Journal articles: 'Thrombopoietin'

1

Kaushansky, K. "Thrombopoietin: a tool for understanding thrombopoiesis." Journal of Thrombosis and Haemostasis 1, no. 7 (July 2003): 1587–92. http://dx.doi.org/10.1046/j.1538-7836.2003.00273.x.

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Miyakawa, Y., A. Oda, BJ Druker, H. Miyazaki, M. Handa, H. Ohashi, and Y. Ikeda. "Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets." Blood 87, no. 2 (January 15, 1996): 439–46. http://dx.doi.org/10.1182/blood.v87.2.439.bloodjournal872439.

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Thrombopoietin is known to be essential for megakaryocytopoiesis and thrombopoiesis. Recently, we and others have shown that thrombopoietin induces rapid tyrosine phosphorylation of Jak2 and other proteins in human platelets and BaF3 cells, genetically engineered to express c- Mpl, a receptor for thrombopoietin. The Jak family of tyrosine kinases are known to mediate some of the effects of cytokines or hematopoietic growth factors by recruitment and tyrosine phosphorylation of a variety of Stat (signal transducers and activators of transcription) proteins. Hence, we have investigated whether Stat proteins are present in platelets and, if so, whether they become tyrosine phosphorylated in response to thrombopoietin. We immunologically identified Stat1, Stat2, Stat3, and Stat5 in human platelet lysates. Thrombopoietin induced tyrosine phosphorylation of Stat3 and Stat5 in these cells. Thrombopoietin also induced tyrosine phosphorylation of Stat3 and Stat5 in FDCP-2 cells genetically engineered to constitutively express human c-Mpl. Thus, our data indicate that Stat3 and Stat5 may be involved in signal transduction after ligand binding to c-Mpl and that this event may have a role in megakaryopoiesis/thrombopoiesis or possibly a mature platelet function such as aggregation.

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Andemariam, Biree, Bethan Psaila, and James B. Bussel. "Novel Thrombopoietic Agents." Hematology 2007, no. 1 (January 1, 2007): 106–13. http://dx.doi.org/10.1182/asheducation-2007.1.106.

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AbstractThrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with chemotherapy. There is a need for additional means to treat thrombocytopenia in these settings. Recombinant thrombopoietin-like agents became available after the cloning of thrombopoietin in 1994. In clinical trials, these agents showed some efficacy in chemotherapy-induced thrombocytopenia, but their use was ultimately discontinued due to the development of neutralizing antibodies that cross-reacted with endogenous thrombopoietin and caused thrombocytopenia in healthy blood donors and other recipients. Subsequently, “second-generation” thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical development and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C–related thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist’s ability to manage these and other causes of thrombocytopenia.

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Oda, A., Y. Miyakawa, BJ Druker, K. Ozaki, K. Yabusaki, Y. Shirasawa, M. Handa, et al. "Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists." Blood 87, no. 11 (June 1, 1996): 4664–70. http://dx.doi.org/10.1182/blood.v87.11.4664.bloodjournal87114664.

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Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine- diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.

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Miyakawa, Yoshitaka, Brian Druker, Katsutoshi Ozaki, Hideya Ohashi, Takashi Kato, Hiroshi Miyazaki, Makoto Handa, Kenji Ikebuchi, Yasuo Ikeda, and Atsushi Oda. "Thrombopoietin-Induced Signal Transduction and Potentiation of Platelet Activation." Thrombosis and Haemostasis 82, no. 08 (1999): 377–84. http://dx.doi.org/10.1055/s-0037-1615856.

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IntroductionThe presence of thrombopoietin, a humoral regulator of megakaryopoiesis and thrombopoiesis, had been suggested for years,1 however, some investigators were skeptical about the existence of such a factor. Modern studies of thrombopoietin begin with the cloning of c-mpl (the cellular counterpart of the v-mpl oncogene) and its cognate ligand genes. Following the cloning of the c-mpl proto-oncogene,2 Methia et al3 found that, in the presence of oligonucleotides antisense to the gene, CD34+ cells developed into megakaryocytic precursors less efficiently. As the development into other lineage was nearly intact, it was reasonably argued that the c-mpl protein may be the receptor for a thrombopoietin-like factor.3 This study inspired numerous investigations, which culminated in the cloning of the thrombopoietin gene in 1994.1, 4-8

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Miyakawa, Y., A. Oda, BJ Druker, T. Kato, H. Miyazaki, M. Handa, and Y. Ikeda. "Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets." Blood 86, no. 1 (July 1, 1995): 23–27. http://dx.doi.org/10.1182/blood.v86.1.23.bloodjournal86123.

