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?
- Granulocyte colony-stimulating factor
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.
- 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.
- 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.
- Cohen-Solal K, Villeval JL, Titeux M, et al. Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood. 1996;88:2578-2584.
- Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607-4616.
- Branehog I, Kutti J, Weinfeld A. Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP). Br J Haematol. 1974;27:127-143.
- 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.
- 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.
- Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-3248.
- 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.
- 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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