Thrombopoietin

Key Terms: Investigational drug.

Definition

Thrombopoietin is an investigational or experimental drug that may increase the number of platelets in the bloodstream.

Purpose

Thrombopoietin is an experimental drug that may be used to treat thrombocytopenia (a reduced number of platelets in the blood).

Description

Thrombocytopenia, or a low number of platelets in the blood, can be a life-threatening condition. Platelets are necessary for the normal process of blood clotting. When someone experiences thrombocytopenia, a cut or bruise might not heal quickly, or at all, without medical intervention. Therefore, patients with a low platelet cell count must take special precautions, and suffer significant risk.

Thrombocytopenia is a common side effect from many common chemotherapy agents. These agents temporarily decrease the production of platelets, as well as white blood cells that fight infection and red blood cells that carry oxygen. Carboplatin is an example of an agent that has a tendency to lower platelet counts. Like other cells of the blood (white blood cells and red blood cells), the number of platelets will generally increase and return to normal over days and weeks following the administration of chemotherapy.

By reducing the severity of platelet-related side effects, thrombopoietin could allow the antitumor medication to be used at higher doses and/or for longer periods of time. Thrombopoietin may also be used in other situations in which patients have low platelet cell counts.

Thrombopoietin is derived from the gene of the same name. A laboratory-synthesized version of the human gene product encourages the development of platelet cells from precursor cells in the blood.

Thrombopoietin is an investigational, or an experimental, drug in the U.S.. This means that the FDA has not approved this drug for general use as of mid-2001. Generally, investigational drugs are made available through participation in clinical trials.

Recommended Dosage, Precautions, Side Effects, and Interactions

As noted above, investigational drugs generally are prescribed as part of a clinical trial. Clinical trials seek to determine how effective a drug is at treating the targeted condition, the effective dose of the drug, any precautions patients should take before the drug is administered, any side effects the drug may have, and any interactions the investigational drug may have with other drugs. Since thrombopoietin is investigational, it is premature to discuss dosage, precautions, side effects, and interactions.

—Michael Zuck, Ph.D.

An α₂-globulin, a hormone involved in the differentiation and maturation of platelets but thought to be responsible for regulating the supply of platelets.

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Thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor)
PDB rendering based on 1v7m.
Available structures: 1v7m, 1v7n
Identifiers
Symbols	THPO; MGC163194; MGDF; MKCSF; ML; MPLLG; TPO
External IDs	OMIM: 600044 MGI: 101875 HomoloGene: 398
Gene ontology Molecular function: • cytokine activity • hormone activity • growth factor activity Cellular component: • extracellular region • extracellular space Biological process: • multicellular organismal development • cell proliferation • myeloid cell differentiation
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	7066	21832
Ensembl	ENSG00000090534	ENSMUSG00000022847
Uniprot	P40225	Q543R9
Refseq	NM_199228 (mRNA) NP_954698 (protein)	NM_009379 (mRNA) NP_033405 (protein)
Location	Chr 3: 185.57 - 185.58 Mb	Chr 16: 20.64 - 20.64 Mb
Pubmed search	[1]	[2]

Thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and development factor), also known as TPO, is a glycoprotein hormone produced mainly by the liver and the kidney that regulates the production of platelets by the bone marrow. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets.^[1]

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.^[2]

Contents 1 Genetics 2 Function and regulation 3 Therapeutic use 4 History 5 References 6 Further reading 7 External links

Genetics

The thrombopoietin gene is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis (high platelet count) and in some cases of leukemia. Thrombopoietin shares its first 153 amino acids with erythropoietin.^[3]

Function and regulation

In the liver it is produced by parenchymal cells and sinusoidal endothelial cells. In the kidney it is made by proximal convoluted tubule cells. Along with these it is made by striated muscle and stromal cells in the bone marrow.^[1] In the liver, its production is augmented by interleukin 6 (IL-6).^[1]

Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile^[1].

