The Pathogenesis of the Antiphospholipid Syndrome: a Hypothesis Based on Parallelisms with Heparin-induced Thrombocytopenia

J Arnout

doi:10.1055/s-0038-1650316

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1996; 75(04): 536-541
DOI: 10.1055/s-0038-1650316

Review Article

Schattauer GmbH Stuttgart

The Pathogenesis of the Antiphospholipid Syndrome: a Hypothesis Based on Parallelisms with Heparin-induced Thrombocytopenia

J Arnout

The Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

› Author Affiliations

Abstract

PDF Download

PDF (460 kb)

References

References
1 Vermylen J, Amout J. Is the antiphospholipid syndrome caused by antibodies directed against physiologically relevant phospholipid-protein complexes?. J Lab Clin Med 1992; 120: 10-12
2 Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood 1994; 84: 2854-2867
3 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. 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 USA 1990; 87: 4120-4124
4 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, Barbui T, Zwaal RF, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
5 Pierangeli SS, Harris EN, Davis SA, DeLorenzo G. Beta 2-glycoprotein 1 (beta 2GP1) enhances cardiolipin binding activity but is not the antigen for antiphospholipid antibodies. Br J Haematol 1992; 82: 565-570
6 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-178
7 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
8 Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992; 1: 75-81
9 Wagenknecht DR, McIntyre JA. Changes in beta 2-glycoprotein I antigenicity induced by phospholipid binding. Thromb Haemost 1993; 69: 361-365
10 Ichikawa K, Khamashta MA, Koike T, Matsuura E, Hughes GR. Β₂-Glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum 1994; 37: 1453-1461
11 Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when Β₂-glycoprotein I is bound to a suitable surface. Thromb Haemost 1995; 73: 29-34
12 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143: 223-229
13 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize Β 2-Glycoprotein I structure altered by interaction with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-462
14 Keeling DM, Wilson AJG, Mackie IJ, Machin SJ, Isenberg DA. Some antiphospholipid antibodies bind to Β 2-glycoprotein I in the absence of phospholipid. Br J Haematol 1992; 82: 571-574
15 Viard JP, Amoura Z, Bach JF. Association of anti-beta 2-glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-186
16 Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Detection of Beta-2-glycoprotein-I-dependent antiphospholipid antibodies and anti-beta-2-glycoprotein-I antibody in patients with systemic lupus erythematosus and in patients with syphilis. Int Arch Allergy Immunol 1994; 103: 239-244
17 Martinuzzo ME, Forastiero RR, Carreras LO. Anti beta 2 glycoprotein I antibodies: detection and association with thrombosis. Br J Haematol 1995; 89: 397-402
18 Gharavi AE, Harris EN, Sammaritano LR, Pierangeli SS, Wen J. Do patients with antiphospholipid syndrome have autoantibodies to Β₂-Glycoprotein I?. J Lab Clin Med 1993; 122: 426-431
19 Roubey RAS, Eisenberg RA, Harper MF, Winfield JB. “Anticardiolipin” autoantibodies recognize Β 2-glycoprotein I in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995; 154: 954-960
20 Oosting JD, Derksen RH, Entjes HT, Bouma BN, de Groot PG. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost 1992; 67: 499-502
21 Roubey RA, Pratt CW, Buy on JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I. J Clin Invest 1992; 90: 1100-1104
22 Galli M, Comfurius P, Barbui T, Zwaal RF, Bevers EM. Anticoagulant activity of beta 2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost 1992; 68: 297-300
23 Keeling DM, Wilson AJG, Mackie IJ, Isenberg DA, Machin SJ. Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound beta 2 glycoprotein I. J Clin Pathol 1993; 46: 665-667
24 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. 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
25 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1993; 81: 2618-2625
26 Arvieux J, Pouzol P, Roussel B, Jacob MC, Colomb MG. Lupus-like anticoagulant properties of murine monoclonal antibodies to Β₂-glycoprotein I. Br J Haematol 1992; 81: 568-573
27 Brandt JT. Antibodies to beta 2-glycoprotein I inhibit phospholipid dependent coagulation reactions. Thromb Haemost 1993; 70: 598-602
28 Branch DW, Dudley DJ, Mitchell MD, Creighton KA, Abbott TM, Hammond EH, Daynes RA. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol 1990; 163: 210-216
29 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA 1991; 88: 3069-3073
30 Bakimer R, Fishman P, Blank M, Sredni B, Djaldetti M, Shoenfeld Y. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89: 1558-1563
31 Gharavi AE, Sammaritano LR, Wen J, Elkon KB. Induction of antiphospholipid autoantibodies by immunization with Β₂-glycoprotein I (apolipo-protein H). J Clin Invest 1992; 90: 1105-1109