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A cDNA for the thrombopoietin has been cloned by several groups. The recombinant thrombopoietin has been reported to stimulate the megakaryocytopoiesis and thrombopoiesis. Little is known regarding the molecular basis of its effects. To elucidate the molecular mechanism involved in signal transduction, we have investigated the effects of thrombopoietin on platelet tyrosine phosphorylation. We report here that thrombopoietin induced time- and dose-dependent tyrosine phosphorylation of several proteins including Janus kinase 2 (Jak2) and a 52-kD protein, Shc, in human blood platelets. Both Jak2 and Shc were tyrosine phosphorylated within 15 seconds after stimulation. The tyrosine phosphorylation of Jak2 was accompanied by increased kinase activity, whereas Shc tyrosine phosphorylation induced its association with a 25-kD protein, Grb2. Thus, our data suggest that Jak2, Shc, and Grb2 may be involved in signal transduction after ligand binding to c- mpl in human platelets.

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Underhill, Craig R., and Russell L. Basser. "Thrombopoietin." BioDrugs 11, no. 4 (1999): 261–76. http://dx.doi.org/10.2165/00063030-199911040-00005.

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8

Kaushansky, Kenneth. "Thrombopoietin." Trends in Endocrinology & Metabolism 8, no. 2 (March 1997): 45–50. http://dx.doi.org/10.1016/s1043-2760(96)00269-x.

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9

Kaushansky, Kenneth. "Thrombopoietin." New England Journal of Medicine 339, no. 11 (September 10, 1998): 746–54. http://dx.doi.org/10.1056/nejm199809103391107.

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10

Thompson, Clare. "Thrombopoietin." Lancet 343, no. 8913 (June 1994): 1630. http://dx.doi.org/10.1016/s0140-6736(94)93079-1.

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Baatout, Sarah. "Thrombopoietin." Pathophysiology of Haemostasis and Thrombosis 27, no. 1 (1997): 1–8. http://dx.doi.org/10.1159/000217427.

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12

Bolam, S. "Thrombopoietin." Transfusion Science 18, no. 1 (March 1997): 129–37. http://dx.doi.org/10.1016/s0955-3886(96)00089-6.

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Basser, Russell L., and C. Glenn Begley. "Thrombopoietin." Cancer Investigation 19, no. 6 (January 2001): 660–66. http://dx.doi.org/10.1081/cnv-100104294.

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14

Alexander, Warren S. "Thrombopoietin." Growth Factors 17, no. 1 (January 1999): 13–24. http://dx.doi.org/10.3109/08977199909001059.

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15

Lok, S., and D. C. Foster. "Thrombopoietin." Drugs of the Future 21, no. 7 (1996): 711. http://dx.doi.org/10.1358/dof.1996.021.07.361419.

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16

KAUSHANSKY, KENNETH. "Thrombopoietin." Annals of the New York Academy of Sciences 996, no. 1 (May 2003): 39–43. http://dx.doi.org/10.1111/j.1749-6632.2003.tb03230.x.

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17

Pick, Marjorie, Chava Perry, Tsvee Lapidot, Cinthya Guimaraes-Sternberg, Elizabeth Naparstek, Varda Deutsch, and Hermona Soreq. "Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis." Blood 107, no. 8 (April 15, 2006): 3397–406. http://dx.doi.org/10.1182/blood-2005-08-3240.