Its negative feedback is different from most hormones in endocrinology: the effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.^[1]

Therapeutic use

Despite numerous trials, thrombopoietin is not used therapeutically. Theoretical uses include the procurement of platelets for donation^[4], recovery of platelet counts after myelosuppressive chemotherapy.^[1]

A modified recombinant form, termed "megakaryocyte growth and differentiation factor" (MGDF), caused a paradoxical reaction, delaying the development of therapeutic thrombopoietin. A quadrivalent peptide analogue is undergoing development, as well as several small molecule agents,^[1] including several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.^[5][6]

History

Thrombopoietin was cloned by five independent groups in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the cell surface receptor c-Mpl, and in older publications thrombopoietin is described as c-Mpl ligand (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.^[1]

References

1. ^ ^{a b c d e f g h} Kaushansky K (2006). "Lineage-specific hematopoietic growth factors". N. Engl. J. Med. 354 (19): 2034–45. doi:10.1056/NEJMra052706. PMID 16687716. 
2. ^ "Entrez Gene: THPO thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7066. 
3. ^ Online 'Mendelian Inheritance in Man' (OMIM) 600044
4. ^ Kuter DJ, Goodnough LT, Romo J, et al. (2001). "Thrombopoietin therapy increases platelet yields in healthy platelet donors". Blood 98 (5): 1339–45. doi:10.1182/blood.V98.5.1339. PMID 11520780. http://www.bloodjournal.org/cgi/content/full/98/5/1339. 
5. ^ Nakamura T, Miyakawa Y, Miyamura A, et al. (2006). "A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis". Blood 107 (11): 4300–7. doi:10.1182/blood-2005-11-4433. PMID 16484588. 
6. ^ Jenkins JM, Williams D, Deng Y, et al. (2007). "Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist". Blood 109 (11): 4739–41. doi:10.1182/blood-2006-11-057968. PMID 17327409. 

