Immune Complex Therapies for Treatment of Immune Thrombocytopenia

  • Rong Deng
  • Joseph P. Balthasar


Approximately 30% of patients with chronic immune thrombocytopenia (ITP), a common autoimmune disease, are refractory to standard therapies. In the last several years, several published reports have suggested that gamma globulin immune complexes may inhibit pathways of platelet destruction in ITP, attenuating thrombocytopenia in human patients and in animal models of ITP. This chapter reviews the literature associated with the use of immune complexes as a treatment of ITP, including a discussion of immune complex therapies that are in current clinical use (e.g., IVIG, anti-D), mechanisms proposed for the effects of immune complexes in ITP, possible adverse effects associated with immune complexes, and translational considerations for the development of novel immune complex therapies (e.g., antibody-coated liposomes).


Immune Complex Immune Thrombocytopenia Antiplatelet Antibody IVIG Preparation Soluble Immune Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work has been supported by NIH/NHLBI grant number HL67347 (to JPB).


  1. Andresen I, Kovarik JM, Spycher M et al (2000) Product equivalence study comparing the tolerability, pharmacokinetics, and pharmacodynamics of various human immunoglobulin-G formulations. J Clin Pharmacol 40:722–730PubMedCrossRefGoogle Scholar
  2. Augener W, Friedmann B, Brittinger G (1985) Are aggregates of IgG the effective part of high-dose immunoglobulin therapy in adult idiopathic thrombocytopenic purpura (ITP)? Blut 50:249–252PubMedCrossRefGoogle Scholar
  3. Avrameas S, Ternynck T (1993) The natural autoantibodies system: between hypotheses and facts. Mol Immunol 30:1133–1142PubMedCrossRefGoogle Scholar
  4. Basta M (1996) Modulation of complement-mediated immune damage by intravenous immune globulin. Clin Exp Immunol 104(Suppl 1):21–25PubMedGoogle Scholar
  5. Basta M, Langlois PF, Marques M et al (1989) High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood 74:326–333PubMedGoogle Scholar
  6. Bazin R, Lemieux R, Tremblay T (2006) Reversal of immune thrombocytopenia in mice by cross-linking human immunoglobulin G with a high-affinity monoclonal antibody. Br J Haematol 135:97–100PubMedCrossRefGoogle Scholar
  7. Bazin R, Lemieux R, Tremblay T et al (2004) Tetramolecular immune complexes are more efficient than IVIg to prevent antibody-dependent in vitro and in vivo phagocytosis of blood cells. Br J Haematol 127:90–96PubMedCrossRefGoogle Scholar
  8. Berchtold P, Dale GL, Tani P et al (1989) Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin. Blood 74:2414–2417PubMedGoogle Scholar
  9. Berneman A, Guilbert B, Eschrich S et al (1993) IgG auto- and polyreactivities of normal human sera. Mol Immunol 30:1499–1510PubMedCrossRefGoogle Scholar
  10. Bleeker WK, Agterberg J, Rigter G et al (1987) An animal model for the detection of hypotensive side effects of immunoglobulin preparations. Vox Sang 52:281–290PubMedCrossRefGoogle Scholar
  11. Bleeker WK, Agterberg J, Rigter G et al (1989) Key role of macrophages in hypotensive side effects of immunoglobulin preparations. Studies in an animal model. Clin Exp Immunol 77:338–344PubMedGoogle Scholar
  12. Bleeker WK, Teeling JL, Verhoeven AJ et al (2000) Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood 95:1856–1861PubMedGoogle Scholar
  13. British Committee for Standards in Haematology General Haematology Task Force (2003) Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 120:574–596CrossRefGoogle Scholar
  14. Bruley-Rosset M, Mouthon L, Chanseaud Y et al (2003) Polyreactive autoantibodies purified from human intravenous immunoglobulins prevent the development of experimental autoimmune diseases. Lab Invest 83:1013–1023PubMedCrossRefGoogle Scholar
  15. Bussel JB (2000) Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol 37:261–266PubMedCrossRefGoogle Scholar
