Platelet Activation Induced by Combined Effects of Anticardiolipin and Lupus Anticoagulant IgG Antibodies in Patients with Systemic Lupus Erythematosus

Summary

Antiphospholipid antibodies (aPL) are well known to be associated with arterial and venous thrombosis. In a series of 180 patients with systemic lupus erythematosus (SLE), the prevalence of arterial thrombosis was obviously higher in the patients who had both anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) (17/35, 48.6%, p <0.05) (Table 1) than in the other patients bearing aCL or LA alone or neither of them (2/145, 1.4%). Since a substantial fraction of the former group of patients with arterial thrombosis also had thrombocytopenia (12/17, 70.6%), there was a possibility that aCL and LA might have enhanced platelet activation and aggregation. To test this possibility, we studied the in vitro effects of aCL and LA on the enhancement of platelet activation by flow cytometric analysis using anti-CD62P and anti-CD41 monoclonal antibodies directed against platelet activation-dependent granule-external membrane (PADGEM) protein and platelet glycoprotein IIb (GPIIb), respectively. Platelet activation defined by the surface expression of CD62P was not induced by aCL⁺·LA⁺ plasma only, but was significantly augmented by aCL⁺·LA⁺ plasma in combination with adenosine diphosphate (ADP) at a low concentration that had only a modest effect on platelet activation. In contrast, aCL⁺·LA^–, aCL^–·LA⁺ and aCL^–·LA^– plasma samples were incapable of enhancing platelet activation in the presence or absence of ADP stimulation. In addition to plasma samples, the purified IgG from aCL⁺·LA⁺ plasma (aCL⁺·LA⁺-IgG) also yielded apparent enhancement of platelet activation induced by ADP. Furthermore, platelet activation was generated by the mixture of aCL⁺·LA^–-IgG and aCL^–·LA⁺-IgG fractions prepared from individual patients, but not by each fraction alone. These results suggest that aCL and LA may cooperate to promote platelet activation, and may be involved, at least partially, in the pathogenesis of arterial thrombosis and thrombocytopenia in patients with SLE.

