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Journal articles on the topic 'Thrombopoiesis'

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Published: 4 June 2021

Last updated: 4 February 2022

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1

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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2

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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3

Kuter, D. J. "Thrombopoietins and Thrombopoiesis: A Clinical Perspective." Vox Sanguinis 74, S2 (June 1998): 75–85. http://dx.doi.org/10.1111/j.1423-0410.1998.tb05400.x.

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4

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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5

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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6

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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7

Kaushansky, Kenneth. "Thrombopoiesis." Seminars in Hematology 52, no. 1 (January 2015): 4–11. http://dx.doi.org/10.1053/j.seminhematol.2014.10.003.

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8

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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9

Radley, JM, and SL Ellis. "Ineffective Thrombopoiesis." Proceedings, annual meeting, Electron Microscopy Society of America 48, no. 3 (August 12, 1990): 266–67. http://dx.doi.org/10.1017/s0424820100158881.

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In effective thrombopoies is has been inferred to occur in several disease sates from considerations of megakaryocyte mass and platelet kinetics. Microscopic examination has demonstrated increased numbers of megakaryocytes, with a typical forms particularly pronounced, in primary myelofibrosis. It has not been documented if megakaryocyte ever fail to reach maturity in non-pathological situations. A major difficulty of establishing this is that the number of megakaryocytes normally present in the marrow is extremely low. A large transient increase in megakaryocytopoiesis can how ever be induced in mice by an injection of 5-fluorouracil. We have utilised this treatment and report here evidence for in effective thrombopoies is in healthy mice.Adult mice were perfused (2% glutaraldehyde in 0.08M phosphate buffer, pH 7.4) 8 days following an injection of 5-fluorouracil (150mg/kg). Femurs were subsequently decalcified in 10% neutral E.D.T.A. and embedded in Spurrs resin. Transverse sections of marrow revealed many megakaryocytes at various stages of maturity. Occasional megakaryocytes (less than 1%) were found to be under going degeneration prior to achieving full maturation and releasing cytoplasm as platelets. These cells were characterized by a peripheral rim of dense cytoplasm which enveloped a mass of organelles and vacuoles (Fig. 1). Numerous microtubules were foundaround and with in the organelle-rich zone (Fig 2).

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10

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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11

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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12

Nishimura, Satoshi, Mika Nagasaki, Shinji Kunishima, Akira Sawaguchi, Asuka Sakata, Hiroyasu Sakaguchi, Tsukasa Ohmori, et al. "IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs." Journal of Cell Biology 209, no. 3 (May 11, 2015): 453–66. http://dx.doi.org/10.1083/jcb.201410052.

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Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture–dependent thrombopoiesis and increased platelet counts. IL-1α–IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.

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13

Kirito, Keita, Masatake Osawa, Haruhiko Morita, Ritsuko Shimizu, Masayuki Yamamoto, Atsushi Oda, Hiroyoshi Fujita, et al. "A functional role of Stat3 in in vivo megakaryopoiesis." Blood 99, no. 9 (May 1, 2002): 3220–27. http://dx.doi.org/10.1182/blood.v99.9.3220.

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Abstract The signal transducer and activator of transcription 3 (Stat3), a member of the Stat family of proteins, is commonly activated by thrombopoietic cytokines including thrombopoietin (TPO), interleukin (IL)-6, and interleukin-11. This finding strongly suggested that Stat3 has an important role in megakaryopoiesis and thrombopoiesis. To clarify the functional role of Stat3 in in vivo megakaryopoiesis and thrombopoiesis, we generated transgenic mice overexpressing a dominant-negative Stat3, Stat3F, to suppress the function of endogenous Stat3. To accomplish the selective expression of Stat3F in megakaryocytic lineage cells, we used the regulatory gene region of GATA-1 transcription factor selectively expressed in megakaryocytic and erythroid lineage cells. Two independent transgenic (Tg) mice lines were established. It was confirmed by Western blotting analysis that Stat3F proteins were highly expressed in the platelets from the Tg mice. In addition, it was found that Stat3 activation induced by TPO stimulation was drastically suppressed in these Tg mice compared with littermates. These findings indicate that Stat3F works well in the Tg mice. Platelet counts were within the normal range in steady-state conditions and were recovered normally from transient thrombocytopenia induced by antiplatelet serum injection. Interestingly, the platelet recovery from myelosuppression after 5-fluorouracil treatment was significantly delayed in the Tg mice. Collectively, our results strongly suggest that Stat3 plays an important role in the early stage of megakaryopoiesis, presumably through the expansion of megakaryocytic progenitor cells.