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AbstractTo study the role of the stress-induced “readthrough” acetylcholinesterase splice variant, AChE-R, in thrombopoiesis, we used transgenic mice overexpressing human AChE-R (TgR). Increased AChE hydrolytic activity in the peripheral blood of TgR mice was associated with increased thrombopoietin levels and platelet counts. Bone marrow (BM) progenitor cells from TgR mice presented an elevated capacity to produce mixed (GEMM) and megakaryocyte (Mk) colonies, which showed intensified labeling of AChE-R and its interacting proteins RACK1 and PKC. When injected with bacterial lipopolysaccharide (LPS), parent strain FVB/N mice, but not TgR mice, showed reduced platelet counts. Therefore, we primed human CD34+ cells with the synthetic ARP26 peptide, derived from the cleavable C-terminus of AChE-R prior to transplantation, into sublethally irradiated NOD/SCID mice. Engraftment of human cells (both CD45+ and CD41+ Mk) was significantly increased in mice that received ARP26-primed CD34+ human cells versus mice that received fresh nonprimed CD34+ human cells. Moreover, ARP26 induced polyploidization and proplatelet shedding in human MEG-01 promegakaryotic cells, and human platelet engraftment increased following ex vivo expansion of ARP26-treated CD34+ cells as compared to cells expanded with thrombopoietin and stem cell factor. Our findings implicate AChE-R in thrombopoietic recovery, suggesting new therapeutic modalities for supporting platelet production.

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Dymicka-Piekarska, Violetta, and Halina Kemona. "Thrombopoietin and reticulated platelets as thrombopoietic markers in colorectal cancer." Thrombosis Research 122, no. 1 (January 2008): 141–43. http://dx.doi.org/10.1016/j.thromres.2007.10.003.

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19

McCormack, Matthew P., Mark A. Hall, Simone M. Schoenwaelder, Quan Zhao, Sarah Ellis, Julia A. Prentice, Ashleigh J. Clarke, et al. "A critical role for the transcription factor Scl in platelet production during stress thrombopoiesis." Blood 108, no. 7 (October 1, 2006): 2248–56. http://dx.doi.org/10.1182/blood-2006-02-002188.

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Abstract The generation of platelets from megakaryocytes in the steady state is regulated by a variety of cytokines and transcription factors, including thrombopoietin (TPO), GATA-1, and NF-E2. Less is known about platelet production in the setting of stress thrombopoiesis, a pivotal event in the context of cytotoxic chemotherapy. Here we show in mice that the transcription factor Scl is critical for platelet production after chemotherapy and in thrombopoiesis induced by administration of TPO. Megakaryocytes from these mice showed appropriate increases in number and ploidy but failed to shed platelets. Ultrastructural examination of Scl-null megakaryocytes revealed a disorganized demarcation membrane and reduction in platelet granules. Quantitative real-time polymerase chain reaction showed that Scl-null platelets lacked NF-E2, and chromatin immunoprecipitation analysis demonstrated Scl binding to the NF-E2 promoter in the human megakaryoblastic-cell line Meg-01, along with its binding partners E47, Lmo2, and the cofactors Ldb1 and GATA-2. These findings suggest that Scl acts up-stream of NF-E2 expression to control megakaryocyte development and platelet release in settings of thrombopoietic stress.

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Kaushansky, Kenneth. "Historical review: megakaryopoiesis and thrombopoiesis." Blood 111, no. 3 (February 1, 2008): 981–86. http://dx.doi.org/10.1182/blood-2007-05-088500.

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Abstract The study of thrombopoiesis has evolved greatly since an era when platelets were termed “the dust of the blood,” only about 100 years ago. During this time megakaryocytes were identified as the origin of blood platelets; marrow-derived megakaryocytic progenitor cells were functionally defined and then purified; and the primary regulator of the process, thrombopoietin, was cloned and characterized and therapeutic thrombopoietic agents developed. During this journey we continue to learn that the physiologic mechanisms that drive proplatelet formation can be recapitulated in cell-free systems and their biochemistry evaluated; the molecular underpinnings of endomitosis are being increasingly understood; the intracellular signals sent by engagement of a large number of megakaryocyte surface receptors have been defined; and many of the transcription factors that drive megakaryocytic fate determination have been identified and experimentally manipulated. While some of these biologic processes mimic those seen in other cell types, megakaryocytes and platelets possess enough unique developmental features that we are virtually assured that continued study of thrombopoiesis will yield innumerable clinical and scientific insights for many decades to come.

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Kaushansky, Kenneth. "Determinants of platelet number and regulation of thrombopoiesis." Hematology 2009, no. 1 (January 1, 2009): 147–52. http://dx.doi.org/10.1182/asheducation-2009.1.147.

