Partial Neutralization of a Lupus Anticoagulant by Human Immunoglobulin^[*]

Summary

In a patient with a Lupus Anticoagulant (LA) and recurrent fetal loss, we observed a significant shortening of the APTT after high-dose intravenous immunoglobulin infusion (IVIg).

The LA activity present in patient’s serum and purified IgG was partially neutralized by IVIg in a dose-dependent way. In addition, IgG purified from IVIg and its F(ab′)₂ fragment neutralized LA activity of the patient’s IgG. In both cases, the neutralization was dose-dependent and it was obtained with similar molar ratios

The “in vitro” neutralization of LA activity and the immediate shortening of the APTT after IVIg infusion, might be mediated through idiotypel antiidiotype interactions.

On the other hand, the long-lasting effect of IVIg in this patient indicates that it may induce specific inhibition of autoantibody synthesis.

We believe that IVIg should be considered as a therapeutic alternative for LA-related clinical disorders.

Dedicated to Professor Marc Verstraete on the occasion of his 65th birthday.

• References

• 1 Lechner K. Acquired inhibitors in non-hemophilic patients. Haemostasis 1974; 3: 65-93
• 2 Thiagarajan P, Shapiro SS, De Marco L. Monoclonal immunoglobulin MA, coagulation inhibitor with phospholipid specificity: mechanism of a lupus anticoagulant. J Clin Invest 1980; 66: 397-405
• 3 Pengo V, Thiagarajan P, Shapiro S, Heine M. Immunological specificity and mechanism of action of IgG lupus anticoagulants. Blood 1987; 70: 69-76
• 4 Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 621-622
• 5 Lechner KA. A new type of coagulation inhibitor. Thromb Diath Haemorrh 1969; 21: 482-499
• 6 Boxer M, Ellman L, Carvalho A. The lupus anticoagulant. Arthr Rheum 1976; 19: 1244-1248
• 7 Schleider MA, Nachman RL, Jaffe EA, Coleman M. A clinical study of the lupus anticoagulant. Blood 1976; 48: 499-509
• 8 Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92: 156-159
• 9 Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Haemostas Thromb 1972; 1: 75-95
• 10 Veltkamp JJ, Kerkhoven P, Loeliger EA. Circulating anticoagulant in disseminated lupus erythematosus. Haemostasis 1973; 2: 253-259
• 11 Elias M, Eldor A. Thromboembolism in patients with the “lupus”-type circulating anticoagulant. Arch Intern Med 1984; 144: 510-515
• 12 Rapaport SI, Ames SB, Duvall BJ. A plasma coagulation defect in systemic lupus erythematosus arising from hypoprothrombinemia combined with antiprothrombinase activity. Blood 1960; 15: 212-227
• 13 Bowie EW, Thompson JH, Cascuzzi PA, Owen GA. Thrombosis in SLE despite circulating anticoagulants. J Lab Clin Med 1963; 62: 416-430
• 14 Boey M, Colaco CB, Gharavi AE, Loizou S, Hughes GR. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J 1983; 287: 1021-1023
• 15 Lechner K, Pabinger-Fasching I. Lupus anticoagulant and thrombosis. Haemostasis 1985; 15: 254-262
• 16 Nilsson IM, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant (“antithromboplastin”). Acta Med Scand 1975; 197: 153-159
• 17 Soulier JP, Boffa MC. Avortements a repetition, thrombose et anticoagulant circulant anti-thromboplastine. Nouvelle Presse Med 1980; 9: 859-864
• 18 Firkin BG, Howard MA, Radford N. Possible relationship between lupus inhibitor and recurrent abortion in young women. Lancet 1980; 2: 366
• 19 Vermylen J, Carreras LO, Van Assche A. Repeated abortion and intrauterine death in women with a lupus anticoagulant. In: Fetal Growth Retardation Van Assche A, Robertson WB. (eds). Churchill-Livingstone; Edinburgh: 1981: 156-160
• 20 Stiehm ER, Ashida E, Kim KS, Winston DJ, Haas A, Gale RP. Intravenous immunoglobulins as therapeutic agents. Ann Intern Med 1987; 107: 367-382
• 21 Sultan Y, Kazatchkine MD, Maisonneuve P, Nydegger UE. Anti-idiotypic suppression of autoantibodies to factor VIII (anti-haemophilic factor) by high-dose intravenous gammaglobulin. Lancet 1984; 2: 765-768
• 22 Zimmermann R, Kommerell B, Harenberg J, Eich W, Rother K, Schimpf KL. Intravenous IgG for patients with spontaneous inhibitor to factor VIII. Lancet 1985; 1: 273-274
• 23 McVerry BA, Spearing R, Smith A. SLE anticoagulant: transient inhibition by high dose immunoglobulin infusions. Br J Haematol 1985; 61: 579-580
• 24 Green D, Hougie C, Kasmier FJ, Lechner K, Mannucci PM, Rizza CR, Sultan Y. Report of the Working Party on Acquired Inhibitors of Coagulation: Studies of “lupus” anticoagulant. Thromb Haemostas 1983; 49: 144-146
• 25 Thiagarajan P, Pengo V, Shapiro SS. The use of the dilute Russell Viper Venom Time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-874
• 26 Triplett DA, Brandt JT, Kaczor D, Schaefer J. Laboratory diagnosis of lupus inhibitors : a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983; 79: 678-682