32 Pierangeli SS, Harris EN. Induction of phospholipid-binding antibodies in mice and rabbits by immunization with human beta 2-glycoprotein I or anticardiolipin antibodies alone. Clin Exp Immunol 1993; 93: 269-272
33 Blank M, Faden D, Tincani A, Kopolovic J, Goldberg I, Gilburd B, Allegri F, Balestrieri G, Valesini G, Shoenfeld Y. Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice. J Autoimmun 1994; 7: 441-455
34 Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 1973; 136: 409-416
35 Chong BH, Grac CS, Rozenberg MC. Heparin-induced thrombocytopenia: effect of heparin platelet antibody on platelets. Br J Haematol 1981; 49: 531-540
36 Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet 1982; 2: 1246-1249
37 Blockmans D, Bounameaux H, Vermylen J, Verstraete M. Heparin-induced thrombocytopenia. Platelet aggregation studies in the presence of heparin fractions or semi-synthetic analogues of various molecular weights and anticoagulant activities. Thromb Haemost 1986; 55: 90-93
38 Kappa JR, Fisher CA, Addonizio Jr VP. Heparin-induced platelet activation: the role of thromboxane A2 synthesis and the extent of platelet granule release in two patients. J Vase Surg 1989; 9: 574-579
39 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
40 Warkentin TE, Hayward CP, Boshkov LK, Santos AV, Sheppard JA, Bode AP, Kelton JG. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 1994; 84: 3691-3699
41 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-930
42 Chong BH, Castaldi PA, Berndt MC. Heparin-induced thrombocytopenia: effects of rabbit IgG, and its Fab and Fc fragments on antibody-heparin-platelet interaction. Thromb Res 1989; 55: 291-295
43 Anderson GP. Insights into heparin-induced thrombocytopenia. Br J Haematol 1992; 80: 504-508
44 Warkentin TE, Hayward CP, Smith CA, Kelly PM, Kelton JG. Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia. J Lab Clin Med 1992; 120: 371-379
45 Chong BH, Pilgrim RL, Cooley MA, Chesterman CN. Increased expression of platelet IgG Fc receptors in immune heparin-induced thrombocytopenia. Blood 1993; 81: 988-993
46 Horsewood P, Hayward CP, Warkentin TE, Kelton JG. Investigation of the mechanisms of monoclonal antibody-induced platelet activation. Blood 1991; 78: 1019-1026
47 De Reys S, Blom C, Lepoudre B, Declerck PJ, De Ley M, Vermylen J, Deckmyn H. Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent. Blood 1993; 81: 1792-1800
48 Green D, Harris K, Reynolds N, Roberts M, Patterson R. Heparin immune thrombocytopenia: evidence for a heparin-platelet complex as the antigenic determinant. J Lab Clin Med 1978; 91: 167-175
49 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545-549
50 Amiral J, Bridey F, Dreyfus M, Vissoc AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-96
51 Kelton JG, Smith JW, Warkentin TE, Hayward CP, Denomme GA, Horse-wood P. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood 1994; 83: 3232-3239
52 Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: 247-251
53 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-589
54 Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994; 93: 81-88
55 Frame JN, Mulvey KP, Phares JC, Anderson MJ. Correction of severe heparin-associated thrombocytopenia with intravenous immunoglobulin. Ann Intern Med 1989; 111: 946-947
56 Grau E, Linares M, Olaso A, Ruvira J, Sauchris J. Heparin-induced throm-bocytopenia-response to intravenous immunoglobulins in vivo and in vitro. Am J Hematol 1992; 39: 312-313
57 Hasselaar P, Derksen RH, Blokzijl L, de Groot PG. Thrombosis associated with antiphospholipid antibodies cannot be explained by effects on endothelial and platelet prostanoid synthesis. Thromb Haemost 1988; 59: 80-85
58 Martinuzzo ME, Maclouf J, Carreras LO, Levy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70: 667-671
59 Lellouche F, Martinuzzo M, Said P, Maclouf J, Carreras LO. Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 1991; 78: 2894-2899
60 Arfors L, Vesterqvist O, Johnsson H, Grien K. Increased thromboxane formation in patients with antiphospholipid syndrome. Eur J Clin Invest 1990; 20: 607-612
61 Lin YL, Wang CT. Activation of human platelets by the rabbit anticardio-lipin antibodies. Blood 1992; 80: 3135-3143
62 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: 1255-1262
63 Arvieux J, Roussel B, Pouzol P, Colomb MG. Platelet activating properties of murine monoclonal antibodies to beta 2-glycoprotein I. Thromb Haemost 1993; 70: 336-341
64 Tannenbaum SH, Finko R, Cines DB. Antibody and immune complexes induce tissue factor production by human endothelial cells. J Immunol 1986; 137: 1532-1537
65 Rustin MH, Bull HA, Machin SJ, Isenberg DA, Snaith ML, Dowd PM. Effects of the lupus anticoagulant in patients with systemic lupus erythematosus on endothelial cell prostacyclin release and procoagulant activity. J Invest Dermatol 1988; 90: 744-748