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Abstract Our understanding of thrombopoiesis has improved greatly in the last two decades with the availability of in vitro assays of megakaryocyte progenitor cell growth, with the cloning and characterization of stem cell factor (SCF) and thrombopoietin (Tpo), the latter the primary humoral regulator of this process, and with the generation of genetically altered murine models of thrombopoietic failure and excess. While SCF affects developmentally early aspects of megakaryocyte growth, Tpo affects nearly all aspects of platelet production, from hematopoietic stem cell (HSC) self-renewal and expansion, through stimulation of megakaryocyte progenitor cell proliferation, to supporting their maturation into platelet-producing cells. The molecular and cellular mechanisms through which the marrow microenvironment and humoral mediators affect platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis, and highlight new opportunities to translate basic biology into clinical advances.

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Sheridan, W. P., and C. F. Toombs. "Discovery, in vitro and in vivo Biology of c-mpl Ligand." Hämostaseologie 16, no. 02 (April 1996): 107–13. http://dx.doi.org/10.1055/s-0038-1656646.

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SummarySince the announcement of the discovery of thrombopoietin in 1994, a tremendous amount of research has determined that recombinant c-mpl ligand (ML) is capable of producing the biological effects of a Meg-CSF and thrombopoietin. Thrombopoietin's effects include the stimulation of primitive hematopoietic stem cells, megakaryocyte progenitor cells, megakaryocyte production and maturation and leading to the formation of platelets both in vitro and in vivo. Animal models of chemotherapy-induced thrombocytopenia have yielded data which fore-shadows a beneficial effect of thrombopoietin in clinical thrombocytopenia. The signaling mechanisms transducing thrombopoietin's actions are currently under research but in progenitor cells most likely involve modulation of the expression of genes regulated by the Jak-STAT signaling pathways, given throm-bopoietin's similarity to erythropoietin. Remnants of the Janus kinase signaling system appear to be active in the platelet and mediate enhanced platelet aggre-gation in response to platelet agonists upon stimulation of the c-mpl receptor with ML. The observation of enhanced platelet aggregation in vitro has not translated to enhanced thrombosis in relevant in vivo animal models. Preliminary clinical reports are returning clear evidence that the lineage-dominant effects of rHuMGDF on megakaryocytopoiesis observed in experimental settings are also holding true in the clinic.

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Jilma-Stohlawetz, P., M. Homoncik, B. Jilma, C. C. Folman, A. E. G. KR Von Dem Borne, G. Bernaschek, J. Deutinger, B. Ulm, W. Eppel, and S. Panzer. "High levels of reticulated platelets and thrombopoietin characterize fetal thrombopoiesis." British Journal of Haematology 112, no. 2 (February 2001): 466–68. http://dx.doi.org/10.1046/j.1365-2141.2001.02524.x.

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Kaser, Arthur, Gerald Brandacher, Wolfgang Steurer, Susanne Kaser, Felix A. Offner, Heinz Zoller, Igor Theurl, et al. "Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis." Blood 98, no. 9 (November 1, 2001): 2720–25. http://dx.doi.org/10.1182/blood.v98.9.2720.

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Abstract Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6–treated cancer patients. It is shown that IL-6–induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6–induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.

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NAGAHISA, Hiroshi, and Kzauo TODOKORO. "Thrombopoietin, TPO." Journal of Japan Atherosclerosis Society 24, no. 1-2 (1996): 9–13. http://dx.doi.org/10.5551/jat1973.24.1-2_9.

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Abe, Masaki, Shinya Yano, Nana Sakaba, Kohki Kitamura, Tetsuya Urasaki, Susumu Nakada, Hiroshi Kawasaki, Chikao Morimoto, and Yasuhiko Masuho. "Surrogate thrombopoietin." Immunology Letters 61, no. 2-3 (April 1998): 73–78. http://dx.doi.org/10.1016/s0165-2478(97)00166-1.

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Haznedaroglu, Ibrahim C., Hakan Goker, Mehmet Turgut, Yahya Buyukasik, and Mustafa Benekli. "Thrombopoietin as a Drug: Biologic Expectations, Clinical Realities, and Future Directions." Clinical and Applied Thrombosis/Hemostasis 8, no. 3 (July 2002): 193–212. http://dx.doi.org/10.1177/107602960200800301.

