Annals of Hematology

, Volume 95, Issue 11, pp 1765–1776 | Cite as

Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis

  • Elaheh Khodadi
  • Ali Amin Asnafi
  • Saeid Shahrabi
  • Mohammad Shahjahani
  • Najmaldin Saki
Review Article


Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased bleeding tendency and thrombocytopenia. In fact, the precise pathogenesis of this disease is still not clear. Megakaryopoiesis involves complete differentiation of megakaryocyte (MK) progenitors to functional platelets. This complex process occurs in specific bone marrow (BM) niches composed of several hematopoietic and non-hematopoietic cell types, soluble factors, and extracellular matrix proteins. These specialized microenvironments sustain MK maturation and localization to sinusoids as well as platelet release into circulation. However, MKs in ITP patients show impaired maturation and signs of degradation. Intrinsic defects in MKs and their extrinsic environment have been implicated in altered megakaryopoiesis in this disease. In particular, aberrant expression of miRNAs directing MK proliferation, differentiation, and platelet production; defective MK apoptosis; and reduced proliferation and differentiation rate of the MSC compartment observed in these patients may account for BM defects in ITP. Furthermore, insufficient production of thrombopoietin is another likely reason for ITP development. Therefore, identifying the signaling pathways and transcription factors influencing the interaction between MKs and BM niche in ITP patients will contribute to increased platelet production in order to prevent incomplete MK maturation and destruction as well as BM fibrosis and apoptosis in ITP. In this review, we will examine the interaction and role of BM niches in orchestrating megakaryopoiesis in ITP patients and discuss how these factors can be exploited to improve the quality of patient treatment and prognosis.


Bone marrow niche Immune thrombocytopenia Megakaryopoiesis 



This paper is issued from thesis of Elahe Khodadi, MSc student of hematology and blood banking. This work was financially supported by grant TH94/1 from vice chancellor for research affairs of Ahvaz Jundishapur University of Medical Sciences.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Authors’ contributions

N.S. conceived the manuscript and revised it; E.Kh., A.A, and M.Sh. wrote the manuscript. S.Sh. and E.Kh. prepared the figure and tables.


