Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies

Junzo Nojima; Hirohiko Kuratsune; Etsuji Suehisa; Teruo Kitani; Yoshinori Iwatani; Yuzuru Kanakura

doi:10.1160/TH03-10-0608

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(05): 967-976
DOI: 10.1160/TH03-10-0608

Platelets and Blood Cells

Schattauer GmbH

Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/β2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies

Co-existence of these antibodies enhances ADP-induced platelet activation in vitro

Junzo Nojima

¹Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan

,

Hirohiko Kuratsune

²Department of Health Science, Faculty of Health Science for Welfare, Kansai University of Welfare Science, Kashiwara, Osaka, Japan

,

Etsuji Suehisa

¹Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan

,

Teruo Kitani

³Honorary Professor, Osaka University, Japan

,

Yoshinori Iwatani

⁴Division of Biomedical Informatics, Course of Health Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

,

Yuzuru Kanakura

¹Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan

⁵Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

› Author Affiliations

Abstract

Summary

Cerebral infarction is the most common arterial thromboembolic complication in the anti-phospholipid antibodies (aPL) syndrome. In an effort to clarify the roles of aPL in the pathogenesis of cerebral infarction in patients with SLE, we examined the levels of anti-cardiolipin/β2-glycoprotein I antibodies (antiCL/β2-GPI) and anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT) in addition to lupus anticoagulant (LA) activity in 126 patients with SLE (35 with cerebral infarction and 91 without thrombosis). Both anti-CL/β2-GPI and antiPS/PT strongly correlated with the presence of LA activity. The prevalence of cerebral infarction was obviously higher in the patients who had both anti-CL/β2-GPI and anti-PS/PT (76.5% [26/34 cases], p<0.0001) than in the other patients having antiCL/β2-GPI or anti-PS/PT alone or neither of them (9.8% [9/92 cases]). Furthermore, we studied the in vitro effects of antiCL/β2-GPI and/or anti-PS/PT on the enhancement of platelet activation induced by stimulation with a low concentration of adenosine diphosphate (ADP). The purified IgG containing both anti-CL/β2-GPI and anti-PS/PT caused significant enhancement of platelet activation caused by ADP. However, the purified IgG containing either anti-CL/β2-GPI or anti-PS/PT had no enhancing effects on it. Furthermore, platelet activation was generated by the mixture of anti-CL/β2-GPI-IgG and anti-PS/PT-IgG prepared from individual patients, but not by each fraction alone. These results indicate that anti-CL/β2-GPI and antiPS/PT may cooperate to promote platelet activation, which may contribute to the risk of cerebral infarction in patients with SLE.

Keywords

Systemic lupus erythematosus - anti-cardiolipin/β2-glycoprotein I antibodies - anti-phosphatidylserine/prothrombin antibodies - platelet activation - cerebral infarction