  16. Bussel JB, Graziano JN, Kimberly RP et al (1991) Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 77:1884–1893PubMedGoogle Scholar
  17. Chan PL, Sinclair NR (1971) Regulation of the immune response. V. An analysis of the function of the Fc portion of antibody in suppression of an immune response with respect to interaction with components of the lymphoid system. Immunology 21:967–981PubMedGoogle Scholar
  18. Cines DB, Blanchette VS (2002) Immune thrombocytopenic purpura. N Engl J Med 346:995–1008PubMedCrossRefGoogle Scholar
  19. Clarkson SB, Kimberly RP, Valinsky JE et al (1986) Blockade of clearance of immune complexes by an anti-Fc gamma receptor monoclonal antibody. J Exp Med 164:474–489PubMedCrossRefGoogle Scholar
  20. Clynes R (2005) Immune complexes as therapy for autoimmunity. J Clin Invest 115:25–27PubMedGoogle Scholar
  21. Clynes R, Ravetch JV (1995) Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 3:21–26PubMedCrossRefGoogle Scholar
  22. Crow AR, Lazarus AH (2003) Role of Fcgamma receptors in the pathogenesis and treatment of idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol 25(Suppl 1):S14–S18PubMedCrossRefGoogle Scholar
  23. Crow AR, Song S, Suppa SJ et al (2011) Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP? Blood 117:971–974PubMedCrossRefGoogle Scholar
  24. Dale DC, Nichol JL, Rich DA et al (1997) Chronic thrombocytopenia is induced in dogs by development of cross-reacting antibodies to the MpL ligand. Blood 90:3456–3461PubMedGoogle Scholar
  25. Debre M, Bonnet MC, Fridman WH et al (1993) Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342:945–949PubMedCrossRefGoogle Scholar
  26. Deng R, Balthasar JP (2005) Investigation of antibody-coated liposomes as a new treatment for immune thrombocytopenia. Int J Pharm 304:51–62PubMedCrossRefGoogle Scholar
  27. Deng R, Balthasar JP (2007a) Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia. Blood 109:2470–2476PubMedCrossRefGoogle Scholar
  28. Deng R, Balthasar JP (2007b) Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia. J Pharm Sci 96(6):1625–1637Google Scholar
  29. Dijstelbloem HM, van de Winkel JG, Kallenberg CG (2001) Inflammation in autoimmunity: receptors for IgG revisited. Trends Immunol 22:510–516PubMedCrossRefGoogle Scholar
  30. Farrugia A, Poulis P (2001) Intravenous immunoglobulin: regulatory perspectives on use and supply. Transfus Med 11:63–74PubMedCrossRefGoogle Scholar
  31. Fehr J, Hofmann V, Kappeler U (1982) Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 306:1254–1258PubMedCrossRefGoogle Scholar
  32. Fernandez N, Jancar S, Sanchez Crespo M (2004) Blood and endothelium in immune complex-mediated tissue injury. Trends Pharmacol Sci 25:512–517PubMedCrossRefGoogle Scholar
  33. George JN, Woolf SH, Raskob GE et al (1996) Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of hematology. Blood 88:3–40PubMedGoogle Scholar
  34. Goldsby RA, Kindt TJ, Osborne BA (2000) Hypersensitive reactions. In: Goldsby RA, Kindt TJ, Osborne BA (eds) Kuby immunology, 4th edn. WH Freeman and Company, New YorkGoogle Scholar
  35. Good RA, Lorenz E (1991) Historic aspects of intravenous immunoglobulin therapy. Cancer 68:1415–1421PubMedCrossRefGoogle Scholar
  36. Grossi A, Vannucchi AM, Casprini P et al (1986) Effects of high-dose intravenous gammaglobulin on kinetic parameters of 51Cr-labelled platelets in chronic ITP. Haematologica 71:123–127PubMedGoogle Scholar
  37. Hansen RJ, Balthasar JP (2002a) Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia. Blood 100:2087–2093PubMedGoogle Scholar
  38. Hansen RJ, Balthasar JP (2002b) Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost 88:898–899PubMedGoogle Scholar
  39. Hansen RJ, Balthasar JP (2003) Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia. J Pharm Sci 92:1206–1215PubMedCrossRefGoogle Scholar