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14

SCHULZE, H., and R. A. SHIVDASANI. "Mechanisms of thrombopoiesis." Journal of Thrombosis and Haemostasis 3, no. 8 (August 2005): 1717–24. http://dx.doi.org/10.1111/j.1538-7836.2005.01426.x.

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15

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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16

Stohlawetz, Petra, Claudia C. Folman, Albert E. G. Kr von dem Borne, Thomas Pernerstorfer, Hans-Georg Eichler, Simon Panzer, and Bernd Jilma. "Effects of Endotoxemia on Thrombopoiesis in Men." Thrombosis and Haemostasis 81, no. 04 (1999): 613–17. http://dx.doi.org/10.1055/s-0037-1614534.

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Summary Background. Febrile conditions are often associated with increased platelet turnover and refractoriness to platelet transfusions, although several pyrogenic cytokines enhance thrombopoiesis. This study aimed to characterize the effects of experimental human endotoxemia on platelet turnover and thrombopoiesis. Methods. Endotoxin (4 ng/kg) was infused into 30 healthy men to study the regulation of thrombopoiesis in systemic human inflammation. Platelet counts, plasma thrombopoietin (TPO) and glycocalicin levels, and reticulated platelets (RP) were measured to evaluate the effect of acute endotoxemia on thrombopoiesis. Ten subjects received pretreatment with 1000 mg aspirin po. to evaluate possible effects of aspirin on platelet turnover, and ten subjects received paracetamol to control for effects of anti-pyresis. Results. Platelet counts dropped by about 15% (p <0.001) one hour after LPS infusion, began to recover at 24 h, and exceeded baseline values by 8% (CI: 5-12; p <0.001) at 7 days after LPS iv. Reticulated platelet counts increased from 1.62% (CI: 1.24-2.0) to a maximum of 2.39% (CI: 1.81-2.98; p = 0.003) at 6 h. TPO levels increased from baseline values of 10 A.U/ml (CI: 8.8-11.2) to 15.5 A.U/ml (CI: 13.6-17.3) at 24 h (p <0.001), whereas plasma glycocalicin was not changed (p >0.05). The number of circulating platelet-neutrophil aggregates increased more than 100% at 6 h (p <0.001). Neither aspirin nor paracetamol affected changes in any of the parameters measured. Conclusion. Low grade endotoxemia induces a rapid fall of platelet counts, which is followed by an early increase in reticulated platelets and TPO levels but not of glycocalicin levels. Finally peripheral platelet counts increase several days after LPS infusion.

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17

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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18

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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19

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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20

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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21

Groopman, Jerome E. "Thrombopoiesis: Capturing the unicorn." Current Biology 4, no. 11 (November 1994): 1016–18. http://dx.doi.org/10.1016/s0960-9822(00)00230-x.

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22

Despotovic, Jenny M., and Russell E. Ware. "Thrombopoiesis: new ITP paradigm?" Blood 118, no. 1 (July 7, 2011): 1–2. http://dx.doi.org/10.1182/blood-2011-05-351700.

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23

Tripathi, Preeti, Arijit Sen, and H. P. Pati. "Thrombopoiesis: At a Glance!" Indian Journal of Hematology and Blood Transfusion 36, no. 3 (January 8, 2020): 599. http://dx.doi.org/10.1007/s12288-019-01251-1.

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24

Cantor, Alan B., Hui Huang, Andrew Woo, James Mann, Ming Yu, Thomas Akie, Nathan Tu, and Barry H. Paw. "Transcriptional Regulation of Thrombopoiesis." Blood 112, no. 11 (November 16, 2008): sci—38—sci—38. http://dx.doi.org/10.1182/blood.v112.11.sci-38.sci-38.

