Seminars in Hematology
Volume 44 , Pages S3-S11 , October 2007

The Pathogenesis of Chronic Immune Thrombocytopenic Purpura

  • Robert McMillan

      Affiliations

    • Corresponding Author InformationAddress correspondence to Robert McMillan, 203 12th St, Del Mar, CA 92014.

References 

  1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008
  2. Semple JW. Immune pathophysiology of autoimmune thrombocytopenic purpura. Blood Rev. 2002;16:9–12
  3. Coopamah MD, Garvey MB, Freedman J, Semple JW. Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update. Trans Med Rev. 2003;17:69–80
  4. Cooper N, Bussel J. The pathogenesis of immune thrombocytopenic purpura. Br J Haematol. 2006;133:364–374
  5. Frank E. Die essentielle Thrombopenia (Konstitutionelle purpura-Pseudohämophilie) (II. Pathogenese). Berl Klin Wochenschr. 1915;52:490–494
  6. Kaznelson P. Verschwinden der hämorrhagischen Diathese bei einem Falle von “essentieller Thrombopenie” (Frank) nach Milzexstirpation (Splenogene thrombolytische Purpura). Wien Klin Wochenschr. 1916;29:1451–1454
  7. Dameshek W, Miller EB. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood. 1946;1:27–52
  8. Diggs LW, Hewlett JS. A study of the bone marrow from thiry-six patients with idiopathic hemorrhagic (thrombopenic) purpura. Blood. 1948;3:1090–1104
  9. Pisciotta AV, Stefanini M, Dameshek W. Studies on platelets (X. Morphologic characteristics of megakaryocytes by phase contrast microscopy in normals and in patients with idiopathic thrombocytopenic purpura). Blood. 1953;8:703–723
  10. Stahl CP, Zucker-Franklin D, McDonald TP. Incomplete antigenic cross-reactivity between platelets and megakaryocytes: Relevance to ITP. Blood. 1986;67:421–428
  11. Epstein RD, Lozner EL, Cobbey TS, Davidson CS. Congenital thrombocytopenic purpura (Purpura hemorrhagica in pregnancy and in the newborn). Am J Med. 1950;9:44
  12. Harrington WJ, Sprague CC, Minnich V, Moore CV, Aulvin RC, Dubach R. Immunologic mechanisms in idiopathic and neonatal thrombocytopenic purpura. Ann Intern Med. 1953;38:433–469
  13. Shulman NR, Marder VJ, Weinrach RS. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura: Physiologic, serologic, and isotopic studies. Ann NY Acad Sci. 1965;124:499–542
  14. Shulman NR, Weinrach RS, Libre EP, Andrews HL, Shannon JA. The role of the reticuloendothelial system in the pathogenesis of idiopathic thrombocytopenic purpura. Trans Assoc Am Physicians. 1965;78:374–390
  15. Kappler JW, Staerz U, White J. Self-tolerance eliminates T cells specific for MLS-modified products of the major histocompatibility complex. Nature. 1988;332:35–40
  16. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: A costimulatory signaling pathway determines the outcome of T cell antigen receptor occupancy. Annual Rev Immunol. 1989;7:445–480
  17. Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 2001;22:251–255
  18. Jonuleit H, Schmitt E, Steinbrink K, Enk AH. Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol. 2001;22:394–400
  19. Sinha AA, Lopez MT, McDevitt HO. Autoimmune diseases: The failure of self tolerance. Science. 1990;248:1380–1388
  20. Mackay IR. The “autoimmune diseases” 40th anniversary. Autoimmunity Rev. 2002;1:5–11
  21. Elson CJ, Barker RN. Helper T cells in antibody-mediated, organ-specific autoimmunity. Curr Opin Immunol. 2000;12:664–669
  22. Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Ann Rev Immunol. 1997;15:821–850
  23. Chambers CA. The expanding world of co-stimulation: the two-signal model revisited. Trends Immunol. 2001;22:217–223
  24. Chess L. Blockade of the CD40L/CD40 pathway. In:  Austen KF,  Burakoff S,  Rosen F,  Strom T editor. Therapeutic Immunology. New York: Blackwell Sciences; 2001;p. 441–456
  25. Solanilla A, Pasquet JM, Viallard JF, Contin C, Grosset C, Dechanet-Merville J, et al. Platelet-associated CD154 in immune thrombocytopenic purpura. Blood. 2005;105:215–218
  26. Piessens WF, Wybran J, Manaster J, Strijckmans PA. Lymphocyte transformation induced by autologous platelets in a case of thrombocytopenic purpura. Blood. 1970;36:421–427
  27. Morimoto C, Abe T, Hara M, Homma M. Cell-mediated immune response in idiopathic thrombocytopenic purpura. Clin Immunol Immunopathol. 1977;8:181–189
  28. Trent RJ, Clancy RL, Danis V, Basten A. Disordered immune homeostasis in chronic idiopathic thrombocytopenic purpura. Clin Exp Immunol. 1981;45:9–17
  29. Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood. 1991;78:2619–2625