  40. Hansen RJ, Balthasar JP (2004) Mechanisms of IVIG action in immune thrombocytopenic purpura. Clin Lab 50:133–140PubMedGoogle Scholar
  41. Harrington WJ (1951) Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. The journal of laboratory and clinical medicine 38:1–10PubMedGoogle Scholar
  42. Hed J (1998) Role of complement in immune or idiopathic thrombocytopenic purpura. Acta Paediatr Suppl 424:37–40PubMedCrossRefGoogle Scholar
  43. Hong F, Ruiz R, Price H et al (1998) Safety profile of WinRho anti-D. Semin Hematol 35:9–13PubMedGoogle Scholar
  44. Hou M, Stockelberg D, Kutti J et al (1997) Immunoglobulins targeting both GPIIb/IIIa and GPIb/IX in chronic idiopathic thrombocytopenic purpura (ITP): evidence for at least two different IgG antibodies. Br J Haematol 98:64–67PubMedCrossRefGoogle Scholar
  45. Huang KJ, Li SY, Chen SC et al (2000) Manifestation of thrombocytopenia in dengue-2-virus-infected mice. J Gen Virol 81:2177–2182PubMedGoogle Scholar
  46. Imbach P, Barandun S, d’Apuzzo V et al (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1:1228–1231PubMedCrossRefGoogle Scholar
  47. Jancar S, Sanchez Crespo M (2005) Immune complex-mediated tissue injury: a multistep paradigm. Trends Immunol 26:48–55PubMedCrossRefGoogle Scholar
  48. Jolles S, Hughes J, Whittaker S (1998) Dermatological uses of high-dose intravenous immunoglobulin. Arch Dermatol 134:80–86PubMedCrossRefGoogle Scholar
  49. Jones HW, Tocantins LM (1933) The history of purpura hemorrhagica. Ann Med Hist 5:349–359Google Scholar
  50. Jordan SC (1989) Intravenous gamma-globulin therapy in systemic lupus erythematosus and immune complex disease. Clin Immunol Immunopathol 53:S164–S169PubMedCrossRefGoogle Scholar
  51. Kazatchkine MD, Kaveri SV (2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345:747–755PubMedCrossRefGoogle Scholar
  52. Kleyweg RP, van der Meche FG, Meulstee J (1988) Treatment of Guillain-Barre syndrome with high-dose gammaglobulin. Neurology 38:1639–1641PubMedGoogle Scholar
  53. Kuter DJ, Rosenberg RD (1995) The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 85:2720–2730PubMedGoogle Scholar
  54. Lamoureux J, Aubin E, Lemieux R (2003) Autoimmune complexes in human serum in presence of therapeutic amounts of intravenous immunoglobulins. Blood 101:1660–1662PubMedCrossRefGoogle Scholar
  55. Lamoureux J, Aubin E, Lemieux R (2004) Autoantibodies purified from therapeutic preparations of intravenous immunoglobulins (IVIg) induce the formation of autoimmune complexes in normal human serum: a role in the in vivo mechanisms of action of IVIg? Int Immunol 16:929–936PubMedCrossRefGoogle Scholar
  56. Lemieux R, Bazin R, Neron S (2005) Therapeutic intravenous immunoglobulins. Mol Immunol 42:839–848PubMedCrossRefGoogle Scholar
  57. Maeda H, Furonaka O, Matsushima K et al (2001) Successful treatment of ‘malignant rheumatoid arthritis’ in Japan with pooled intravenous immunoglobulin. Rheumatology (Oxford) 40:955–956CrossRefGoogle Scholar
  58. McMillan R (2000a) Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin Hematol 37:239–248PubMedCrossRefGoogle Scholar
  59. McMillan R (2000b) The pathogenesis of chronic immune (idiopathic) thrombocytopenic purpura. Semin Hematol 37:5–9PubMedCrossRefGoogle Scholar
  60. Meade CJ, Heuer H, Kempe R (1991) Biochemical pharmacology of platelet-activating factor (and PAF antagonists) in relation to clinical and experimental thrombocytopenia. Biochem Pharmacol 41:657–668PubMedCrossRefGoogle Scholar
  61. Mizutani H, Engelman RW, Kurata Y et al (1993) Development and characterization of monoclonal antiplatelet autoantibodies from autoimmune thrombocytopenic purpura-prone (NZW x BXSB)F1 mice. Blood 82:837–844PubMedGoogle Scholar
  62. Mollnes TE, Andreassen IH, Hogasen K et al (1997) Effect of whole and fractionated intravenous immunoglobulin on complement in vitro. Mol Immunol 34:719–729PubMedCrossRefGoogle Scholar