Further reading

• Kato T, Matsumoto A, Ogami K, et al. (1999). "Native thrombopoietin: structure and function". Stem Cells 16 (5): 322–8. PMID 9766811. 
• Kato T (2000). "Protein characteristics of thrombopoietin". Stem Cells 14 Suppl 1: 139–47. PMID 11012214. 
• Geddis AE, Linden HM, Kaushansky K (2002). "Thrombopoietin: a pan-hematopoietic cytokine". Cytokine Growth Factor Rev. 13 (1): 61–73. doi:10.1016/S1359-6101(01)00030-2. PMID 11750880. 
• von dem Borne A, Folman C, van den Oudenrijn S, et al. (2002). "The potential role of thrombopoietin in idiopathic thrombocytopenic purpura". Blood Rev. 16 (1): 57–9. doi:10.1054/blre.2001.0184. PMID 11913997. 
• Kaushansky K (2003). "Thrombopoietin: from theory to reality". Int. J. Hematol. 76 Suppl 1: 343–5. PMID 12430879. 
• Kralovics R, Skoda RC (2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders". Blood Rev. 19 (1): 1–13. doi:10.1016/j.blre.2004.02.002. PMID 15572213. 
• Migliaccio AR, Rana RA, Vannucchi AM, Manzoli FA (2007). "Role of thrombopoietin in mast cell differentiation". Ann. N. Y. Acad. Sci. 1106: 152–74. doi:10.1196/annals.1392.024. PMID 17468237. 
• Foster DC, Sprecher CA, Grant FJ, et al. (1995). "Human thrombopoietin: gene structure, cDNA sequence, expression, and chromosomal localization". Proc. Natl. Acad. Sci. U.S.A. 91 (26): 13023–7. doi:10.1073/pnas.91.26.13023. PMID 7809166. 
• Ritchie A, Vadhan-Raj S, Broxmeyer HE. (1996). "Thrombopoietin suppresses apoptosis and behaves as a survival factor for the human growth factor-dependent cell line, M07e.". Stem Cells. 14 (3): 330–6. doi:10.1016/0014-5793(94)01008-0. PMID 8724699
• Chang MS, McNinch J, Basu R, et al. (1995). "Cloning and characterization of the human megakaryocyte growth and development factor (MGDF) gene". J. Biol. Chem. 270 (2): 511–4. PMID 7822271. 
• Gurney AL, Kuang WJ, Xie MH, et al. (1995). "Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin". Blood 85 (4): 981–8. PMID 7849319. 
• Sohma Y, Akahori H, Seki N, et al. (1994). "Molecular cloning and chromosomal localization of the human thrombopoietin gene". FEBS Lett. 353 (1): 57–61. doi:10.1016/0014-5793(94)01008-0. PMID 7926023. 
• Bartley TD, Bogenberger J, Hunt P, et al. (1994). "Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl". Cell 77 (7): 1117–24. doi:10.1016/0092-8674(94)90450-2. PMID 8020099. 
• de Sauvage FJ, Hass PE, Spencer SD, et al. (1994). "Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand". Nature 369 (6481): 533–8. doi:10.1038/369533a0. PMID 8202154. 
• Kaushansky K, Lok S, Holly RD, et al. (1994). "Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin". Nature 369 (6481): 568–71. doi:10.1038/369568a0. PMID 8202159. 
• Wendling F, Maraskovsky E, Debili N, et al. (1994). "cMpl ligand is a humoral regulator of megakaryocytopoiesis". Nature 369 (6481): 571–4. doi:10.1038/369571a0. PMID 8202160. 
• Kato T, Ogami K, Shimada Y, et al. (1996). "Purification and characterization of thrombopoietin". J. Biochem. 118 (1): 229–36. PMID 8537317. 
• Hoffman RC, Andersen H, Walker K, et al. (1997). "Peptide, disulfide, and glycosylation mapping of recombinant human thrombopoietin from ser1 to Arg246". Biochemistry 35 (47): 14849–61. doi:10.1021/bi961075b. PMID 8942648. 
• Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC (1998). "An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia". Nat. Genet. 18 (1): 49–52. doi:10.1038/ng0198-49. PMID 9425899. 
• Kondo T, Okabe M, Sanada M, et al. (1998). "Familial essential thrombocythemia associated with one-base deletion in the 5'-untranslated region of the thrombopoietin gene". Blood 92 (4): 1091–6. PMID 9694695. . 

v • d • e PDB Gallery 1v7m: Human Thrombopoietin Functional Domain Complexed To Neutralizing Antibody TN1 Fab   1v7n: Human Thrombopoietin Functional Domain Complexed To Neutralizing Antibody TN1 Fab

External links

• Longer summary on thrombopoietin

v • d • e Cytokines, glycoproteins: colony-stimulating factors CFU-GEMM Interleukin 3 CFU-GM Granulocyte macrophage colony-stimulating factor: Granulocyte colony-stimulating factor - Macrophage colony-stimulating factor CFU-E Erythropoietin CFU-Meg Thrombopoietin

v • d • e Protein, glycoconjugate: glycoproteins Activin and inhibin - ADAM protein - Alpha 1-antichymotrypsin - Apolipoprotein H - CD70 - Asialoglycoprotein - Avidin - B-cell activating factor - 4-1BB ligand - Cholesterylester transfer protein - Clusterin - Colony-stimulating factor - Haemopexin - Lactoferrin - Membrane glycoproteins - Mucoprotein - Myelin protein zero - Osteonectin - Protein C - Protein S - Proteoglycan - Serum amyloid P component - Sialoglycoprotein (CD43, Glycophorin, Glycophorin C) - Thrombopoietin - Thyroglobulin - Thyroxine-binding proteins - Transcortin - Tumor necrosis factor-alpha - Uteroglobin - Vitronectin see also enzymes, glycoproteinoses

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