Piecing Together the Humoral and Cellular Mechanisms of Immune Thrombocytopenia

 

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Abstract

The precise mechanisms leading to platelet-targeted autoimmunity in immune thrombocytopenia (ITP) are not known. Cellular checkpoints normally regulate immunological self-reactivity during the development of B and T cells through cell deletion, receptor editing, induction of anergy, and extrinsic cellular suppression. When these checkpoints fail, tolerance to self-antigens may be lost. In this review, we summarize the various immune mechanisms contributing to the development of ITP and relate them back to the checkpoint model of autoimmunity. These mechanisms, including increased levels of lymphocyte growth factors, resistance to death signals, and loss of T-regulatory function, result in an environment permissive to the development of platelet-reactive B and T cells. The mechanisms that lead to thrombocytopenia once tolerance for platelet antigens is lost are examined, including complement-dependent and apoptotic pathways. An improved understanding of ITP pathogenesis will ultimately guide the development of better therapies.

REFERENCES

• 1 Warner M N, Moore J C, Warkentin T E, Santos A V, Kelton J G. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura.  Br J Haematol. 1999;  104 (3) 442-447
  Google Scholar
• 2 McMillan R. Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes.  J Pediatr Hematol Oncol. 2003;  25 (Suppl 1) S57-S61
  Google Scholar
• 3 Cines D B, Bussel J B, Liebman H A, Luning Prak E T. The ITP syndrome: pathogenic and clinical diversity.  Blood. 2009;  113 (26) 6511-6521
  Google Scholar
• 4 Goodnow C C, Sprent J, Fazekas de St Groth B, Vinuesa C G. Cellular and genetic mechanisms of self tolerance and autoimmunity.  Nature. 2005;  435 (7042) 590-597
  Google Scholar
• 5 Hartley S B, Cooke M P, Fulcher D A et al.. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death.  Cell. 1993;  72 (3) 325-335
  Google Scholar
• 6 Hsu B L, Harless S M, Lindsley R C, Hilbert D M, Cancro M P. Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators.  J Immunol. 2002;  168 (12) 5993-5996
  Google Scholar
• 7 Thien M, Phan T G, Gardam S et al.. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches.  Immunity. 2004;  20 (6) 785-798
  Google Scholar
• 8 Cheema G S, Roschke V, Hilbert D M, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases.  Arthritis Rheum. 2001;  44 (6) 1313-1319
  Google Scholar
• 9 Zhang J, Roschke V, Baker K P et al.. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus.  J Immunol. 2001;  166 (1) 6-10
  Google Scholar
• 10 Groom J, Kalled S L, Cutler A H et al.. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.  J Clin Invest. 2002;  109 (1) 59-68
  Google Scholar
• 11 Emmerich F, Bal G, Barakat A et al.. High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura.  Br J Haematol. 2007;  136 (2) 309-314
  Google Scholar
• 12 Zhu X J, Shi Y, Sun J Z et al.. High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia.  J Clin Immunol. 2009;  29 (5) 603-610
  Google Scholar
• 13 Zhu X J, Shi Y, Peng J et al.. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia.  Blood. 2009;  114 (26) 5362-5367
  Google Scholar
• 14 Zhou Z, Chen Z, Li H et al.. BAFF and BAFF-R of peripheral blood and spleen mononuclear cells in idiopathic thrombocytopenic purpura.  Autoimmunity. 2009;  42 (2) 112-119
  Google Scholar
