High-Dose Intravenous Immunoglobulin Treatment of a Pregnant Patient with an Antiphospholipid Syndrome: Immunological Changes Associated with a Successful Outcome

J Arnout; B Spitz; C Wittevrongel; M Vanrusselt; A Van Assche; J Vermylen

doi:10.1055/s-0038-1642516

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1994; 71(06): 741-747
DOI: 10.1055/s-0038-1642516

Review Article

Schattauer GmbH Stuttgart

High-Dose Intravenous Immunoglobulin Treatment of a Pregnant Patient with an Antiphospholipid Syndrome: Immunological Changes Associated with a Successful Outcome

J Arnout

¹The Center for Molecular and Vascular Biology, University of Leuven, Belgium

,

B Spitz

²The Department of Gynecology and Obstetrics, University of Leuven, Belgium

,

C Wittevrongel

¹The Center for Molecular and Vascular Biology, University of Leuven, Belgium

,

M Vanrusselt

¹The Center for Molecular and Vascular Biology, University of Leuven, Belgium

,

A Van Assche

²The Department of Gynecology and Obstetrics, University of Leuven, Belgium

,

J Vermylen

¹The Center for Molecular and Vascular Biology, University of Leuven, Belgium

› Author Affiliations

Abstract

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Summary

A patient with a history of habitual abortion, deep venous thrombosis, thrombocytopenia, high titer IgG anticardiolipin antibodies and a clearly positive lupus anticoagulant, was treated during her seventh pregnancy with high-dose intravenous immunoglobulins (IVIg) from the third month onwards. Every month, a daily infusion of 400 mg immunoglobulins per kg body weight was given during five consecutive days. The patient’s pregnancy ended preterm with a live birth, delivered by caesarian section because of a placental abruption. The 1070 g (P20-P25) weighing girl was in good health, apart from a bradycardia, due to dysfunction of the atrioventricular conduction.

Each treatment with IVIg resulted in a slight reduction of both anticardiolipin antibodies and lupus anticoagulant levels and in an increase in platelet count. During the six-month observation period, a gradual decline in antiphospholipid antibodies and an increase in platelet count was found. The potential role of anti-idiotypic antibodies, present in the IVIg used for treatment, was studied. In vitro, IVIg were able to reduce the binding of the patient’s anticardiolipin antibodies to cardiolipin coated microtiter plates. The presence of anti-idiotypic antibodies in IVIg was further documented by affinity chromatography and by realtime biospecific interaction analysis (BIA) on a BIA-core instrument. Affinity purified anticardiolipin antibodies were retarded on a column of insolubilized IVIg and a weak interaction was found between IVIg and affinity purified patient antiphospholipid antibodies, coupled to the BIA-core biosensor. In addition, the same technology revealed increased levels of anti-antiphospholipid antibodies in the patient’s plasma following IVIg therapy. The partial and transient reduction of anti-phospholipid antibody levels observed immediately following each treatment course seems compatible with low affinity complexation of idiotype-antiidiotypes, resulting in an accelerated clearance of the autoantibodies. Despite the low affinity for the patient’s idiotypes, the beneficial long term effects observed could be related to an immune regulatory role of these anti-idiotypic antibodies on the synthesis of antiphospholipid antibodies.

