T. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-3891
15 Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to β₂-glycoprotein I clearly differentiates anticardiolipin antibodies from antiphospholipid syndrome and syphilis. Thromb Haemost 1996; 75: 717-720
16 Arvieux J, Damige L, Caron C, Reber G, Bensa JC, Colomb MG. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 1120-1125
17 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. 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
18 Pierangeli SS, Harris EN, Gharavi AE, Goldsmith G, Branch DW, Dean WL. Are immunoglobulins with lupus anticoagulant activity specific for phospholipids? Br J Haematol. 1993; 85: 124-132
19 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-3691
20 Martinuzzo ME, Forastiero RR, Carreras LO. Anti β₂-glycoprotein I: Detection and association with thrombosis. Br J Haematol 1995; 89: 397-402
21 Vaarala O, Puurunen M, Mänttäri M, Manninen V, Aho K, Palosuo T. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost 1996; 75: 456-459
22 Galli M, Finazzi G, Bevers E, Barbui T. Kaolin clotting time and dilute Russell’s viper venom time distinguish between prothrombin-dependent and β₂-glycoprotein I-dependent antiphospholipid antibodies. Blood 1995; 86: 617-623
23 Forastiero RR, Cerrato GS, Carreras LO. Evaluation of recently described tests for detection of the lupus anticoagulant. Thromb Haemost 1994; 72: 728-733
24 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: An update. Thromb Haemost 1995; 74: 1185-1190
25 Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood 1994; 84: 2854-2867
26 Triplett DA. Antiphospholipid-protein antibodies: laboratory detection and clinical relevance. Thromb Res 1995; 78: 01-31
27 Pierangeli SS, Hams EN, Davis SA, DeLorenzo G. β₂-glycoprotein I (β₂-GPI) enhances cardiolipin binding activity but is not the antigen for antiphospholipid antibodies. Br J Haematol 1992; 82: 565-570
28 Sorice M, Circella A, Griggi T, Garofalo T, Nicodemo G, Pittoni V, Pontieri GM, Lenti L, Valesini G. Anticardiolipin and anti-β₂-GPI are two distinct populations of autoantibodies. Thromb Haemost 1996; 75: 303-308
29 Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffatti A. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75: 721-724
30 Balestrieri G, Tincani A, Spatola L, Allegri F, Prati E, Cattaneo R, Valesini G, Del PapaN, Meroni P. Anti-beta₂-glycoprotein I antibodies: a marker of antiphospholipid syndrome? Lupus. 1995; 04: 122-130
31 Cabiedes J, Cabral A, Alarcon-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-β₂-glycoprotein I than with antiphospholipid antibodies. J Rheumatol 1995; 22: 1899-1906
32 Arvieux J, Roussel B, Ponard D, Colomb MG. IgG₂ subclass restriction of anti-β₂-glycoprotein I antibodies in autoimmune patients. Clin Exp Immunol 1994; 95: 310-315
33 Arvieux J, Damige L, Hachulla E, Roussel B, Bensa JC, Colomb MG. Species specificity of anti-β₂-glycoprotein I autoantibodies and its relevance to anticardiolipin antibody quantitation. Thromb Haemost 1996; 75: 725-730
34 Horbach DA, Oort EV, Donders RCJM, Derksen RHWM, de Groot PG. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Thromb Haemost 1996; 76: 916-924
35 Carreras LO, Forastiero RR. Pathogenic role of antiprotein-phospholipid antibodies. Haemostasis 1996; 26: 340-357
36 Amout J. The pathogenesis of the antiphospholipid syndrome: A hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996; 75: 536-541
37 Permpikul P, Rao LVM, Rapaport SI. Functional and binding studies of the roles of prothrombin and β₂"gty^coP^roteiⁿ I iⁿ the expression of lupus anticoagulant activity. Blood 1994; 83: 2878-2892