• References

• 1 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; ii: 1211-4.
• 2 Koike T, Sueishi M, Funaki H, Tomioka H, Yoshida S. Anticardiolipin antibodies and biological false positive serological test for syphilis in patients with systemic lupus erythematosus. Clin Exp Immunol 1984; 56: 193-9.
• 3 Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-9.
• 4 Cabiedes J, Cabral AR, Alarcon-Segovia D. Clinical manifestation 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: 1899-906.
• 5 McNally T, Mackie IJ, Machin SJ, Isenberg DA. Increased levels of β2-glycoprotein I antigen and β2-glycoprotein I binding antibodies are associated with a history of thromboembolic complications in patients with SLE and primary antiphospholipid syndrome. Br J Reumatol 1995; 34: 1031-6.
• 6 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anticardiolipin 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: 4120-4.
• 7 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
• 8 Galli M, Comfurius P, Maassen C, Hemker HC, De Baets MH, Van BredaVriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7.
• 9 Roubey RAS. Autoantibodies to phospholipid-binding plasma protein: A new view of lupus anticoagulant and other ’antiphospholipid’ autoanti-bodies. Blood 1994; 84: 2854-67.
• 10 Galli M, Finazzi G, Barbui T. Antiphospholipid antibodies: predictive value of laboratory tests. Thromb Haemost 1997; 78: 75-8.
• 11 Horbach DA, Oort E, 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: 916-24.
• 12 Martinuzzo ME, Maclouf J, Carreras LO, Lévy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70 (04) 667-71.
• 13 Shi W, Chong BH, Chesterman CN. β2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants. Blood 1993; 81: 1255-62.
• 14 Machin SJ. Platelets and antiphospholipid antibodies. Lupus 1996; 5: 386-7.
• 15 Carreras LO, Vermylen J. “Lupu” anticoagulant and thrombosis. Possible role of inhibition of prostacyclin formation. Thromb Haemost 1982; 48: 38-40.
• 16 Cariou R, Tobelem G, Belucci S, Soria J, Soria C, Maclouf J, Caen J. Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells. Inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost 1988; 60 (01) 54-9.
• 17 Malia RG, Kitchen S, Greaves M, Preston FE. Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies. Br J Haematol 1990; 76: 101-7.
• 18 Greaves M, Lindsay N, Malia RG, Henderson F, Hughes P. Inhibition of thrombin-induced prostacyclin release by sera containing antiphospholipid antibodies is masked by products of platelet activation. Thromb Haemost 1991; 65: 1257 (Abstr).
• 19 Oosting JD, Derkesn RHWM, Bobbink IWG, Hackeng TM, Bouma BN, De Groot PG. Antiphospholipid antibodies directed against a combination of phospholipid with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism. Blood 1993; 81: 2618-25.
• 20 Lockshin MD. Pathogenesis of the antiphospholipid antibody syndrome. Lupus 1996; 5: 404-8.
• 21 Lin YL, Wang CT. Activation of human platelets by the rabbit anticardiolipin antibodies. Blood 1992; 180: 3135-43.
• 22 Tokita S, Arai M, Yamamoto N, Katagiri Y, Tanoue K, Igarashi K, Umeda M, Inoue K. Specific cro-reaction of IgG anti-phospholipid antibody with platelet glycoprotein IIIa. Thromb Haemost 1996; 75: 168-74.
• 23 Escolar G, Font J, Referter JC, Lopez-Soto A, Garrido M, Cervera R, Inglemo M, Castillo R, Ordinas A. Plasma from systemic lupus erythematosus patients with antiphospholipid antibodies promotes platelet aggregation. Arterioscler Thromb 1992; 12: 196-200.
• 24 Campbell AL, Pierangeli SS, Wellhausen S, Harris EN. 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.
• 25 Nojima J, Suehisa E, Akita N, Toku M, Fushimi R, Tada H, Kuratsune H, Machii T, Kitani T, Amino N. Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant. Br J Haematol 1997; 96: 447-50.
• 26 Nojima J, Suehisa E, Kuratsune H, Machii T, Toku M, Tada H, Yamaguchi K, Koike T, Kanakura Y, Kitani T, Amino N. 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.
• 27 Lellouche F, Martinuzzo M, Said P, Maclouf J, Carreras LO. Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 1991; 78: 2894-9.
• 28 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: 3885-91.
• 29 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62.
• 30 Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to β2-glycoprotein I clearly differentiates anticardiolipin antibodies from anti-phospholipid syndrome and syphilis. Thromb Haemost 1996; 75: 717-20.
• 31 Larson E, Celi A, Gilbert G, Furie BC, Erban J, Bonfanti R, Furie B. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 1989; 59: 305-12.
• 32 Israels SJ, Gerrard JM, Jacques YV, McNicol A, Cham B, Nishibori M, Bainton DF. Platelet dense granule membranes contain both granulophysin and P-selectin. Blood 1992; 80: 143-52.
• 33 Roubey RAS. Antigenic specificities of antiphospholipid autoantibodies: implications for clinical laboratory testing and diagnosis of the antiphospholipid syndrome. Lupus 1996; 5: 425-30.
• 34 Forastiero RR, Martinuzzo ME, Cerrato GS, Kordich LC, Carreras LO. Relationship of anti β2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 1997; 78: 1008-14.
• 35 Khamashta MA, Harris EN, Gharavi AE, Derve G, Gil A, Vazquez JJ, Hughes GRV. Immune mediated mechanism for thrombosis: antiphospholipid antibody binding to platelet membranes. Ann Rheum Dis 1988; 47: 849-54.
• 36 Slupsky JR, Cawley JC, Grifith LS, Shaw ARE, Zugel M. Role of FcγRII in platelet activation by monoclonal antibodies. J Immunol 1992; 148: 3189-94.
• 37 Meroni PL, Papa ND, Gambini D, Tincani A, Balestrieri G. Antiphospholipid antibodies and endothelial cell: an unending story. Lupus 1995; 4: 169-71.
• 38 Tonqueze ML, Salozhin K, Dueymes M, Piette JC, Kovalev V, Shoenfeld Y, Nassonov E, Youinou P. Role of β2-glycoprotein I in the antiphospholipid antibody binding to endothelial cells. Lupus 1995; 4: 179-86.
• 39 Simantov R. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 1995; 96: 2211-19.
• 40 Nakamura N, Shidara Y, Kawaguchi N, Azuma C, Mitsuda N, Onishi S, Yamaji K, Wada Y. Lupus anticoagulant autoantibody induces apoptosis in umbilical vein endothelial cells: involvement of annexin·. Biochem Biophy Res Commun 1994; 205: 1488-93.
• 41 Triplett DA. Protean clinical presentation of antiphospholipid-protein antibodies (APA). Thromb Haemost 1995; 74: 329-37.