• 15 Gu D, Ge J, Du W et al.. Raised expression of APRIL in Chinese patients with immune thrombocytopenia and its clinical implications.  Autoimmunity. 2009;  42 (8) 692-698
  Google Scholar
• 16 Palmer E. Negative selection—clearing out the bad apples from the T-cell repertoire.  Nat Rev Immunol. 2003;  3 (5) 383-391
  Google Scholar
• 17 Sakaguchi N, Takahashi T, Hata H et al.. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.  Nature. 2003;  426 (6965) 454-460
  Google Scholar
• 18 Gong Q, Cheng A M, Akk A M et al.. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency.  Nat Immunol. 2001;  2 (1) 29-36
  Google Scholar
• 19 McCarty N, Paust S, Ikizawa K, Dan I, Li X, Cantor H. Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes.  Nat Immunol. 2005;  6 (1) 65-72
  Google Scholar
• 20 Olsson B, Andersson P O, Jacobsson S, Carlsson L, Wadenvik H. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura.  Thromb Haemost. 2005;  93 (1) 139-144
  Google Scholar
• 21 Olsson B, Andersson P O, Jernås M et al.. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.  Nat Med. 2003;  9 (9) 1123-1124
  Google Scholar
• 22 Salgame P, Abrams J S, Clayberger C et al.. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones.  Science. 1991;  254 (5029) 279-282
  Google Scholar
• 23 Romagnani S. Th1 and Th2 in human diseases.  Clin Immunol Immunopathol. 1996;  80 (3 Pt 1) 225-235
  Google Scholar
• 24 Mosmann T R, Coffman R L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.  Annu Rev Immunol. 1989;  7 145-173
  Google Scholar
• 25 Mosmann T R, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more.  Immunol Today. 1996;  17 (3) 138-146
  Google Scholar
• 26 Liblau R S, Singer S M, McDevitt H O. Th1 and Th2 CD4 + T cells in the pathogenesis of organ-specific autoimmune diseases.  Immunol Today. 1995;  16 (1) 34-38
  Google Scholar
• 27 Druet P, Sheela R, Pelletier L. Th1 and Th2 cells in autoimmunity.  Clin Exp Immunol. 1995;  101 (Suppl 1) 9-12
  Google Scholar
• 28 Semple J W, Milev Y, Cosgrave D 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 (10) 4245-4254
  Google Scholar
• 29 Panitsas F P, Theodoropoulou M, Kouraklis A et al.. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response.  Blood. 2004;  103 (7) 2645-2647
  Google Scholar
• 30 Ogawara H, Handa H, Morita K et al.. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura.  Eur J Haematol. 2003;  71 (4) 283-288
  Google Scholar
• 31 Gu D, Chen Z, Zhao H et al.. Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia.  Hum Immunol. 2010;  71 (6) 586-591
  Google Scholar
• 32 Zhang J, Ma D, Zhu X, Qu X, Ji C, Hou M. Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura.  Haematologica. 2009;  94 (9) 1326-1329
  Google Scholar
• 33 Zhu X, Ma D, Zhang J et al.. Elevated interleukin-21 correlated to Th17 and Th1 cells in patients with immune thrombocytopenia.  J Clin Immunol. 2010;  30 (2) 253-259
  Google Scholar
• 34 Huetz F, Carlsson L, Tornberg U C, Holmberg D. V-region directed selection in differentiating B lymphocytes.  EMBO J. 1993;  12 (5) 1819-1826
  Google Scholar
• 35 Yancopoulos G D, Alt F W. Regulation of the assembly and expression of variable-region genes.  Annu Rev Immunol. 1986;  4 339-368
  Google Scholar
• 36 Tonegawa S. Somatic generation of antibody diversity.  Nature. 1983;  302 (5909) 575-581
  Google Scholar
• 37 Fischer P, Jendreyko N, Hoffmann M et al.. Platelet-reactive IgG antibodies cloned by phage display and panning with IVIG from three patients with autoimmune thrombocytopenia.  Br J Haematol. 1999;  105 (3) 626-640