  1. 1.
    Ku FC, Tsai CR, Wang J et al (2013) Stromal‐derived factor‐1 gene variations in pediatric patients with primary immune thrombocytopenia. Eur J Haematol 90(1):25–30CrossRefPubMedGoogle Scholar
  2. 2.
    Rank A, Weigert O, Ostermann H et al (2010) Management of chronic immune thrombocytopenic purpura: targeting insufficient megakaryopoiesis as a novel therapeutic principle. Biol Targets Ther 4:139CrossRefGoogle Scholar
  3. 3.
    Olsson B, Andersson P-O, Jernås M et al (2003) T-cell mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 9(9):1123–4CrossRefPubMedGoogle Scholar
  4. 4.
    Badenhorst P, Lotter M, Pieters H et al (1986) Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 67(1):86–92PubMedGoogle Scholar
  5. 5.
    Malara A, Currao M, Gruppi C et al (2014) Megakaryocytes contribute to the bonemarrow-matrix environment by expressing fibronectin, type IVcollagen, and laminin. Stem Cells 32(4):926–937CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Blau O, Baldus CD, Hofmann WK et al (2011) Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 118:5583–92CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Zhang D, Li H, Ma L, Zhang X, Xue F, Zhou Z, Chi Y, Liu X, Huang Y, Yang Y, Yang R (2014) The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia. Autoimmunity 47(8):519–29Google Scholar
  8. 8.
    Shiozawa Y, Havens AM, Pienta KJ et al (2008) The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22:941–50CrossRefPubMedGoogle Scholar
  9. 9.
    Taichman RS, Emerson SG (1994) Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 179:1677–82CrossRefPubMedGoogle Scholar
  10. 10.
    Deutsch VR, Tomer A (2013) Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside. Br J Haematol 161(6):778–93Google Scholar
  11. 11.
    Avecilla ST, Hattori K, Heissig B et al (2004) Chemokine-mediated interaction of progenitors with the bone marrow vascular hematopoietic niche is required for thrombopoiesis. Nat Med 10:64–71CrossRefPubMedGoogle Scholar
  12. 12.
    Malara A, Abbonante V, Di Buduo CA, Tozzi L, Currao M, Balduini A (2015) The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control. Cell Mol Life Sci 72(8):1517–36Google Scholar
  13. 13.
    Wang L, Li Y, Houa M (2007) Idiopathic thrombocytopenic purpura and dysmegakaryocytopoiesis. Crit Rev Oncol Hematol 64:83–9CrossRefPubMedGoogle Scholar
  14. 14.
    Edelstein LC, Bray PF (2011) MicroRNAs in platelet production and activation. Blood 117(20):5289–96CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Baya A, Coskunb E, Oztuzcuc S et al (2014) Plasma microRNA profiling of pediatric patients with immune thrombocytopenic purpura. Blood Coagul Fibrinolysis 25:379–83CrossRefGoogle Scholar
  16. 16.
    Son B, Shin KS, Bae SY et al (2004) Bone marrow expression and plasma concentration of basic fibroblast growth factor in patients with idiopathic thrombocytopenic purpura. IJH 80:193–6Google Scholar
  17. 17.
    Deutsch VR, Tomer A (2006) Megakaryocyte development and platelet production. BJH 134:453–66CrossRefPubMedGoogle Scholar
  18. 18.
    Pasquet JM, Gross BS, Gratacap MP et al (2000) Thrombopoietin potentiates collagen receptor signaling in platelets through a phosphatidylinositol 3-kinase-dependent pathway. Blood 95:3429–34PubMedGoogle Scholar
  19. 19.
    Nutt SL, Metcalf D, D’Amico A et al (2005) Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med 201:221–31CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Arinobu Y, Mizuno S, Chong Y et al (2007) Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell 1:416–27CrossRefPubMedGoogle Scholar
  21. 21.
    Kobayashi M, Laver JH, Kato T et al (1996) Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3. Blood 88:429–36PubMedGoogle Scholar
  22. 22.
    Norol F, Vitrat N, Cramer E et al (1998) Effects of cytokines on platelet production from blood and marrow CD34+ cells. Blood 91:830–43PubMedGoogle Scholar
  23. 23.
    Hou M, Andersson PO, Stockelberg D et al (1998) Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes. Br J Haematol 101:420–4CrossRefPubMedGoogle Scholar
  24. 24.
    Craddock CG Jr, Adams WS, Perry S et al (1955) The dynamics of platelet production as studied by a depletion technique in normal and irradiated dogs. J Lab Clin Med 45:906–19PubMedGoogle Scholar
  25. 25.
    Pisciotta AV, Stefanini M, Dameshek W et al (1953) Studies on platelets. X. Morphologic characteristics of megakaryocytes by phase contrast microscopy in normals and in patients with idiopathic thrombocytopenic purpura. Blood 8:703–23PubMedGoogle Scholar
  26. 26.
    Houwerzijl EJ, Blom NR, van der Want JJL et al (2006) Megakaryocytic dysfunction in myelodys- plastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia 20:1937–42CrossRefPubMedGoogle Scholar
  27. 27.
    Houwerzijl EJ, Blom NR, van der Want JJL et al (2004) Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 103:500–6CrossRefPubMedGoogle Scholar
  28. 28.
    Gunten SV, Wehrli M, Simon HU et al (2013) Cell death in immune thrombocytopenia: novel insights and perspectives. Semin Hematol 50:109–15CrossRefGoogle Scholar