  63. Mollnes TE, Hogasen K, Hoaas BF et al (1995) Inhibition of complement-mediated red cell lysis by immunoglobulins is dependent on the IG isotype and its C1 binding properties. Scand J Immunol 41:449–456PubMedCrossRefGoogle Scholar
  64. Newburger JW, Takahashi M, Burns JC et al (1986) The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 315:341–347PubMedCrossRefGoogle Scholar
  65. Oksenhendler E, Bierling P, Brossard Y et al (1988) Anti-RH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura. Blood 71:1499–1502PubMedGoogle Scholar
  66. Oyaizu N, Yasumizu R, Miyama-Inaba M et al (1988) (NZW x BXSB)F1 mouse. A new animal model of idiopathic thrombocytopenic purpura. J Exp Med 167:2017–2022PubMedCrossRefGoogle Scholar
  67. Ravetch JV (2002) A full complement of receptors in immune complex diseases. J Clin Invest 110:1759–1761PubMedGoogle Scholar
  68. Ravetch JV, Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19:275–290PubMedCrossRefGoogle Scholar
  69. Ravetch JV, Lanier LL (2000) Immune inhibitory receptors. Science 290:84–89PubMedCrossRefGoogle Scholar
  70. Salama A, Mueller-Eckhardt C, Kiefel V (1983) Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 2:193–195PubMedCrossRefGoogle Scholar
  71. Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486PubMedCrossRefGoogle Scholar
  72. Scaradavou A, Woo B, Woloski BM et al (1997) Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 89:2689–2700PubMedGoogle Scholar
  73. Siragam V, Brinc D, Crow AR et al (2005) Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J Clin Invest 115:155–160PubMedGoogle Scholar
  74. Song S, Crow AR, Freedman J et al (2003) Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG. Blood 101:3708–3713PubMedCrossRefGoogle Scholar
  75. Song S, Crow AR, Siragam V et al (2005) Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg. Blood 105:1546–1548PubMedCrossRefGoogle Scholar
  76. Spycher MO, Bolli R, Hodler G (1999) Well-tolerated liquid intravenous immunoglobulin G preparations(IVIGs) have a low immunoglobulin G dimer content. J Autoimmun 96(suppl):96 abstractGoogle Scholar
  77. Tankersley DL (1994) Dimer formation in immunoglobulin preparations and speculations on the mechanism of action of intravenous immune globulin in autoimmune diseases. Immunol Rev 139:159–172PubMedCrossRefGoogle Scholar
  78. Teeling JL, Bleeker WK, Rigter GM et al (2001a) Intravenous immunoglobulin preparations induce mild activation of neutrophils in vivo via triggering of macrophages–studies in a rat model. Br J Haematol 112:1031–1040PubMedCrossRefGoogle Scholar
  79. Teeling JL, Jansen-Hendriks T, Kuijpers TW et al (2001b) Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 98:1095–1099PubMedCrossRefGoogle Scholar
  80. Tovo PA, Miniero R, Fiandino G et al (1984) Fc-depleted vs intact intravenous immunoglobulin in chronic ITP. J Pediatr 105:676–677PubMedGoogle Scholar
  81. Tsubakio T, Kurata Y, Katagiri S et al (1983) Alteration of T cell subsets and immunoglobulin synthesis in vitro during high dose gamma-globulin therapy in patients with idiopathic thrombocytopenic purpura. Clin Exp Immunol 53:697–702PubMedGoogle Scholar
  82. van Leeuwen EF, van der Ven JT, Engelfriet CP et al (1982) Specificity of autoantibodies in autoimmune thrombocytopenia. Blood 59:23–26PubMedGoogle Scholar
  83. Wallace PK, Keler T, Guyre PM et al (1997) Fc gamma RI blockade and modulation for immunotherapy. Cancer Immunol Immunother 45:137–141PubMedCrossRefGoogle Scholar
  84. Ware RE, Zimmerman SA (1998) Anti-D: mechanisms of action. Semin Hematol 35:14–22PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Genentech, IncSouth San FranciscoUSA
  2. 2.Department of Pharmaceutical SciencesUniversity at Buffalo, The state University of New YorkBuffaloUSA

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