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Abstract Over the past two decades, a number of key transcription factors have been identified that play essential roles in megakaryocyte development. These include GATA-1, GATA-2, Friend of GATA-1 (FOG-1), Runx-1, Cbf-β, Fli-1, GABPα, TEL, NF-E2 p45, Gfi-1b, and SCL/TAL. Importantly, mutations in genes encoding several of these have been linked to human disorders of thrombopoieisis. Germline GATA-1 mutations that disrupt binding to FOG-1 cause X-linked macrothrombocytopenia and dyserythropoietic anemia. Acquired GATA-1 mutations that lead to exclusive production of a short isoform (GATA-1s) play initiating roles in Down Syndrome Transient Myeloproliferative Disorder (DS-TMD) and subsequent Acute Megakaryoblastic Leukemia (DS-AMKL). Haploinsufficiency of Runx-1 causes Familial Platelet Disorder with Propensity to Develop AML (FPD/ AML). Heterozygous loss of the Fli-1 gene leads to the macrothrombocytopenia seen in Jacobsen’s (Paris-Trousseau) syndrome. Important outstanding questions include: how these transcription factors act together to control megakaryocyte terminal maturation; how they differentially act as activators or repressors depending on gene context; how they intersect with cell signaling pathways; how they may coordinate terminal megakaryocyte maturation with spatial location within the bone marrow; how they may control cell fate decisions of bipotential erythroid/megakaryocytic progenitor cells; and whether additional key transcription factors exist. Application of proteomic approaches involving multi-protein complex purification has provided novel insights into some of these questions. We have isolated GATA-1 containing complexes from megakaryocytic cells and identified the Krüppel-type zinc finger transcription factor ZBP-89 as a novel regulator of megakaryocyte and erythroid development. Knockdown of ZBP-89 expression in zebrafish embryos and mice results in blocked early megakaryopoiesis and definitive erythropoiesis, phenocopying aspects of GATA-1- and FOG-1-deficient animals. We have also found that the focal adhesion component Kindlin-3 co-localizes to the nucleus and interacts with FOG-1, suggesting a possible link between integrin signaling and megakaryocyte transcriptional control. Runx-1 multi-protein complex purifications have led to the identification of Fli-1 as a direct binding partner. This interaction results in synergistic transcriptional activation of megakaryocyte-specific genes. Interestingly, the interaction between Runx-1 and Fli-1 occurs preferentially in cells that are differentiating, even though both proteins are expressed abundantly in undifferentiated megakaryoblastic cells. This binding event correlates with assembly of a large complex containing Runx-1/ Fli-1/GATA-1/FOG-1 based on gel filtration chromatography experiments. These factors may, therefore, act as a megakaryocyte-specific enhancesome. Key future directions are aimed at elucidating the molecular mechanisms that regulate these protein-protein interactions and how cell signaling pathways may modulate them.

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Pallotta, Isabella, Michael L. Lovett, David L. Kaplan, and Alessandra Balduini. "3D Model of Thrombopoiesis." Blood 116, no. 21 (November 19, 2010): 1609. http://dx.doi.org/10.1182/blood.v116.21.1609.1609.