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After the cloning of thrombopoietin (c-mpl ligand, Tpo) in 1994, 2 recombinant thrombopoietic growth factors, full-length glycosylated recombinant human Tpo (reHuTPO) and polyethylene glycol conjugated megakaryocyte growth and development factor (PEG-reHuMGDF), have been studied in humans in a variety of clin- ical settings. Both thrombopoietins are generally well tolerated if ad- ministered intravenously (IV). The c-mpl ligands produce a dose-re- lated enhancement of platelet levels, reduce nonmyeloablative chemotherapy-induced mild thrombocytopenia, and mobilize hematopoietic progenitors. On September 11, 1998, the development of PEG-reHuMGDF was suspended in the U.S., due to formation of the neutralizing anti-Tpo antibody. Those neutralizing antibodies lead to thrombocytopenia and pancytopenia in some patients receiv- ing subcutaneous (SC) PEG-reHuMGDF. Japanese investigators in- dicate that the probability of antibody formation against PEG- reHuMGDF is low when the drug is administered IV instead of SC. reHuTPO has a more favorable safety profile from the point of anti- body production. The c-mpl ligands can improve apheresis yields when administered to normal platelet donors. Preliminary data about the use of PEG-reHuMGDF in myelodysplasia, aplastic anemia, and immune thrombocytopenic purpura are promising. Tpo is usually not effective in myeloablative thrombocytopenia when bone marrow hematopoietic progenitors are not present. The major obstacle for the thrombopoietins is their delayed action for managing clinical thrombocytopenia. This review will focus on the biologic basis, cur- rent clinical experience, and future directions for the use of throm- bopoietic molecules as drugs. The identification of a safe, effective, and potent pharmacologic platelet growth factor could significantly improve the management of thrombocytopenia-induced bleeding.

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Wörmann, Bernhard. "Clinical Indications for Thrombopoietin and Thrombopoietin-Receptor Agonists." Transfusion Medicine and Hemotherapy 40, no. 5 (2013): 3. http://dx.doi.org/10.1159/000355006.

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Kuter, David J. "The biology of thrombopoietin and thrombopoietin receptor agonists." International Journal of Hematology 98, no. 1 (July 2013): 10–23. http://dx.doi.org/10.1007/s12185-013-1382-0.

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Basser, Russell. "Clinical Biology and Potential Use of Thrombopoietin." Canadian Journal of Gastroenterology 14, suppl d (2000): 73D—78D. http://dx.doi.org/10.1155/2000/681394.

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The discovery of platelet growth factors raised expectations that an effective method for abrogating thrombocytopenia would soon be available in the clinic. The cytokines initially described were pleiotropic in nature, and stimulation of platelet production was generally modest. However, one of these agents, interleukin-11, was successfully shown to reduce the incidence of severe thrombocytopenia in patients receiving dose-intensive chemotherapy, and has now received approval from the United States Food and Drug Administration for this purpose. Initial clinical trials of thrombopoietin, the central regulator of megakaryocytopoiesis and thrombopoiesis, and its analogues showed these agents to be the most potent stimulators of thrombopoiesis and to be associated with few adverse effects. They have also been shown to enhance platelet recovery after chemotherapy, but early results from trials investigating their ability to prevent severe thrombocytopenia associated with the treatment of leukemia and bone marrow transplantation have been disappointing. In addition, subcutaneous administration of one of these agents, megakaryocyte growth and development factor, has been shown to induce the formation of antibodies that neutralize native thrombopoietin and cause thrombocytopenia. Platelet growth factors remain promising therapeutic agents; however, there are a number of obstacles to overcome before they find general use in the clinic.

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Evangelista, Maria Laura, Elisa Stipa, Francesco Buccisano, Adriano Venditti, Sergio Amadori, and Roberto Stasi. "Idiopathic thrombocytopenic purpura: Current concepts in pathophysiology and management." Thrombosis and Haemostasis 99, no. 01 (2008): 4–13. http://dx.doi.org/10.1160/th07-08-0513.

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SummaryIdiopathic thrombocytopenic purpura (ITP) is characterized by a low platelet count, which is the result of both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP, several abnormalities involving the cellular mechanisms of immune modulation have been identified. Conventional treatments for ITP aim at reducing platelet destruction, either by immunosuppression or splenectomy. Two new thrombopoietic agents, AMG 531 and eltrombopag, have been used in clinical trials to stimulate platelet production in ITP patients not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin, but still bind and activate the thrombopoietin receptor. This review will focus on the pathophysiology and treatment of ITP in adults, highlighting recent advances in both fields.

