Thrombopoietin

Human TPO is a 332 amino acid, 60 kDa glycoprotein, containing six potential N-linked glycosylation sites. These are all localized towards the C-terminus of the molecule. The N-terminal half exhibits a high degree of amino acid homology with EPO and represents the biologically active domain of the molecule. 

TPO is the haemopoietic growth factor now shown to be the primary physiological regulator of platelet production. This molecule may, therefore, represent an important future therapeutic agent in combating thrombocytopenia, a condition characterized by reduced blood platelet levels. The most likely initial TPO therapeutic target is thrombocytopenia induced by cancer chemo- or 

A number of disorders have been identified that are primarily caused by the presence of abnormal platelet levels in the blood. Thrombocythaemia is a disease characterized by abnormal megakaryocyte proliferation, leading to elevated blood platelet levels. In many instances, this results in an elevated risk of spontaneous clot formation within blood vessels. In other instances, the platelets produced are defective, which can increase the risk of spontaneous or prolonged bleeding events. 

Thrombocytopenia, on the other hand, is a condition characterized by reduced blood platelet levels. Spontaneous bruising, bleeding into the skin (purpura) and prolonged bleeding after injury represent typical symptoms. Thrombocytopenia is induced by a number of clinical conditions, including  

TPO should alleviate thrombocytopenia in most instances by encouraging platelet production. Currently, the standard therapy for the condition entails administration of 5 units of platelets to the sulferer (1 unit equals the quantity of platelets derived in one sitting from a single blood donor). TPO therapy is a particularly attractive potential alternative because  

Sources of TPO include kidney and skeletal muscle cells but it is primarily produced by the liver, from where it is excreted constantly into the blood. This regulatory factor supports the proliferation, differentiation and maturation of megakaryocytes and their progenitors and 

TPO induces its characteristic effects by binding to a specific TPO receptor present on the surface of sensitive cells. The receptor, also known as c-mpl, is a single chain, 610 amino acid transmembrane glycoprotein. The mechanism of signal transduction triggered upon TPO-binding remains to be elucidated. 

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Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

Hodohara K, Fujii N, Yamamoto N, Kaushansky K. Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of mega-karyocytic progenitor cells (CFU-MK). Blood 2000 95(3) 769-775. 

JAK2 is critical for thrombopoietin (TPO) and erythropoietin (EPO) receptor signaling that controls the growth and differentiation of platelets and erythrocytes, respectively [10,11]. Transgenic reconstitution of the activated... 

TPO thrombopoietin EGF epidermal growth factor NGF nerve growth factor LH luteinizing hormone. 

Kuter, D., Hunt, P., Sheridan, W.P., and Zucker-Franklin, D. (eds). 1997. Thrombopoiesis and Thrombopoietins. Humana Press. 

Basser, R. 2002. The impact of thrombopoietin on clinical practice. Current Pharmaceutical Design 8(5), 369-377. 

Geddis, A.E., Linden, H.M., and Kaushansky, K. 2002. Thrombopoietin a pan-hematopoietic cytokine. Cytokine and Growth Factor Reviews 13(1), 61-73. 

Kaushansky, K. 1997. Thrombopoietin - understanding and manipulating platelet production. Annual Review of Medicine 48, 1-11. 

Kaushansky, K. and Drachman, J. 2002. The molecular and cellular biology of thrombopoietin the primary regulator of platelet production. Oncogene 21(21), 3359-3367. 

Presnell, S.R., O Hara, P.J., Hagen, F.S., Roth, G.J., and Foster, D.C. 1994. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369, 565-568. 

Miyazaki, H. and Kato, T. 1999. Thrombopoietin biology and clinical potential. International Journal of Haematology 70(4), 216-225. 

Ogden, J. 1994. Thrombopoietin - the erythropoietin of platelets Trends in Biotechnology 12, 389-390. 

Recombinant human IL-11 was under evaluation in human clinical trials for use as a thrombopoietin product for chemotherapy support.18 An ELISA was developed to measure adsorption (residual concentration in various containers over time). The ELISA was formatted with an anti-IL-11 MAb for capture and a biotinylated antibody for detection.18 A combination of HSA and Tween-20 was required to address both the adsorption of IL-11 to glass and retention of biological activity postlyophilization. 

Erythropoietin Thrombopoietin Tissue plasminogen activator -Antitrypsin... 

Basser, R. (2002). The impact of thrombopoietin on clinical practice. Curr. Pharmaceut. Design 8(5), 369-377. Bottomley, A. et al. (2002). Human recombinant erythropoietin and quality of life a wonder drug or something to wonder about Lancet Oncol. 3(3), 145-153. 

Geddis, A. et al. (2002). Thrombopoietin a pan-hematopoietic cytokine. Cytokine Growth Factor Rev. 13(1), 61-73. Kaushansky, K. (1995). Thrombopoietin the primary regulator of platelet production. Blood 86(2), 419-431. Kaushansky, K. (1997). Thrombopoietin—understanding and manipulating platelet production. Armu. Rev. Med. 48, 1-11. 

Lok, S. et al. (1994). Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production... 

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