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Abstract Abstract 1609 Background. The mechanisms that regulate megakaryocytic (Mk) development within the bone marrow environment remain poorly understood. The underlying relationships between Mk maturation and bone marrow components are key factors in this process. Mk development occurs in a complex microenvironment where extracellular matrices are fundamental regulatory components. The first events occur in the osteoblastic niche and include commitment of the hemopoietic progenitor cell to Mk, arrest of proliferation and initiation of endomitosis. The second step is Mk maturation and is associated with rapid cytoplasm expansion and intense synthesis of proteins. Finally Mks, which migrate to the vascular niche, convert the bulk of their cytoplasm into multiple long processes called proplatelets that protrude through the vascular endothelium into the sinusoid lumen, where the platelets are released. Hypothesis. The hypothesis for the present work is that a complex in vitro 3D bone marrow-like environment can be used to gain fundamental mechanistic insight into cell signalling and matrix-cell interactions in the bone marrow niche related to Mk development. Methods. We propose the first 3D model for Mk function in the bone marrow environment, by refining a recently proposed bioreactor platform (Lovett et al., 2007). These bioreactors consist of 3 wells (10 mm × 15 mm × 5 mm) within a PDMS block (25 mm × 60 mm × 5 mm) which is plasma bonded to cover glass for imaging. Each bioreactor well was perfused by 23 G stainless steel needles, spanned by porous silk microtubes as blood vessel scaffolds (640 μm inner diameter), positioned approximately 500–750 μm from the bottom of the bioreactor and connected to tubing for media perfusion using a programmable syringe pump. These microtubes were prepared by dipping several times straight lengths of stainless steel wire into 10–14% (w/v) aqueous silk fibroin to obtain blood vessel scaffolds with a wall thickness of around 50 mm. Defined pore sizes of 6–8 μm were obtained by adding 6 w/t % poly(ethylene oxide) (PEO) to the silk fibroin. The perfused silk tubes comprised the vascular niche and were embedded within a cell-seeded hydrogel which comprises the osteoblastic niche. The silk microtubes were coated with a combination of fibrinogen, von Willebrand Factor, type IV collagen and SDF-1 alpha, to better establish the composition of the vascular niche. Control experiments were performed by coating silk microtubes with type I collagen. After staining human umbilical cord blood derived Mks, the cell suspension was added to the hydrogel and Mk migration was analyzed in a time-dependent manner using confocal microscopy analysis. Further, flow effluent through the vascular tubes in the bioreactor was collected at regular time intervals and platelet numbers and function were analyzed by flow cytometry and microscopy. Culture released platelets were counted as CD61+ events with the same scatter properties of human blood platelets. Results. Our results showed that Mks migrated towards the vascular microtube coated with Fibrinogen, von Willebrand Factor, type IV collagen and SDF-1. Mks were also able to complete their maturation in the proximity of the microtube by extending proplatelets. Interestingly, confocal microscopy analysis revealed that Mks were able to extend proplatelets through the vascular microtube wall and release CD61+ platelet-like particles inside the vascular microtube. Cytofluorimentric analysis demonstrated that the particles collected in the flow effluent of the vascular microtube were CD61+ cells with the same scatter properties of human peripheral blood platelets. Finally, upon coating with only type I collagen Mks did not migrate towards the vascular microtube or extend proplatelets to release platelets. Thus, by mimicking the relationship between Mks and the bone marrow environment, a model to reproduce the different steps of Mk development, such as Mk migration, proplatelet formation and platelet release, is established. This is a first significant step towards relevant systems for the study of these cellular processes in detail as well as toward potentially useful in vitro platelet production systems. Conclusions. In this work we developed a new 3D bone marrow system in vitro that could represent a new tool to understand the mechanistic basis for Mk development and function, and the diseases related to these cells. Disclosures: No relevant conflicts of interest to declare.

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26

Eller, J., I. Györi, M. Zöllei, and F. Krizsa. "Modelling thrombopoiesis regulation—I." Computers & Mathematics with Applications 14, no. 9-12 (1987): 841–48. http://dx.doi.org/10.1016/0898-1221(87)90233-1.

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27

Györi, I., and J. Eller. "Modelling thrombopoiesis regulation—II." Computers & Mathematics with Applications 14, no. 9-12 (1987): 849–59. http://dx.doi.org/10.1016/0898-1221(87)90234-3.

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Soehnlein, Oliver. "The ABC of Thrombopoiesis." Arteriosclerosis, Thrombosis, and Vascular Biology 34, no. 4 (April 2014): 700–701. http://dx.doi.org/10.1161/atvbaha.114.303365.

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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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30

Barsam, Sarah J., Bethan Psaila, Marc Forestier, Lemke K. Page, Peter A. Sloane, Julia T. Geyer, Glynis O. Villarica, et al. "Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia." Blood 117, no. 21 (May 26, 2011): 5723–32. http://dx.doi.org/10.1182/blood-2010-11-321398.

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Abstract This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 109/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r2 = −0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.

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31

Hacein-Bey-Abina, Salima, Machadiya Estienne, Stéphanie Bessoles, Hamid Echchakir, Magali Pederzoli-Ribeil, Andrada Chiron, Lydia Aldaz-Carroll, et al. "Erythropoietin is a major regulator of thrombopoiesis in thrombopoietin-dependent and -independent contexts." Experimental Hematology 88 (August 2020): 15–27. http://dx.doi.org/10.1016/j.exphem.2020.07.006.

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32

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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33

Thompson, Cheryl A. "FDA approves thrombopoiesis-stimulating agent." American Journal of Health-System Pharmacy 65, no. 19 (October 1, 2008): 1788. http://dx.doi.org/10.2146/news080078.

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34

&NA;. "Interleukin-6 may stimulate thrombopoiesis." Inpharma Weekly &NA;, no. 1182 (April 1999): 10. http://dx.doi.org/10.2165/00128413-199911820-00015.