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Kuter, David J. "Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia." Annual Review of Medicine 60, no. 1 (February 2009): 193–206. http://dx.doi.org/10.1146/annurev.med.60.042307.181154.

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Miyakawa, Yoshitaka, Atsushi Oda, Brian J. Druker, Katsutoshi Ozaki, Makoto Handa, Hideya Ohashi, and Yasuo Ikeda. "Thrombopoietin and Thrombin Induce Tyrosine Phosphorylation of Vav in Human Blood Platelets." Blood 89, no. 8 (April 15, 1997): 2789–98. http://dx.doi.org/10.1182/blood.v89.8.2789.

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Abstract Thrombopoietin has an essential role in megakaryopoiesis and thrombopoiesis. To investigate the signaling processes induced by thrombopoietin, we have employed human platelets and recently demonstrated that thrombopoietin induces rapid tyrosine phosphorylation of Jak-2, Tyk2, Shc, Stat3, Stat5, p120c-cbl and other proteins in human platelets. Because the apparent molecular weight of a major tyrosine phosphorylated protein in platelets stimulated by thrombopoietin is approximately 85 to 95 kD, we examined the possibility that this could be Vav, a 95-kD proto-oncogene product. Specific antisera against Vav recognized the same 95 kD protein in lysates of Jurkat cells, which are known to express Vav, and platelets, indicating that platelets have Vav. Thrombopoietin induced rapid tyrosine phosphorylation of Vav in platelets without an elevation in cytosolic free calcium concentration or activation of protein kinase C. Vav was also tyrosine phosphorylated upon treatment of platelets with thrombin, collagen, or U46619, which activate phospholipase C, leading to an increased ionized calcium concentration and activation of protein kinase C. Ionomycin or phorbol 12-myristate 13-acetate (PMA) also induces tyrosine phosphorylation of Vav, suggesting that an increase in ionized calcium concentration or activation of protein kinase C may lead to phosphorylation of Vav. Thrombopoietin also induced tyrosine phosphorylation of Vav in FDCP-2 cells, genetically engineered to express human c-Mpl (FDCP-hMpl5). However, neither ionomycin nor PMA induced an increase in tyrosine phosphorylation of Vav in FDCP-hMpl5 cells, suggesting that the calcium and protein kinase C pathways of Vav phosphorylation may be unique to platelets. Further, Vav became incorporated into the Triton X-100 insoluble 10,000g sedimentable residue in an aggregation-dependent manner, suggesting that it may have a regulatory role in platelet cytoskeletal processes. Vav was constitutively associated with a 28-kD adapter protein, Grb2, which is also incorporated into the cytoskeleton in an aggregation-dependent fashion. Lastly, we found that Vav is cleaved when there is activation of calpain, a protease that may have a role in postaggregation signaling processes. Our data suggest that thrombopoietin and other agonists may induce tyrosine phosphorylation of Vav by different mechanisms and Vav may also be involved in signaling during platelet aggregation by its redistribution to the cytoskeleton.

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Turner, KJ, SJ Goldman, JA Kaye, and SC Clark. "Thrombopoiesis and thrombopoietin: the significance of "non-Tpo" cytokines [letter; comment]." Blood 87, no. 7 (April 1, 1996): 3065–67. http://dx.doi.org/10.1182/blood.v87.7.3065.bloodjournal8773065.

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35

Kim, Boing-Soon, Purevjargal Naidansuren, and Kwan-Sik Min. "Biological Activity of Recombinant Human Thrombopoietin." Journal of Life Science 17, no. 11 (November 30, 2007): 1497–504. http://dx.doi.org/10.5352/jls.2007.17.11.1497.

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HIGASHIHARA, Masaaki, and Koji MIYAZAKI. "Thrombopoietin-producing Tumor." Internal Medicine 42, no. 8 (2003): 632–33. http://dx.doi.org/10.2169/internalmedicine.42.632.

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MIYAZAKI, Hiroshi. "The thrombopoietin receptor." Japanese Journal of Thrombosis and Hemostasis 26, no. 1 (2015): 35–41. http://dx.doi.org/10.2491/jjsth.26.35.