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References

References
1 Triplett DA, Brandt JT. Lupus anticoagulants: misnomer, paradox, riddle, epiphenomenon. Hematol Pathol 1988; 2: 121-43
2 Loizou S, Mc Crea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-45
3 Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112: 682-98
4 Hughes GRV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J 1983; 287: 1088-9
5 Asherson RA, Khamashta MA, Hughes GRV. Antiphospholipid antibodies, lupus-like disease and the “primary” antiphospholipid syndrome. Clin Rheumatol 1989; 8: 115-7
6 Lubbe WF, Butler WS, Palmer SJ, Liggins GC. Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet 1983; 1: 1361-3
7 Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985; 313: 1322-6
8 Rosove MH, Tabsh K, Wasserstrum N, Howard P, Hahn BH, Kalunian KC. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 1990; 75: 630-4
9 Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992; 166: 1318-23
10 Lockshin MD, Druzin ML, Qamar T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 1989; 160: 439-43
11 Frampton G, Cameron JS, Thom M, Jones S, Raftery M. Successful removal of antiphospholipid antibody during pregnancy using plasma exchange and low-dose prednisolone. Lancet 1987; 2: 1023-4
12 Fulcher D, Stewart G, Exner T, Trudinger B, Jeremy R. Plasma exchange and the anticardiolipin syndrome in pregnancy. Lancet 1989; 2: 171
13 Carreras LO, Perez ON, Vega HR, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988; 2: 393-4
14 Wapner RJ, Cowchock FS, Shapiro SS. Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous gammaglobulin infusions. Am J Obstet Gynecol 1989; 161: 1271-2
15 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: 1055-6
16 Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gammaglobulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 1989; 110: 495-6
17 Kaaja R, Julkunen H, Ämmälä 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: 63-6
18 Arnout J, Vanrusselt M, Huybrechts E, Vermylen J. Optimisation of the dilute prothrombin time for the detection of the lupus anticoagulant by use of a recombinant tissue thromboplastin. Brit J Haematol. 1994. (; 87). in press
19 Arnout J, Huybrechts E, Vanrusselt M, Vermylen J. A New lupus anticoagulant neutralization test based on platelet-derived vesicles. Br J Haematol 1992; 80: 341-6
20 Arnout J, Huybrechts E, Vanrusselt M, Falcon C, Vermylen J. Detection of lupus-like anticoagulants by an enzyme-linked immunosorbent assay using a partial thromboplastin as antigen; A comparative study. Thromb Haemost 1990; 64: 26-31
21 Karlsson R, Michaelsson A, Mattsson L. Kinetic analysis of monoclonal antibody-antigen interactions with a new biosensor based analytical system. J Immunol Methods 1991; 145: 229-40
22 Altschuh D, Dubs MC, Weiss E, Zeder-Lutz G, Van Regenmortel MH. Determination of kinetic constants for the interaction between a monoclonal antibody and peptides using surface plasmon resonance. Biochemistry 1992; 31: 6298-304
23 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-5
24 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54
25 Kaveri SV, Dietrich G, Hurez V, Kazatchkine MD. Intravenous immunoglobulins (IVIg) in the treatment of autoimmune diseases. Clin Exp Immunol 1991; 86: 192-8
26 Todd AA, Yap PL. Applications of intravenous immunoglobulin in haematology. Blood Rev 1992; 6: 105-17
27 Sultan Y, Kazatchkine MD, Maisonneuve P, Nydegger UE. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet 1984; 2: 765-8
28 Abdou NI, Wall H, Lindsley HB, Halsey JF, Suzuki T. Network theory in autoimmunity. In vitro suppression of serum anti-DNA antibody binding to DNA by anti-idiotypic antibody in systemic lupus erythematosus. J Clin Invest 1981; 67: 1297-304
29 Mc Verry BA, Spearing R, Smith A. SLE anticoagulant: transient inhibition by high dose immunoglobulin infusions. Br J Haematol 1985; 61: 579-80
30 Gris JC, Schved JF, Tousch D, Hereil S, Feugeas O. Antiidiotypic antibodies against anti-phospholipid autoantibodies which suppress lupus-like anticoagulant activity. Nouv Rev Fr Hematol 1988; 30: 143-7
31 Carreras LO, Pérez GN, Martinuzzo ME, Malan-Borel I, Malbran A, Said PB. Partial neutralization of a lupus anticoagulant by human immunoglobulin. Thromb Haemost 1990; 64: 32-7
32 Anderson CL. Human IgG Fc receptors. Clin Immunol Immunopathol 1989; 53: S63-71
33 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: 210-6
34 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA 1991; 88: 3069-73
35 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: 1558-63
36 Bakimer R, Guilburd B, Zurgil N, Shoenfeld Y. The effect of intravenous gammaglobulin on the induction of experimental antiphospholipid syndrome. Clin Immunol Immunopathol 1993; 69: 97-102