  30. Kuwana K, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura (Role in production of anti-platelet autoantibody). J Clin Invest. 1998;102:1393–1402
  31. Kuwana K, Kaburaki J, Kitasato H, Kato M, Kawai S, Kawakami Y, et al. Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura. Blood. 2001;98:130–139
  32. Kuwana M, Okazaki Y, Kaburaki J, Kawakami Y, Ikeda Y. Spleen is the primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J Immunol. 2002;168:3675–3682
  33. Sukati H, Watson HG, Urbaniak SJ, Barker RN. Mapping helper T-cell epitopes on platelet membrane glycoprotein IIIa in chronic autoimmune thrombocytopenic purpura. Blood. 2007;109:4528–4538
  34. Mosmann RT, Sad D. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–146
  35. Romangnani S. Th1 and Th2 subsets in human diseases. Clin Immunol Immunopathol. 1996;80:225–235
  36. Semple JW, Milev Y, Cosgrave D, Mody M, Homstein A, Blanchette V, et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: Relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood. 1996;87:4245–4254
  37. Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zournbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103:2645–2647
  38. van Leeuwen EF, van der Ven JTH, Engelfriet CP, von dem Borne AEG. Specificity of autoantibodies in autoimmune thrombocytopenia. Blood. 1982;59:23–26
  39. Warner MN, Moore JC, Warkentin TE, Santos AV, Kelton JG. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura. Br J Haematol. 1999;104:442–447
  40. Berchtold P, Muller D, Beardsley D, Fujisawa K, Kaplan C, Kekomaki R, et al. International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies. Br J Haematol. 1997;96:477–483
  41. Brighton TA, Evans S, Castaldi PA, Chesterman CN, Chong BH. Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Blood. 1996;88:194–201
  42. McMillan R, Wang L, Tani P. Prospective evaluation of the immunobead assay for the diagnosis of adult chronic immune thrombocytopenic purpura (ITP). J Thomb Haemost. 2003;1:485–491
  43. Varon D, Karpatkin S. A monoclonal antiplatelet antibody with decreased reactivity for autoimmune thrombocytopenic platelets. Proc Natl Acad Sci U S A. 1983;80:6992–6995
  44. Hou M, Stockelberg D, Kutti J, Wadenvik H. Glycoprotein IIb/IIIa autoantigenic repertoire in chronic idiopathic thrombcytopenic purpura. Br J Haematol. 1995;91:971–975
  45. Escher R, Muller D, Vogel M, Miescher S, Stadler BM, Berchtold P. Recombinant human natural autoantibodies against GPIIb/IIIa inhibit binding of autoantibodies from patients with AITP. Br J Haematol. 1998;102:820–828
  46. He R, Reid DM, Jones CE, Shulman NR. Extracellular epitopes of platelet glycoprotein Ibα reactive with serum antibodies from patients with chronic idiopathic thrombocytopenic purpura. Blood. 1995;86:3789–3796
  47. Nugent DJ. Human monoclonal antibodies in the characterization of platelet antigens. In:  Kunicki T,  George JN editor. Platelet Immunobiology: Molecular and Clinical Aspects. Philadelphia, PA: Lippincott; 1989;p. 273–290
  48. Stockelberg D, Hou M, Jacobsson S, Kutti J, Wadenvik H. Evidence for a light chain restriction of glycoprotein Ib/IX and IIb/IIIa reactive antibodies in chronic idiopathic thrombocytopenic purpura. Br J Haematol. 1995;90:175–179
  49. McMillan R, Lopez-Dee J, Bowditch R. Clonal restriction of platelet-associated anti-GPIIb/IIIa autoantibodies in patients with chronic ITP. Thromb Haemost. 2001;85:821–823
  50. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood. 2002;100:1388–1398
  51. Askonas BA, Humphrey JH. Formation of specific antibodies and g-globulin in vitro: A study of the synthetic ability of various tissues from rabbits immunized by different methods. Biochem J. 1958;68:252–261
  52. McMillan R, Longmire RL, Yelenosky R, Donnell RL, Armstrong S. Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engl J Med. 1974;291:812–817
  53. Karpatkin S, Strick N, Siskind GW. Detection of splenic anti-platelet antibody synthesis in idiopathic autoimmune thrombocytopenic purpura (ATP). Br J Haematol. 1972;23:167–176
  54. McMillan R, Luiken GA, Levy R, Yelenosky R, Longmire RL. Antibody against megakaryocytes in idiopathic thrombocytopenic purpura. JAMA. 1978;239:2460–2462
  55. McMillan R, Yelenosky RJ, Longmire RL. Antiplatelet antibody production by the spleen and bone marrow in immune thrombocytopenic purpura. In:  Battisto JR,  Streinlein JW editor. Immunoaspects of the Spleen. Amsterdam, the Netherlands: North Holland Biomedical; 1976;p. 227–237