  Google Scholar
• 38 Roark J H, Bussel J B, Cines D B, Siegel D L. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation.  Blood. 2002;  100 (4) 1388-1398
  Google Scholar
• 39 van Dijk-Härd I, Feld S, Holmberg D, Lundkvist I. Increased utilization of the VH6 gene family in patients with autoimmune idiopathic thrombocytopenic purpura.  J Autoimmun. 1999;  12 (1) 57-63
  Google Scholar
• 40 Söderström I, van Dijk-Härd I, Feld S, Hillörn V, Holmberg D, Lundkvist I. Altered VH6-D-JH repertoire in human insulin-dependent diabetes mellitus and autoimmune idiopathic thrombocytopenic purpura.  Eur J Immunol. 1999;  29 (9) 2853-2862
  Google Scholar
• 41 Kato T, Kurokawa M, Sasakawa H et al.. Analysis of accumulated T cell clonotypes in patients with systemic lupus erythematosus.  Arthritis Rheum. 2000;  43 (12) 2712-2721
  Google Scholar
• 42 Matsumoto Y, Yoon W K, Jee Y et al.. Complementarity-determining region 3 spectratyping analysis of the TCR repertoire in multiple sclerosis.  J Immunol. 2003;  170 (9) 4846-4853
  Google Scholar
• 43 Sun W, Nie H, Li N et al.. Skewed T-cell receptor BV14 and BV16 expression and shared CDR3 sequence and common sequence motifs in synovial T cells of rheumatoid arthritis.  Genes Immun. 2005;  6 (3) 248-261
  Google Scholar
• 44 Hedlund-Treutiger I, Elinder G, Wigzell H, Grunewald J, Wahlström J. T cell receptor V gene usage by CD4⁺ and CD8⁺ peripheral blood T lymphocytes in immune thrombocytopenic purpura.  Acta Paediatr. 2004;  93 (5) 633-637
  Google Scholar
• 45 Shimomura T, Fujimura K, Takafuta T et al.. Oligoclonal accumulation of T cells in peripheral blood from patients with idiopathic thrombocytopenic purpura.  Br J Haematol. 1996;  95 (4) 732-737
  Google Scholar
• 46 Zhang X L, Li Y Q, Chen S H et al.. The feature of clonal expansion of TCR Vbeta repertoire, thymic recent output function and TCRzeta chain expression in patients with immune thrombocytopenic purpura.  Int J Lab Hematol. 2009;  31 (6) 639-648
  Google Scholar
• 47 Stasi R, Del Poeta G, Stipa E et al.. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura.  Blood. 2007;  110 (8) 2924-2930
  Google Scholar
• 48 Rui L, Vinuesa C G, Blasioli J, Goodnow C C. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling.  Nat Immunol. 2003;  4 (6) 594-600
  Google Scholar
• 49 Carreno B M, Bennett F, Chau T A et al.. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression.  J Immunol. 2000;  165 (3) 1352-1356
  Google Scholar
• 50 Peng J, Liu C, Liu D et al.. Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura.  Blood. 2003;  101 (7) 2721-2726
  Google Scholar
• 51 Zhang X L, Peng J, Sun J Z et al.. Modulation of immune response with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura.  J Thromb Haemost. 2008;  6 (1) 158-165
  Google Scholar
• 52 von Boehmer H. Mechanisms of suppression by suppressor T cells.  Nat Immunol. 2005;  6 (4) 338-344
  Google Scholar
• 53 Mellanby R J, Thomas D C, Lamb J. Role of regulatory T-cells in autoimmunity.  Clin Sci (Lond). 2009;  116 (8) 639-649
  Google Scholar
• 54 Sakakura M, Wada H, Tawara I et al.. Reduced Cd4⁺ Cd25⁺ T cells in patients with idiopathic thrombocytopenic purpura.  Thromb Res. 2007;  120 (2) 187-193
  Google Scholar
• 55 Yu J, Heck S, Patel V et al.. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura.  Blood. 2008;  112 (4) 1325-1328
  Google Scholar
