American Society of Hematology

Case Study: ITP is Also a Platelet Production Problem

The following case study focuses on a 60-year-old female who noticed the sudden appearance of multiple petechiae on her extremities and mild epistaxis. Test your knowledge by reading the background information below and making the proper selection.

A 60-year-old Caucasian female with no comorbidities noticed the sudden appearance of multiple petechiae on her extremities and mild epistaxis. She had no other symptoms and denied taking any medications. A CBC performed by her primary-care physician identified an isolated thrombocytopenia with a platelet count of 30 x 109/L. She was referred to a hematologist who did an extensive work-up revealing no other significant abnormalities. A bone marrow biopsy was unremarkable, apart from numerous megakaryocytes. She was given a diagnosis of immune thrombocytopenic purpura (ITP). 

What cytokine is important in the pathogenesis of thrombocytopenia in ITP? 

  1. Erythropoietin
  2. Granulocyte colony-stimulating factor
  3. Thrombopoietin
  4. IL-12
  5. IL-1
  6. IFN-γ


  1. Thrombopoietin 


ITP is characterized by isolated thrombocytopenia of <100 x 109/L that is not explained by any other cause.1 For many years, it was believed that the main mechanism involved in the pathogenesis of this disorder was immune (mainly antibody)-mediated destruction and clearance of platelets and megakaryocytes. Hence, treatment was based mainly on immunosuppression with steroids, rituximab, and IVIg. However, it is important to recognize that ITP is not just an immune-mediated process but is influenced by cytokines. Cytokines such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) are important regulators of RBC and WBC production, respectively. Similarly, thrombopoiesis is regulated by a cytokine named thrombopoietin (TPO), which was cloned in the 1990s.2 TPO is a ligand for the c-mpl receptor, a product of the cellular proto-oncogene c-MPL.3 It is an acidic glycoprotein produced mainly in the liver with minor production occurring in the kidney, bone marrow, and spleen. TPO is necessary for the expansion of the megakaryocytic precursor pool, differentiation, and, ultimately, maturation, culminating in platelet production.4 TPO levels may vary depending on disease states. In ITP, TPO levels are found to be inappropriately normal or low for the degree of thrombocytopenia,5-6 thus forming the basis for use of TPO agonists in this disorder. Unfortunately, the clinical use of earlier TPO agonists was severely hampered by the formation of neutralizing antibodies that cross-reacted with endogenous TPO leading to worsening thrombocytopenia.7-8 Recent breakthroughs in drug development have led to the introduction of novel TPO agonists that lack this complication. The first of these novel agents was AMG-531, also known as romiplostim, which is given subcutaneously. This was followed later by an orally bioavailable agent, eltrombopag. Both agents have been tested in phase 3 randomized controlled studies and lead to durable improvements in platelet counts in both splenectomized and non-splenectomized ITP patients.9-10 Both romiplostim and eltrombopag received FDA approval in 2008 for use in chronic ITP patients who have had insufficient responses to corticosteroids, IVIG, or splenectomy. 


  1. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113:2386-2393.
  2. Kaushansky K, Broudy VC, Lin N, et al. Thrombopoietin, the Mp1 ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci USA. 1995;92:3234-3238.
  3. Cohen-Solal K, Villeval JL, Titeux M, et al. Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood. 1996;88:2578-2584.
  4. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607-4616.
  5. Branehog I, Kutti J, Weinfeld A. Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP). Br J Haematol. 1974;27:127-143.
  6. Ballem PJ, Segal GM, Stratton JR, et al. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80:33-40.
  7. Basser RL, O’Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599-2602.
  8. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-3248.
  9. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355:1672-1681.
  10. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395-403.

Case study submitted by Ramon V. Tiu, MD, Cleveland Clinic Taussig Cancer Institute.

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