  29. 29.
    Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–7CrossRefPubMedGoogle Scholar
  30. 30.
    Broudy VC, Lin NL, Kaushansky K et al (1995) Thrombopoietin (cmpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 85(7):1719–26PubMedGoogle Scholar
  31. 31.
    Pallotta I, Lovett M, Rice W et al (2009) Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis. PLoS One 4(12):e8359CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Majumdar MK, Keane-Moore M, Buyaner D et al (2003) Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10(2):228–41CrossRefPubMedGoogle Scholar
  33. 33.
    Dimitriou HE, Linardakis G, Martimianaki et al (2008) Properties and potential of bone marrow mesenchymal stromal cells from children with hematologic diseases. Cytotherapy 10:125–133CrossRefPubMedGoogle Scholar
  34. 34.
    Sun LY, Zhang HY, Feng XB et al (2007) Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 16:121–8CrossRefPubMedGoogle Scholar
  35. 35.
    Stasi R (2012) Immune thrombocytopenia: pathophysiologic and clinical update. Semin Thromb Hemost 38:454–62CrossRefPubMedGoogle Scholar
  36. 36.
    Uccelli A, Moretta L, Pistoia V (2006) Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 36:2566–73CrossRefPubMedGoogle Scholar
  37. 37.
    Liu B, Zhao H, Poon MC et al (2007) Abnormality of CD4+CD25+ regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol 78:139–43PubMedGoogle Scholar
  38. 38.
    Perez-Simon JA, Tabera S, Sarasquete ME et al (2009) Mesenchymal stem cells are functionally abnormal in patients with immune thrombocytopenic purpura. Cytotherapy 11:698–705CrossRefPubMedGoogle Scholar
  39. 39.
    Carvalho JF, Blank M, Shoenfeld Y et al (2007) Vascular endothelial growth factor (VEGF) in autoimmune diseases. J Clin Immunol 27:246–56CrossRefPubMedGoogle Scholar
  40. 40.
    Skibinski G (2003) The role of hepatocyte growth factor/c-met interactions in the immune system. Arch Immunol Ther Exp 51:277–82Google Scholar
  41. 41.
    Roncarolo MG, Gregori S, Battaglia M et al (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50CrossRefPubMedGoogle Scholar
  42. 42.
    Kastrinaki MC, Pavlaki K, Batsali AK et al (2013) Mesenchymal stem cells in immune-mediated bone marrow failure syndromes. Clin Dev Immunol 10:1–10CrossRefGoogle Scholar
  43. 43.
    Kacena MA, Nelson T, Clough ME et al (2006) Megakaryocyte-mediated inhibition of osteoclast development. Bone 39(5):991–99CrossRefPubMedGoogle Scholar
  44. 44.
    Ciovacco WA, Goldberg CG, Tayloret AF et al (2009) The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation. Bone 44(1):80–86CrossRefPubMedGoogle Scholar
  45. 45.
    Lemieux JM, Horowitz MC, Kacena MA et al (2010) Involvement of integrins alpha(3)beta(1) and alpha(5)beta(1) and glycoprotein IIb in megakaryocyte-induced osteoblast proliferation. J Cell Biochem 109(5):927–32PubMedPubMedCentralGoogle Scholar
  46. 46.
    Azizdoost S, Fakher R, Saki N (2013) Bone marrow neoplastic niche in leukemia. ISH 10:1–8Google Scholar
  47. 47.
    Ciovacco WA, Cheng YH, Horowitz MC et al (2010) Immature and mature megakaryocytes enhance osteoblast proliferation and inhibit osteoclast formation. J Cell Biochem 109(4):774–81PubMedPubMedCentralGoogle Scholar
  48. 48.
    Hamada T, Mohle R, Hesselgesser J et al (1998) Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 188:539–548CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Pitchford SC, Lodie T, Rankin SM et al (2012) VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice. Blood 120:2787–95CrossRefPubMedGoogle Scholar
  50. 50.
    Dominici M, Rasini V, Bussolari R et al (2009) Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114:2333–43CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kostyak JC, Naik MU, Naik UP et al (2012) Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration. Blood 119:838–46CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mo¨hle R, Green D, Moore MA et al (1997) Constitutive production and thrombin-induced release of vascularendothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci U S A 94(2):663–68CrossRefGoogle Scholar
  53. 53.
    Kwon SM, Lee JH, Lee SH et al (2014) Cross talk with hematopoietic cells regulates the endothelial progenitor cell differentiation of cd34 positive cells. PLoS One 9(8):e106310CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kong Y, Hu Y, Wang YZ et al (2014) Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. BB & MT 20(8):1190–97Google Scholar
  55. 55.
    Mazharian A (2012) Assessment of megakaryocyte migration and chemotaxis. Methods Mol Biol 788:275–88CrossRefPubMedGoogle Scholar
  56. 56.
    Tew JG, Dilosa RM, Burton G et al (1992) Germinal centers and antibody production in bone marrow. Immunol Rev 126:99–112CrossRefPubMedGoogle Scholar
  57. 57.
    Belnoue E, Pihlgren M, McGaha T et al (2008) APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 11(5):2755–64CrossRefGoogle Scholar
  58. 58.
    Winter O, Moser K, Mohr E et al (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116(11):1867–75CrossRefPubMedGoogle Scholar