• 56 Ling Y, Cao X, Yu Z, Ruan C. Circulating dendritic cells subsets and CD4 + Foxp3 + regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome.  Eur J Haematol. 2007;  79 (4) 310-316
  Google Scholar
• 57 Stasi R, Cooper N, Del Poeta G et al.. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab.  Blood. 2008;  112 (4) 1147-1150
  Google Scholar
• 58 Li Z, Mou W, Lu G et al.. Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia.  Int J Hematol. 2011;  93 (1) 91-98
  Google Scholar
• 59 Bao W, Bussel J B, Heck S et al.. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents.  Blood. 2010;  116 (22) 4639-4645
  Google Scholar
• 60 Semple J W, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia.  Blood. 1991;  78 (10) 2619-2625
  Google Scholar
• 61 Kuwana M, Kaburaki J, Kitasato H et al.. Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura.  Blood. 2001;  98 (1) 130-139
  Google Scholar
• 62 Sukati H, Watson H G, Urbaniak S J, Barker R N. Mapping helper T-cell epitopes on platelet membrane glycoprotein IIIa in chronic autoimmune thrombocytopenic purpura.  Blood. 2007;  109 (10) 4528-4538
  Google Scholar
• 63 Aster R H. Molecular mimicry and immune thrombocytopenia.  Blood. 2009;  113 (17) 3887-3888
  Google Scholar
• 64 Stasi R, Sarpatwari A, Segal J B et al.. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review.  Blood. 2009;  113 (6) 1231-1240
  Google Scholar
• 65 Arnold D M, Bernotas A, Nazi I et al.. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: a systematic review.  Haematologica. 2009;  94 (6) 850-856
  Google Scholar
• 66 Takahashi T, Yujiri T, Shinohara K et al.. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura.  Br J Haematol. 2004;  124 (1) 91-96
  Google Scholar
• 67 Maeda S, Ogura K, Yoshida H et al.. Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan.  Gut. 1998;  42 (3) 338-343
  Google Scholar
• 68 Nardi M A, Liu L X, Karpatkin S. GPIIIa-(49-66) is a major pathophysiologically relevant antigenic determinant for anti-platelet GPIIIa of HIV-1-related immunologic thrombocytopenia.  Proc Natl Acad Sci U S A. 1997;  94 (14) 7589-7594
  Google Scholar
• 69 Li Z, Nardi M A, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia.  Blood. 2005;  106 (2) 572-576
  Google Scholar
• 70 Karpatkin S, Nardi M. Autoimmune anti-HIV-1gp120 antibody with antiidiotype-like activity in sera and immune complexes of HIV-1-related immunologic thrombocytopenia.  J Clin Invest. 1992;  89 (2) 356-364
  Google Scholar
• 71 Nardi M, Tomlinson S, Greco M A, Karpatkin S. Complement-independent, peroxide-induced antibody lysis of platelets in HIV-1-related immune thrombocytopenia.  Cell. 2001;  106 (5) 551-561
  Google Scholar
• 72 Sakaguchi M, Sato T, Groopman J E. Human immunodeficiency virus infection of megakaryocytic cells.  Blood. 1991;  77 (3) 481-485
  Google Scholar
• 73 Sundell I B, Koka P S. Thrombocytopenia in HIV infection: impairment of platelet formation and loss correlates with increased c-Mpl and ligand thrombopoietin expression.  Curr HIV Res. 2006;  4 (1) 107-116
  Google Scholar
• 74 Zhang W, Nardi M A, Borkowsky W, Li Z, Karpatkin S. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia.  Blood. 2009;  113 (17) 4086-4093
  Google Scholar
• 75 Ballem P J, Segal G M, Stratton J R, Gernsheimer T, Adamson J W, Slichter S J. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance.  J Clin Invest. 1987;  80 (1) 33-40
  Google Scholar