Full Text

References

References
1 Roubey RA. Autoantibodies to phospholipidbinding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood 1994; 84: 2854-67.
2 Roubey RA. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996; 39: 1444-54.
3 Cabiedes J, Cabral AR, Alarcon-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-beta2-glycoprotein I than with antiphospholipid antibodies. J Rheumatol 1995; 22: 1899-906.
4 Horbach DA, van Oort E, Donders RC. et al. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996; 76: 916-24.
5 D’Angelo A, Safa O, Crippa L. et al. Relationship of lupus anticoagulant, anticardiolipin, anti-betβ2-GPI and anti-prothrombin autoantibodies with history of thrombosis in patients with the clinical suspicion of APAsyndrome. Thromb Haemost 1997; 78: 967-8.
6 Forastiero RR, Martinuzzo ME, Cerrato GS. et al. Relationship of anti beta2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 1997; 78: 1008-14.
7 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332-8.
8 Galli M, Finazzi G, Norbis F. et al. The risk of thrombosis in patients with lupus anticoagulants is predicted by their specific coagulation profile. Thromb Haemost 1999; 81: 695-700.
9 Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348-53.
10 Galli M, Luciani D, Bertolini G. et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101: 1827-32.
11 Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-9.
12 Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
13 Khamashta MA, Hughes GR. Antiphospholipid antibodies and antiphospholipid syndrome. Curr Opin Rheumatol 1995; 07: 389-94.
14 Wilson WA, Gharavi AE, Koike T. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-11.
15 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-57.
16 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.
17 Matsuura E, Igarashi Y, Fujimoto M. et al. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8.
18 McNeil HP, Simpson RJ, Chesterman CN. et al. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87: 4120-4.
19 Bevers EM, Galli M. Beta 2-glycoprotein I for binding of anticardiolipin antibodies to cardiolipin. Lancet 1990; 336: 952-3.
20 Matsuura E, Igarashi Y, Fujimoto M. et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-91.
21 Matsuura E, Igarashi Y, Yasuda T. et al. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62.
22 Igarashi M, Matsuura E, Igarashi Y. et al. Human beta2-glycoprotein I as an anticardiolipin cofactor determined using mutants expressed by a baculovirus system. Blood 1996; 87: 3262-70.
23 Koike T, Matsuura E. Anticardiolipin antibodies and beta 2-glycoprotein I. Lupus 1996; 05: 156-7.
24 Bevers EM, Galli M, Barbui T. et al. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipidbound human prothrombin. Thromb Haemost 1991; 66: 629-32.
25 Rao LV, Hoang AD, Rapaport SI. Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipid. Blood 1996; 88: 4173-82.
26 Galli M, Beretta G, Daldossi M. et al. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77: 486-91.
27 Escolar G, Font J, Reverter JC. et al. Plasma from systemic lupus erythematosus patients with antiphospholipid antibodies promotes platelet aggregation. Studies in a perfusion system. Arterioscler Thromb 1992; 12: 196-200.
28 Slupsky JR, Cawley JC, Griffith LS. et al. Role of Fc gamma RII in platelet activation by mono-clonal antibodies. J Immunol 1992; 148: 3189-94.
29 Martinuzzo ME, Maclouf J, Carreras LO. et al. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70: 667-71.
30 Galli M, Bevers EM, Comfurius P. et al. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and plateletderived microvesicles. Br J Haematol 1993; 83: 466-72.
31 Campbell AL, Pierangeli SS, Wellhausen S. et al. Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. Thromb Haemost 1995; 73: 529-34.
32 Machin SJ. Platelets and antiphospholipid antibodies. Lupus 1996; 05: 386-7.
33 Panzer S, Gschwandtner ME, Hutter D. et al. Specificities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome. Ann Hematol 1997; 74: 239-42.
34 Joseph JE, Harrison P, Mackie IJ. et al. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001; 115: 451-9.
35 Wang L, Su CY, Chou KY. et al. Enhancement of human platelet activation by the combination of low concentrations of collagen and rabbit anticardiolipin antibodies. Br J Haematol 2002; 118: 1152-62.
36 Arvieux J, Roussel B, Pouzol P. et al. Platelet activating properties of murine monoclonal antibodies to beta 2-glycoprotein I. Thromb Haemost 1993; 70: 336-41.
37 Nojima J, Suehisa E, Akita N. et al. Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant. Br J Haematol 1997; 96: 447-50.
38 Nojima J, Suehisa E, Kuratsune H. et al. High prevalence of thrombocytopenia in SLE patients with a high level of anticardiolipin antibodies combined with lupus anticoagulant. Am J Hematol 1998; 58: 55-60.
39 Nojima J, Kuratsune H, Suehisa E. et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem 2001; 47: 1008-15.
40 Nojima J, Suehisa E, Kuratsune H. et al. Platelet activation induced by combined effects of anticardiolipin and lupus anticoagulant IgG antibodies in patients with systemic lupus erythematosus—possible association with thrombotic and thrombocytopenic complications. Thromb Haemost 1999; 81: 436-41.
41 Galli M, Finazzi G, Bevers EM. et al. Kaolin clotting time and dilute Russell’s viper venom time distinguish between prothrombindependent and beta 2-glycoprotein I-dependent antiphospholipid antibodies. Blood 1995; 86: 617-23.
42 Takeya H, Mori T, Gabazza EC. et al. Antibeta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids. J Clin Invest 1997; 99: 2260-8.
43 Galli M, Barbui T. Prothrombin as cofactor for antiphospholipids. Lupus 1998; 07: S37-40.
44 Atsumi T, Ieko M, Bertolaccini ML. et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43: 1982-93.
45 Watson KV, Schorer AE. Lupus anticoagulant inhibition of in vitro prostacyclin release is associated with a thrombosis-prone subset of patients. Am J Med 1991; 90: 47-53.
46 Shi W, Chong BH, Chesterman CN. Beta 2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants. Blood 1993; 81: 1255-62.
47 Lindsey NJ, Henderson FI, Malia R. et al. Inhibition of prostacyclin release by endothelial binding anticardiolipin antibodies in thrombosis-prone patients with systemic lupus erythematosus and the antiphospholipid syndrome. Br J Rheumatol 1994; 33: 20-26.
48 Diez-Ewald M, Torres-Guerra E, Vizcaino G. et al. Platelet function in patients with lupus anticoagulant and thrombosis. Invest Clin 1995; 36: 13-21.
49 Ieko M, Ichikawa K, Triplett DA. et al. Beta2-glycoprotein I is necessary to inhibit protein C activity by monoclonal anticardiolipin antibodies. Arthritis Rheum 1999; 42: 167-74.
50 Galli M, Luciani D, Bertolini G. et al. Lupus anticoagulant are strong risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101: 1827-32.
51 Simantov R. Activation of cultured vascular endothelial cell by antiphospholipid antibodies. J Clin Invest 1995; 96: 2211-9.