66 Hasselaar P, Derksen RH, Oosting JD, Blokzijl L, de Groot PG. Synergistic effect of low doses of tumor necrosis factor and sera from patients with systemic lupus erythematosus on the expression of procoagulant activity by cultured endothelial cells. Thromb Haemost 1989; 62: 654-660
67 Oosting JD, Derksen RH, Blokzijl L, Sixma JJ, de Groot PG. Antiphospholipid antibody positive sera enhance endothelial cell procoagulant activity: studies in a thrombosis model. Thromb Haemost 1992; 68: 278-284
68 Hasselaar P, Derksen RH, Blokzijl L, de Groot Ph. Crossreactivity of antibodies directed against cardiolipin, DNA, endothelial cells and blood platelets. Thromb Haemost 1990; 63: 169-173
69 Del Papa N, Meroni PL, Tincani A, Harris EN, Pierangeli SS, Barcellini W, Borghi MO, Balestrieri G, Zanussi C. Relationship between antiphospholipid and anti-endothelial cell antibodies: further characterization of the reactivity on resting and cytokine-activated endothelial cells. Clin exp Rheumatol 1992; 10: 37-42
70 Arvieux J, Jacob MC, Roussel B, Bensa JC, Colomb MG. Anti-B₂ Glycoprotein I monoclonal antibodies induce neutrophil activation and could promote endothelial dysfunction. Lupus 1994 3. 333 (Abstract).
71 Chamley LW, Pattison NS, McKay EJ. Elution of anticardiolipin antibodies and their cofactor (3 2-glycoprotein I from placentae of patients with a poor obstetric history. J Reprod Immunol 1993; 25: 209-220
72 La Rosa L, Meroni PL, Tincani A, Balestrieri G, Faden D, Lojacono A, Morassi L, Brocchi E, Del Papa N, Gharavi A, Sammaritano L, Lockshin M. Β 2 glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome. J Rheumatol 1994; 21: 1684-1693
73 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb 1991; 10: 1-34
74 Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995; 89: 431-439
75 Vermylen J, Blockmans D, Spitz B, Arnout J, Grillet B. Thrombosis as an immune phenomenon. Baillière’s Clin Immunol Allergy 1987; 1: 619-641
76 Rosove MH, Brewer PM. Antiphospholipid thrombosis: Clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303-308
77 Lenaerts J, Vanneste S, Knockaert D, Arnout J, Vermylen J. SLE and acute Addisonian crisis due to bilateral adrenal hemorrhage: association with the antiphospholipid syndrome. Clin Exp Rheumatol 1991; 9: 407-409
78 Souied F, Pourriat JL, Le Roux G, Hoang P, Kemeny JL, Cupa M. Adrenal hemorrhagic necrosis related to heparin-associated thrombocytopenia. Crit Care Med 1991; 19: 297-299
79 Boshkov LK, Warkentin TE, Hayward CP, Andrew M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993; 84: 322-328
80 Makhoul RG, Greenberg CS, McCann RL. Heparin-associated thrombocytopenia and thrombosis: a serious clinical problem and potential solution. J Vase Surg 1986; 4: 522-528
81 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-997
82 Pierangeli SS, Barker JH, Stickovic D, Stikovac D, Ackerman D, Anderson G, Barquinero J, Acland R, Harvies EN. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice. Thromb Haemost 1994; 71: 670-674
83 Stasi R, Stipa E, Masi M, Oliva F, Sciarra A, Perrotti A, Olivieri M, Zaccari G, Gandolfo GM, Galli M, Barbui T, Papa G. Prevalence and clinical significance of elevated antiphospholipid antibodies in patients with idiopathic thrombocytopenic purpura. Blood 1994; 84: 4203-4208
84 Nomura S, Yanabu M, Miyake T, Miyazaki Y, Kido H, Kagawa H, Fuku-hara S, Komiyama Y, Matsuura E, Koike T. Relationship of microparticles with b 2-glycoprotein I and P-selectin positivity to anticardiolipin antibodies in immune thrombocytopenic purpura. Ann Hematol 1995; 70: 25-30
85 Carreras LD, Perez GN, Vega HR, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988; 2: 393-394
86 Wapner RJ, Cowchock FS, Shapiro SS. Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions. Am J Obstet Gynecol 1989; 161: 1271-1272
87 Scott JR, Branch DW, Kochenour NK, Ward K. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am J Obstet Gynecol 1988; 159: 1055-1056
88 Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gammaglobulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 1989; 110: 495-496
89 Kaaja R, Julkunen H, Ammala P, Palosuo T, Kurki P. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy losses associated with antiphospholipid antibodies. Acta Obstet Gynecol Scand 1993; 72: 63-66
90 Arnout J, Spitz B, Wittevrongel C, Vanrusselt M, Van Assche A, Vermylen J. High-dose intravenous immunoglobulin treatment of a pregnant patient with an antiphospholipid antibody syndrome: immunological changes associated with a successful outcome. Thromb Haemost 1994; 71: 741-747
91 Debre M, Bonnet MC, Fridman WH, Carosella E, Philippe N, Reinert P, Vilmer E, Kaplan C, Teillauld JL, Griscelli C. Infusion of FC7 fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 1993; 342: 945-949
92 McNeil HP, Chesterman CN, Krilis SA. Immulogy and clinical importance of antiphospholipid antibodies. Adv Immunol 1991; 49: 193-280
93 Pierangeli SS, Liu XW, Barker JH, Anderson G, Harris EN. Induction of thrombosis in a mouse model by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemost 1995; 74: 1361-1367