• 76 Kuter D J, Rummel M, Boccia R et al.. Romiplostim or standard of care in patients with immune thrombocytopenia.  N Engl J Med. 2010;  363 (20) 1889-1899
  Google Scholar
• 77 Cheng G, Saleh M N, Marcher C et al.. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.  Lancet. 2011;  377 (9763) 393-402
  Google Scholar
• 78 Dighiero G, Lymberi P, Guilbert B, Ternynck T, Avrameas S. Natural autoantibodies constitute a substantial part of normal circulating immunoglobulins.  Ann N Y Acad Sci. 1986;  475 135-145
  Google Scholar
• 79 Filion M C, Proulx C, Bradley A J et al.. Presence in peripheral blood of healthy individuals of autoreactive T cells to a membrane antigen present on bone marrow-derived cells.  Blood. 1996;  88 (6) 2144-2150
  Google Scholar
• 80 Shlomchik M J, Marshak-Rothstein A, Wolfowicz C B, Rothstein T L, Weigert M G. The role of clonal selection and somatic mutation in autoimmunity.  Nature. 1987;  328 (6133) 805-811
  Google Scholar
• 81 Tsubakio T, Tani P, Woods Jr V L, McMillan R. Autoantibodies against platelet GPIIb/IIIa in chronic ITP react with different epitopes.  Br J Haematol. 1987;  67 (3) 345-348
  Google Scholar
• 82 Harrington W J, Minnich V, Hollingsworth J W, Moore C V. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura.  J Lab Clin Med. 1951;  38 (1) 1-10
  Google Scholar
• 83 Luk S C, Musclow E, Simon G T. Platelet phagocytosis in the spleen of patients with idiopathic thrombocytopenic purpura (ITP).  Histopathology. 1980;  4 (2) 127-136
  Google Scholar
• 84 Panzer S, Szamait S, Bödeker R H, Haas O A, Haubenstock A, Mueller-Eckhardt C. Platelet-associated immunoglobulins IgG, IgM, IgA and complement C3 in immune and nonimmune thrombocytopenic disorders.  Am J Hematol. 1986;  23 (2) 89-99
  Google Scholar
• 85 Piguet P F, Vesin C. Modulation of platelet caspases and life-span by anti-platelet antibodies in mice.  Eur J Haematol. 2002;  68 (5) 253-261
  Google Scholar
• 86 Leytin V, Mykhaylov S, Starkey A F et al.. Intravenous immunoglobulin inhibits anti-glycoprotein IIb-induced platelet apoptosis in a murine model of immune thrombocytopenia.  Br J Haematol. 2006;  133 (1) 78-82
  Google Scholar
• 87 Usuki Y, Kohsaki M, Nagai K, Ohe Y, Hara H. Complement-dependent cytotoxic factor to megakaryocyte progenitors in sera from patients with idiopathic thrombocytopenic purpura.  Int J Cell Cloning. 1986;  4 (6) 447-463
  Google Scholar
• 88 Takahashi R, Sekine N, Nakatake T. Influence of monoclonal antiplatelet glycoprotein antibodies on in vitro human megakaryocyte colony formation and proplatelet formation.  Blood. 1999;  93 (6) 1951-1958
  Google Scholar
• 89 Alimardani G, Guichard J, Fichelson S, Cramer E M. Pathogenic effects of anti-glycoprotein Ib antibodies on megakaryocytes and platelets.  Thromb Haemost. 2002;  88 (6) 1039-1046
  Google Scholar
• 90 Karpatkin S. Autoimmune thrombocytopenic purpura.  Blood. 1980;  56 (3) 329-343
  Google Scholar
• 91 Kelton J G, Gibbons S. Autoimmune platelet destruction: idiopathic thrombocytopenic purpura.  Semin Thromb Hemost. 1982;  8 (2) 83-104
  Google Scholar
• 92 Isaka Y, Kambayashi J, Kimura K et al.. Platelet production, clearance and distribution in patients with idiopathic thrombocytopenic purpura.  Thromb Res. 1990;  60 (2) 121-131
  Google Scholar
• 93 Cooper N. Intravenous immunoglobulin and anti-RhD therapy in the management of immune thrombocytopenia.  Hematol Oncol Clin North Am. 2009;  23 (6) 1317-1327
  Google Scholar