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35

Stiegler, Gabriele, Petra Stohlawetz, Stefan Brugger, Bernd Jilma, Heinrich Vierhapper, Paul Höcker, and Simon Panzer. "Thrombopoiesis Is Increased in Hyperthyroidisme." Journal of Clinical Endocrinology & Metabolism 83, no. 5 (May 1998): 1823. http://dx.doi.org/10.1210/jcem.83.5.4821-5.

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36

Levine, Richard F., Jerry L. Spivak, Richard C. Meagher, and Fritz Sieber. "Effect of ethanol on thrombopoiesis." British Journal of Haematology 62, no. 2 (February 1986): 345–54. http://dx.doi.org/10.1111/j.1365-2141.1986.tb02938.x.

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37

Zhang, Bing, and James L. Zehnder. "ROS: novel regulators of thrombopoiesis." Blood 128, no. 5 (August 4, 2016): 613–14. http://dx.doi.org/10.1182/blood-2016-06-718544.

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38

Ertenli, İhsan, Sedat Kiraz, M. Akif Öztürk, İbrahim C. Haznedaroğlu, İsmail Çelik, and Meral Çalgüneri. "Pathologic thrombopoiesis of rheumatoid arthritis." Rheumatology International 23, no. 2 (February 11, 2003): 49–60. http://dx.doi.org/10.1007/s00296-003-0289-0.

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39

Geissler, K., P. Valent, P. Bettelheim, C. Sillaber, B. Wagner, P. Kyrle, W. Hinterberger, K. Lechner, E. Liehl, and P. Mayer. "In vivo synergism of recombinant human interleukin-3 and recombinant human interleukin-6 on thrombopoiesis in primates." Blood 79, no. 5 (March 1, 1992): 1155–60. http://dx.doi.org/10.1182/blood.v79.5.1155.1155.

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Abstract Using a primate model, we examined the effect of recombinant human interleukin-3 (rhIL-3) and rhIL-6 on thrombopoiesis in vivo. Administration of 33 micrograms/kg/d of rhIL-3 for 11 to 14 days increased levels of circulating colony-forming units megakaryocyte (CFU- Mk) by approximately 15-fold in five rhesus monkeys without raising their platelet counts. In contrast, administration of 30 micrograms/kg/d of rhIL-6 for 10 days in four animals did not increase CFU-Mk levels but significantly raised platelet counts from a mean pretreatment value of 460 x 10(3)/microL (range 360 to 610) to a mean maximum of 746 x 10(3)/microL (665 to 790) on day 8. If monkeys were pretreated with rhIL-3 (33 or 100 micrograms/kg/d for 11 days) to expand their CFU-Mk compartment, the thrombopoietic effect of rhIL-6 was synergistically enhanced leading to platelet counts above 1,000 x 10(3)/microL (mean maximum value 1,247) in all three primates studied. The sequential administration of rhIL-3 and rhIL-6 might represent a powerful strategy to stimulate thrombopoiesis in vivo.

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40

Geissler, K., P. Valent, P. Bettelheim, C. Sillaber, B. Wagner, P. Kyrle, W. Hinterberger, K. Lechner, E. Liehl, and P. Mayer. "In vivo synergism of recombinant human interleukin-3 and recombinant human interleukin-6 on thrombopoiesis in primates." Blood 79, no. 5 (March 1, 1992): 1155–60. http://dx.doi.org/10.1182/blood.v79.5.1155.bloodjournal7951155.

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Using a primate model, we examined the effect of recombinant human interleukin-3 (rhIL-3) and rhIL-6 on thrombopoiesis in vivo. Administration of 33 micrograms/kg/d of rhIL-3 for 11 to 14 days increased levels of circulating colony-forming units megakaryocyte (CFU- Mk) by approximately 15-fold in five rhesus monkeys without raising their platelet counts. In contrast, administration of 30 micrograms/kg/d of rhIL-6 for 10 days in four animals did not increase CFU-Mk levels but significantly raised platelet counts from a mean pretreatment value of 460 x 10(3)/microL (range 360 to 610) to a mean maximum of 746 x 10(3)/microL (665 to 790) on day 8. If monkeys were pretreated with rhIL-3 (33 or 100 micrograms/kg/d for 11 days) to expand their CFU-Mk compartment, the thrombopoietic effect of rhIL-6 was synergistically enhanced leading to platelet counts above 1,000 x 10(3)/microL (mean maximum value 1,247) in all three primates studied. The sequential administration of rhIL-3 and rhIL-6 might represent a powerful strategy to stimulate thrombopoiesis in vivo.