• 27 Rosove MH, Ismail M, Koriol BJ, Runge A, Kosper CK. Lupus anticoagulants: improved diagnosis with a kaolin clotting time using rabbit brain phospholipid in standard and high concentrations. Blood 1986; 68: 472-478
• 28 Weir DM. (ed) Handbook of Experimental Immunology. Vol I.. Immunochemistry Blackwell Sci Publ; Oxford: 1973
• 29 Lechner K. Lupus anticoagulants and thrombosis. In: Thrombosis and Haemostasis 1987 Verstraete M, Vermylen J, Lijnen HR, Amout J. (eds). International Society on Thrombosis and Haemostasis and Leuven University Press; Leuven: 1987: 525-547
• 30 De Wolf F, Carreras LO, Moerman P, Vermylen J, Van Assche A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss and lupus anticoagulant. Am J Obstet Gynecol 1982; 142: 829-834
• 31 Lubbe WF, Butler WS, Palmer SJ, Liggins GC. Lupus anticoagulant in pregnancy. Br J Obstet Gynecol 1984; 91: 357-363
• 32 Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with lupus anticoagulant. N Engl J Med 1985; 313: 1322-1326
• 33 Lockshin MD, Druzin ML, Goei S, Qamar T, Magid MS, Jovanovic L, Ferenc M. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985; 313: 152-156
• 34 Branch DW. Immunologic disease and fetal death. Clin Obstet Gynecol 1987; 30: 295-311
• 35 Branch DW, Dudley DJ, Daynes R, Mitchell MD, Abbott TM. IgG fractions from patients with antiphospholipid antibodies cause fetal death in Balb C mice: a new model for autoimmune abortion. Proc Soc Gynecol Invest 1989 (Abstract)
• 36 Carreras LO, Defreyn G, Machin S, Vermylen J, Deman R, Spitz B, Van Assche A. Arterial thrombosis, intrauterine death and “lupus” anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981; 1: 244-246
• 37 Carreras LO, Vermylen J, Spitz B, Van Assche A. “Lupus” anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauterine death. Br J Obstet Gynaecol 1981; 88: 890-894
• 38 Carreras LO, Vermylen JG. “Lupus” anticoagulant and thrombosis. Possible role of inhibition of prostacyclin formation. Thromb Haemostas 1982; 48: 38-40
• 39 Schorer AE, Wickham NW R, Watson KV. Lupus anticoagulant induces a selective defect in thrombin-mediated endothelial prostacyclin release and platelet aggregation. Br J Haematol 1989; 71: 399-407
• 40 Carreras LO, Vermylen J. Antiphospholipid antibodies and impairment of prostacyclin synthesis by the endothelium. In: Phospholipid Binding Antibodies Harris EN, Exner T, Hughes GR V, Asherson R. (eds). CRC Press; New York: (in press)
• 41 Lubbe WF, Butler WS, Palmer SJ, Liggins GC. Fetal survival after prednisone suppression of maternal lupus anticoagulant. Lancet 1983; 1: 1361-1363
• 42 Feinstein DI. Lupus anticoagulant, thrombosis and fetal loss. N Engl J Med 1985; 313: 1348-1350
• 43 Frampton G, Cameron JS, Thom M, Jones S, Raftery M. Successful removal of anti-phospholipid antibody during pregnancy using plasma exchange and low-dose prednisolone. Lancet 1987; 2: 1023-1024
• 44 Carreras LO, Perez GN, Ruda VegaH, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988; 2: 393-394
• 45 Mueller-Eckhardt G, Heine O, Neppert J, Kunzel W, Mueller-Eckhardt C. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin. Vox Sang 1989; 56: 151-154
• 46 Hedge UM. Immune thrombocytopenia in pregnancy and the newborn: a review. J Infect 1987; 15 (Suppl. 01) 55-58
• 47 Carreras LO, Perez GN, Xavier DL, Blanco AN, Penalva LB. Autoimmune factor VIII inhibitor responsive to gammaglobulin without in vitro neutralization. Thromb Haemostas 1988; 60: 343
• 48 Bernstein RM, Crawford RJ. IVIg therapy for anticardiolipin syndrome: a case report. Proceedings Third International Symposium on Antiphospholipid Antibodies Jamaica: 1988. (Abstract 8)
• 49 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
• 50 Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gamma-globulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 1989; 110: 495-496
• 51 Barbui T, Finazzi G, Falanga A, Cortelazzo S. Intravenous gammaglobulin, antiphospholipid antibodies, and thrombocytopenia. Lancet 1988; 2: 969
• 52 Gris JC, Schved JF, Tousch D, Hereil S, Feugeras O. Anti-idiotypic antibodies against anti-phospholipid autoantibodies which suppress lupus-like anticoagulant activity. Nouv Rev Fr Hematol 1988; 30: 143-147
• 53 Sultan Y, Rossi F, Kazatchkine MD. Recovery from anti VIII (antihaemophilic factor) autoimmune disease is dependent on generation of anti-idiotypes against anti VIII :C autoantibodies. Proc Natl Acad Sci USA 1987; 84: 828-831
• 54 Rossi F, Dietrich G, Kazatchkine MD. Antiidiotypic suppression of autoantibodies with normal polyspecific immunoglobulins. Res Immunol 1989; 140: 19-31