• 94 Kelton J G, Singer J, Rodger C, Gauldie J, Horsewood P, Dent P. The concentration of IgG in the serum is a major determinant of Fc-dependent reticuloendothelial function.  Blood. 1985;  66 (3) 490-495
  Google Scholar
• 95 Kojouri K, Vesely S K, Terrell D R, George J N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications.  Blood. 2004;  104 (9) 2623-2634
  Google Scholar
• 96 Sarpatwari A, Provan D, Erqou S, Sobnack R, David Tai F W, Newland A C. Autologous 111 In-labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry.  Br J Haematol. 2010;  151 (5) 477-487
  Google Scholar
• 97 Peerschke E I, Andemariam B, Yin W, Bussel J B. Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura.  Br J Haematol. 2010;  148 (4) 638-645
  Google Scholar
• 98 Jin Z, El-Deiry W S. Overview of cell death signaling pathways.  Cancer Biol Ther. 2005;  4 (2) 139-163
  Google Scholar
• 99 Falcieri E, Bassini A, Pierpaoli S et al.. Ultrastructural characterization of maturation, platelet release, and senescence of human cultured megakaryocytes.  Anat Rec. 2000;  258 (1) 90-99
  Google Scholar
• 100 Kaluzhny Y, Yu G, Sun S et al.. BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation.  Blood. 2002;  100 (5) 1670-1678
  Google Scholar
• 101 Bouillet P, Metcalf D, Huang D C et al.. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.  Science. 1999;  286 (5445) 1735-1738
  Google Scholar
• 102 De Botton S, Sabri S, Daugas E et al.. Platelet formation is the consequence of caspase activation within megakaryocytes.  Blood. 2002;  100 (4) 1310-1317
  Google Scholar
• 103 Morison I M, Cramer Bordé E M, Cheesman E J et al.. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia.  Nat Genet. 2008;  40 (4) 387-389
  Google Scholar
• 104 Chang M, Nakagawa P A, Williams S A et al.. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro.  Blood. 2003;  102 (3) 887-895
  Google Scholar
• 105 McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP.  Blood. 2004;  103 (4) 1364-1369
  Google Scholar
• 106 Houwerzijl E J, Blom N R, van der Want J J et al.. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura.  Blood. 2004;  103 (2) 500-506
  Google Scholar
• 107 Kaushansky K. Thrombopoietin.  N Engl J Med. 1998;  339 (11) 746-754
  Google Scholar
• 108 Borge O J, Ramsfjell V, Veiby O P, Murphy Jr M J, Lok S, Jacobsen S E. Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro.  Blood. 1996;  88 (8) 2859-2870
  Google Scholar
• 109 Houwerzijl E J, Blom N R, van der Want J J, Vellenga E, de Wolf J T. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death.  Leukemia. 2006;  20 (11) 1937-1942
  Google Scholar
• 110 Yang L, Wang L, Zhao C H et al.. Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia.  Blood. 2010;  116 (20) 4307-4316
  Google Scholar
• 111 Zhang F, Chu X, Wang L et al.. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura.  Eur J Haematol. 2006;  76 (5) 427-431
  Google Scholar
• 112 Chow L, Aslam R, Speck E R et al.. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8 + T cell-mediated responses that are differentially sensitive to therapy.  Blood. 2010;  115 (6) 1247-1253
  Google Scholar
• 113 Li S, Wang L, Zhao C, Li L, Peng J, Hou M. CD8⁺ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura.  Br J Haematol. 2007;  139 (4) 605-611
  Google Scholar

Donald M ArnoldM.D.C.M. M.Sc. 

Department of Medicine, McMaster University, 1280 Main Street West

HSC 3V50, Hamilton, ON L8S 4K1 Canada

Email: arnold@mcmaster.ca