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McDonald, Ted P. "Assays for Thrombopoietin." Scandinavian Journal of Haematology 18, no. 1 (April 24, 2009): 5–12. http://dx.doi.org/10.1111/j.1600-0609.1977.tb01471.x.

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Levin, Jack. "Thrombopoietin — Clinically Realized?" New England Journal of Medicine 336, no. 6 (February 6, 1997): 434–36. http://dx.doi.org/10.1056/nejm199702063360609.

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40

Metcalf, Donald. "Thrombopoietin — at last." Nature 369, no. 6481 (June 1994): 519–20. http://dx.doi.org/10.1038/369519a0.

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41

Broudy, Virginia C., and Kenneth Kaushansky. "Biology of thrombopoietin." Current Opinion in Pediatrics 10, no. 1 (February 1998): 60–64. http://dx.doi.org/10.1097/00008480-199802000-00012.

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Basciano, Paul A., and James B. Bussel. "Thrombopoietin-receptor agonists." Current Opinion in Hematology 19, no. 5 (September 2012): 392–98. http://dx.doi.org/10.1097/moh.0b013e328356e909.

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Neunert, Cindy E. "Thrombopoietin Receptor Agonist Use for Immune Thrombocytopaenia." Hämostaseologie 39, no. 03 (January 15, 2019): 272–78. http://dx.doi.org/10.1055/s-0038-1676129.

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AbstractManagement of patients with corticosteroid-refractory immune thrombocytopaenia (ITP) possesses a significant challenge to practitioners. Until recently, options included splenectomy and immunosuppression. With improved knowledge of both thrombopoiesis and the pathophysiology of ITP, novel drug development with thrombopoietin-receptor agonists (TPO-RAs) was undertaken. Two agents, romiplostim and eltrombopag, are currently approved for use in patients with chronic ITP. Both agents have been shown to increase the platelet count, improve health-related quality of life and reduce bleeding symptoms and concomitant medication use. This review will highlight the discovery of TPO-RA agents, appraise key clinical trials and explore future directions.

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Mouthon, Marc-André, Anne Van der Meeren, Marie Vandamme, Claire Squiban, and Marie-Hélène Gaugler. "Thrombopoietin protects mice from mortality and myelosuppression following high-dose irradiation: importance of time scheduling." Canadian Journal of Physiology and Pharmacology 80, no. 7 (July 1, 2002): 717–21. http://dx.doi.org/10.1139/y02-090.

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Thrombopoietin is the major regulator of platelet production and a stimulator of multilineage hematopoietic recovery following irradiation. The efficacy of three different schedules of thrombopoietin administration was tested on blood cell counts, hematopoietic bone marrow progenitors, and 30-day animal survival in C57BL6/J mice receiving a total body irradiation, with doses ranging from 7 to 10 Gy. A single dose of murine thrombopoietin was injected 2 h before, 2 h after, or 24 h after irradiation. Thrombopoietin promoted multilineage hematopoietic recovery in comparison to placebo up to 9 Gy at the level of both blood cells and bone marrow progenitors, whatever the schedule of administration. The injection of thrombopoietin 2 h before or 2 h after irradiation equally led to the best results concerning hematopoietic recovery. On the other hand, thrombopoietin administration promoted 30-day survival up to 9 Gy with the highest efficacy obtained when thrombopoietin was injected either 2 h before or 2 h after irradiation. However, when its injection was delayed at 24 h, thrombopoietin had almost no effect on survival of 9 Gy irradiated mice. Altogether, our results show that the time schedule for thrombopoietin injection is of critical importance and when thrombopoietin is administered before or shortly after irradiation, it efficiently promotes mice survival to supra-lethal irradiation (up to 9 Gy) in relation with hematopoietic recovery.Key words: irradiation, thrombopoietin, survival, hematopoiesis.

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45

Marcucci, Roberto, and Maurizio Romano. "Thrombopoietin and its splicing variants: Structure and functions in thrombopoiesis and beyond." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1782, no. 7-8 (July 2008): 427–32. http://dx.doi.org/10.1016/j.bbadis.2008.03.007.

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Khorshed, Amira, Aziza Abbas, Samia Abdel Kawy, Naglaa Kholoussi, Eman A. El-Ghorour, and Hala Abdel Salam. "Role of Thrombopoietin in Megakaryopoiesis and Thrombopoiesis with Relation to Platelets Ultrastructure." Journal of Medical Sciences 7, no. 2 (February 1, 2007): 179–86. http://dx.doi.org/10.3923/jms.2007.179.186.