  59. 59.
    Psaila B, Lyden D, Roberts I et al (2012) Megakaryocytes, malignancy and bone marrow vascular niches. Thromb Haemost 10(2):177–188CrossRefGoogle Scholar
  60. 60.
    Kimura R, Nishioka T, Soemantri A et al (2005) Allele-specific transcript quantification detects haplotypic variation in the levels of the SDF-1 transcripts. Hum Mol Genet 14:1579–85CrossRefPubMedGoogle Scholar
  61. 61.
    Lima G, Soto-Vega E, Atisha-Fregoso Y et al (2007) MCP-1, RANTES, and SDF-1 polymorphisms in Mexican patients with systemic lupus erythematosus. Hum Immunol 68:980–5CrossRefPubMedGoogle Scholar
  62. 62.
    McMillan R (2007) The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 44:3–11CrossRefGoogle Scholar
  63. 63.
    Cheng G, Saleh MN, Marcher C et al (2011) Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomized, phase 3 study. Lancet 377:393–402CrossRefPubMedGoogle Scholar
  64. 64.
    Sheng GY, Huang XL, Bai ST et al (2004) Expression levels of CXCR4 on megakaryocytes and its ligand in bone marrow in children with acute idiopathic thrombocytopenic purpura. ZhonghuaErKeZaZhi 42:499–501Google Scholar
  65. 65.
    Apostolidis PA, Woulfe DS, Chavez M et al (2012) Role of tumor suppressor P53 in megakaryopoiesis and platelet function. Exp Hematol 40(2):131–42CrossRefPubMedGoogle Scholar
  66. 66.
    Smith MJ, Koch GL (1989) Multiple zones in the sequence of calreticulin (CRP55, calregulin, HACBP), a major calcium binding ER/SR protein. EMBO J 8(12):3581–86PubMedPubMedCentralGoogle Scholar
  67. 67.
    Anindo MIK, Yaqinuddin A (2012) Insights into the potential use of microRNAs as biomarker in cancer. Int J Surg 10:443–49CrossRefPubMedGoogle Scholar
  68. 68.
    Li H, Zhao H, Wang D et al (2011) MicroRNA regulation in megakaryocytopoiesis. BJH 155:298–07CrossRefPubMedGoogle Scholar
  69. 69.
    Ishibashi T, Kimura H, Uchida T et al (1989) Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci U S A 86(15):5953–57CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Garzon R, Pichiorri F, Palumbo T et al (2006) MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci U S A 103(13):5078–83CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Li J, Wan Y, Guo Q et al (2010) Altered microRNA expression profile with miR-146a upregulation in CD4þ T cells from patients with rheumatoid arthritis. Arthritis Res Ther 12:81–8CrossRefGoogle Scholar
  72. 72.
    Paul AB, James B, Zeeshan H et al (2013) The beta 1 tubulin R307H single nucleotide polymorphism is associated with treatment failures in immune thrombocytopenia (ITP). Br J Haematol 160:237–243CrossRefGoogle Scholar
  73. 73.
    Maia MH, PeixotoRde L, de Lima CP et al (2009) Predisposition to idiopathic thrombocytopenic purpura maps close to the major histocompatibility complex class I chain-related gene A. Hum Immunol 70:179–83CrossRefPubMedGoogle Scholar
  74. 74.
    Saıtoh T, Kasamatsu T, Inoue M et al (2011) Interleukin-10 gene polymorphism reflects the severity of chronic immune thrombocytopenia in Japanese patients. Int J Lab Hematol 33:526–32PubMedGoogle Scholar
  75. 75.
    Tesse R, Del Vecchio GC, De Mattia D et al (2012) Association of interleukin-(IL-10) haplotypes and serum IL-10 levels in the progression of childhood immune thrombocytopenic purpura. Gene 505:53–56CrossRefPubMedGoogle Scholar
  76. 76.
    Abuzenadah AM, Zaher GF, Dallol A et al (2013) Identification of a novel SBF2 missense mutationassociated with a rare case of thrombocytopenia using whole-exome sequencing. J Thromb Thrombolysis 36:501–06CrossRefPubMedGoogle Scholar
  77. 77.
    Li H, Zhao H, Xue F et al (2013) Reduced expression of mIR409-3p in primary immune thrombocytopenia. Br J Haematol 161:128–135CrossRefPubMedGoogle Scholar
  78. 78.
    Martyre MC, Le Bousse-Kerdiles MC, Romquin N et al (1997) Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis. Br J Haematol 97:441–48CrossRefPubMedGoogle Scholar
  79. 79.
    Avraham H, Banu N, Scadden DT et al (1994) Modulation of megakaryocytopoiesis by human basic fibroblastgrowth factor. Blood 83:2126–2132PubMedGoogle Scholar
  80. 80.
    Allouche M (1995) Basic fibroblast growth factor and hematopoiesis. Leukemia 9:937–942PubMedGoogle Scholar
  81. 81.
    Yoon SY, Tefferi A, Li CY et al (2001) Bone marrow stromal cell distribution of basic fibroblast growth factor in chronic myeloid disorders. Haematologica 86:52–57PubMedGoogle Scholar
  82. 82.
    Basciano PA, Bussel JB (2012) Thrombopoietin-receptor agonists. Curr Opin Hematol 19:392–398CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Elaheh Khodadi
    • 1
  • Ali Amin Asnafi
    • 1
  • Saeid Shahrabi
    • 2
  • Mohammad Shahjahani
    • 1
  • Najmaldin Saki
    • 1
  1. 1.Health Research Institute, Thalassemia and Hemoglobinopathy Research CenterAhvaz Jundishapur University of Medical SciencesAhvazIran
  2. 2.Department of Biochemistry and Hematology, Faculty of MedicineSemnan University of Medical SciencesSemnanIran

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