  56. Fujisawa K, McMillan R. Platelet-associated antibody to glycoprotein IIb/IIIa from chronic immune thrombocytopenic purpura patients often binds to divalent cation-dependent antigens. Blood. 1993;81:1284–1289
  57. Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Mizutani H, Kanakura Y, et al. Platelet-associated anti-glycoprotein (GP) IIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura mainly recognize cation-dependent conformations: Comparison with the epitopes of serum autoantibodies. Thromb Haemost as. 1996;75:339–345
  58. Bowditch RD, Tani P, McMillan R. Reactivity of autoantibodies from chronic ITP patients with recombinant glycoprotein IIIa peptides. Br J Haematol. 1995;91:178–184
  59. McMillan R, Lopez-Dee J, Loftus JC. Autoantibodies to αIIbβ3 in patients with chronic immune thrombocytopenic purpura bind primarily to epitopes on αIIb. Blood. 2001;97:2171–2172
  60. McMillan R, Wang L, Lopez-Dee J, Jiu S, Loftus JC. Many αIIbβ3 autoepitopes are localized to αIIb between amino acids L1 and Q459. Br J Haematol. 2002;118:1132–1136
  61. Kosugi S, Tomiyama Y, Honda S, Kato H, Kiyoi T, Kashiwagi H, et al. Platelet-associated anti-GPIIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura recognizing epitopes close to the ligand-binding site of GPIIb. Blood. 2001;98:1819–1827
  62. Harker LA. Thrombokinetics in idiopathic thrombocytopenic purpura. Br J Haematol. 1970;19:95–104
  63. Stoll D, Cines DB, Aster RH, Murphy S. Platelet kinetics in patients with idiopathic thrombocytopenic purpura and moderate thrombocytopenia. Blood. 1985;65:584–588
  64. Branehog I, Kutti J, Weinfeld A. Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP). Br J Haematol. 1974;27:127–143
  65. Heyns AP, Badenhorst PN, Lotter MG, Pieters H, Wessels P, Kotze HF. Platelet turnover and kinetics in immune thrombocytopenic purpura: Results with autologous 111-In-labeled and homologous 51-Cr-labeled platelets differ. Blood. 1986;67:86–92
  66. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter S. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura (Evidence for both impaired platelet production and increased platelet clearance). J Clin Invest. 1987;80:33–40
  67. Handin RI, Stossel TP. Phagocytosis of antibody-coated platelets by human granulocytes. N Engl J Med. 1974;290:989–993
  68. Zucker-Franklin D, Karpatkin S. Red-cell and platelet fragmentation in idiopathic autoimmune thrombocytopenic purpura. N Engl J Med. 1977;297:517–523
  69. McMillan R, Longmire RL, Tavassoli M, Armstrong S, Yelenosky R. In vitro platelet phagocytosis by ITP splenic leukocytes in idiopathic thrombocytopenic purpura. N Engl J Med. 1974;290:249–251
  70. Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC. Treatment of refractory immune thrombocytopenic purpura with anti-Fcg-receptor antibody. N Engl J Med. 1986;314:1236–1239
  71. McMillan R, Bowditch R, Tani P, Anderson H, Goodnight S. A non-thrombocytopenic bleeding disorder due to an IgG4-kappa anti-GPIIb/IIIa autoantibody. Br J Haematol. 1996;95:747–749
  72. Hauch TW, Rosse WF. Platelet-bound complement (C3) in immune thrombocytopenia. Blood. 1977;50:1129–1136
  73. Kurata Y, Curd JG, Tamerius JD, McMillan R. Platelet-associated complement in chronic ITP. Br J Haematol. 1985;60:723–733
  74. McMillan R, Martin M. Fixation of the third component of complement (C3) to platelets in vitro by antiplatelet antibody for patients with ITP. Br J Haematol. 1981;47:251–256
  75. Olsson B, Andersson P, Jernas M, Jacobsson S, Carlsson B, Carlsson LMS, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9:1123–1124
  76. Olsson B, Andersson PO, Jacobsson S, Carlsson L, Wadenvik H. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost. 2005;93:139–144
  77. Houwerzijl EJ, Blom NR, van der Want JJL, Esselink MT, Koomstra JJ, Smit JW, et al. Ultrastructural study shows morphological features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103:500–506
  78. Heyns AP, Lotter MG, Badenhorst PN, de Kock F, Pieters H, Herbst C, et al. Kinetics and sites of destruction of 111-Indium-oxine-labeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am J Hematol. 1982;12:167–177
  79. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult chronic ITP patients. Blood. 2004;103:1364–1369
  80. Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102:887–895

 STATEMENT OF CONFLICT OF INTEREST: Dr McMillan has nothing to disclose.

PII: S0037-1963(07)00159-X

doi: 10.1053/j.seminhematol.2007.11.002

Seminars in Hematology
Volume 44 , Pages S3-S11 , October 2007

Article Tools

* Image Usage & Resolution