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Füreder, W., U. Firbas, J. L. Nichol, J. Pistillo, S. Winkler, H. Hiesberger, W. R. Sperr, J. Smolen, and G. Schett. "Serum thrombopoietin levels and anti-thrombopoietin antibodies in systemic lupus erythematosus." Lupus 11, no. 4 (April 2002): 221–26. http://dx.doi.org/10.1191/0961203302lu177oa.

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Sood, Anil, Rebecca L. Stone, and Vahid Afshar-Kharghan. "Causes and Consequences of Cancer-Associated Thrombocytosis." Blood 122, no. 21 (November 15, 2013): SCI—33—SCI—33. http://dx.doi.org/10.1182/blood.v122.21.sci-33.sci-33.

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Abstract Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count >450,000/µL) occurs in patients with solid malignancies was made over 100 years ago. However, mechanisms of paraneoplastic thrombocytosis and the role that platelets play in abetting cancer growth are unclear. We have used clinical data coupled with sophisticated mouse models to identify the mechanisms and biological implications of paraneoplastic thrombocytosis. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an anti-platelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. Biologically, platelets were detected within the tumor microenvironment and affected tumor growth and response to chemotherapeutic agents. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. Blocking the stimulatory effects of platelets may have implications for new therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

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Peck-Radosavljevic, Markus. "Thrombocytopenia in Liver Disease." Canadian Journal of Gastroenterology 14, suppl d (2000): 60D—66D. http://dx.doi.org/10.1155/2000/617428.

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Moderate thrombocytopenia is a frequent finding in cirrhosis of the liver and well tolerated in most instances. The pathophysiology of thrombocytopenia in liver disease has long been associated with the concept of hypersplenism, where portal hypertension was thought to cause pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes in the enlarged spleen. The concept of hypersplenism was never proven beyond any doubt but was widely accepted for the lack of alternative explanations.With the discovery of the lineage-specific cytokine thrombopoietin (TPO) the missing link between hepatocellular function and thrombopoiesis was found. TPO is predominantly produced by the liver and constitutively expressed by hepatocytes.TPOproduction in humans is dependent on functional liver cell mass and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver disease.With recombinant TPOs in development, patients with liver disease and TPO seem to be the ideal target population for this drug. Once the efficacy of thrombopoietin in patients with liver disease is proven, a potent yet safe drug may be available to treat cirrhotic patients undergoing invasive or surgical procedures, during bleeding episodes or when undergoing therapy with myelosuppressive drugs such as interferon-alpha.

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Kuter, DJ, and RD Rosenberg. "The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit." Blood 85, no. 10 (May 15, 1995): 2720–30. http://dx.doi.org/10.1182/blood.v85.10.2720.bloodjournal85102720.

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Thrombopoietin (c-Mpl ligand) has recently been purified and is considered to be the humoral regulator of platelet production. To see whether this molecule possessed the physiologic characteristics necessary to mediate the feed-back loop between blood platelets and the bone marrow megakaryocytes, we determined the relationship between blood levels of thrombopoietin and changes in the circulating platelet mass. We developed a model of nonimmune thrombocytopenia in rabbits by the subcutaneous administration of busulfan. Compared with pretreatment plasma, plasma taken from all thrombocytopenic rabbits at their platelet nadir contained increased amounts of thrombopoietin. All of this activity was neutralized by soluble c-Mpl receptor. We subsequently measured the level of thrombopoietin in the circulation over the entire time course after the administration of busulfan. As the platelet mass declined, levels of thrombopoietin increased inversely and proportionally and peaked during the platelet nadir. With return of the platelet mass toward normal, thrombopoietin levels decreased accordingly. When platelets were transfused into thrombocytopenic rabbits near the time of their platelet count nadir, the elevated levels of thrombopoietin decreased. In addition, platelets were observed to remove thrombopoietin from thrombocytopenic plasma in vitro. These results confirm that thrombopoietin is the humoral mediator of megakaryocytopoiesis and suggest that the platelet mass may directly play a role in regulating the circulating levels of this factor.

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Journal articles on the topic 'Thrombopoietin'

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