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41

Poirault-Chassac, Sonia, Valérie Nivet-Antoine, Amandine Houvert, Alexandre Kauskot, Evelyne Lauret, René Lai-Kuen, Isabelle Dusanter-Fourt, and Dominique Baruch. "Mitochondrial dynamics and reactive oxygen species initiate thrombopoiesis from mature megakaryocytes." Blood Advances 5, no. 6 (March 15, 2021): 1706–18. http://dx.doi.org/10.1182/bloodadvances.2020002847.

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Abstract Blood platelets are essential for controlling hemostasis. They are released by megakaryocytes (MKs) located in the bone marrow, upon extension of cytoplasmic protrusions into the lumen of bone marrow sinusoids. Their number increases in postpulmonary capillaries, suggesting a role for oxygen gradient in thrombopoiesis (ie, platelet biogenesis). In this study, we show that initiation of thrombopoiesis from human mature MKs was enhanced under hyperoxia or during pro-oxidant treatments, whereas antioxidants dampened it. Quenching mitochondrial reactive oxygen species (mtROS) with MitoTEMPO decreased thrombopoiesis, whereas genetically enhancing mtROS by deacetylation-null sirtuin-3 expression increased it. Blocking cytosolic ROS production by NOX inhibitors had no impact. Classification according to the cell roundness index delineated 3 stages of thrombopoiesis in mature MKs. Early-stage round MKs exhibited the highest index, which correlated with low mtROS levels, a mitochondrial tubular network, and the mitochondrial recruitment of the fission activator Drp1. Intermediate MKs at the onset of thrombopoiesis showed high mtROS levels and small, well-delineated mitochondria. Terminal MKs showed the lowest roundness index and long proplatelet extensions. Inhibiting Drp1-dependent mitochondrial fission of mature MKs by Mdivi-1 favored a tubular mitochondrial network and lowered both mtROS levels and intermediate MKs proportion, whereas enhancing Drp1 activity genetically had opposite effects. Reciprocally, quenching mtROS limited mitochondrial fission in round MKs. These data demonstrate a functional coupling between ROS and mitochondrial fission in MKs, which is crucial for the onset of thrombopoiesis. They provide new molecular cues that control initiation of platelet biogenesis and may help elucidate some unexplained thrombocytopenia.

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42

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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43

Do, Minh-Ha T., Wei Zhang, Kyle Chiang, Chi-Fang Wu, Chulho Park, Quansheng Zhou, My-Nuong Vo, et al. "Novel Protein Agonist of Thrombopoiesis Acts Via a Physiocrine Pathway Distinct From That of Thrombopoietin." Blood 118, no. 21 (November 18, 2011): 2376. http://dx.doi.org/10.1182/blood.v118.21.2376.2376.

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Abstract Abstract 2376 Thrombopoietin (TPO) is recognized as the main regulator of platelet production, yet its genetic ablation in mice does not completely obliterate thrombopoiesis, suggesting that alternate pathways could lead to platelet formation. We recently identified a naturally-occurring protein that acts as a potent agonist of platelet production by a mechanism distinct from that of TPO. This protein belongs to a novel class of human extracellular signaling proteins called physiocrines that are generated from tRNA synthetases by alternative splicing or proteolysis. Physiocrines interact with several classes of receptors through unique mechanisms to modulate cellular differentiation and tissue homeostasis in normal and pathological processes. The newly identified thrombopoietic physiocrine, termed ATYR0030, is an engineered version of a naturally-occurring physiocrine derived from the tyrosyl tRNA synthetase (YRS). In vivo, systemic administration of ATYR0030 or YRS physiocrine to rats led to an increase in platelets counts comparable to that seen with TPO treatment, but with a greater effect in animals with low baseline platelet levels. When injected into normal animals preselected for low platelet counts, ATYR0030 treatment resulted in an increase in platelets up to, but not beyond, normal levels (Figure 1), suggesting a role in platelet homeostasis and differentiating its effects from the known activity of TPO. Intravenous administration of ATYR0030 also accelerated recovery of platelet counts in carboplatin-treated rats, indicating a possible role in bone marrow reconstitution after chemical insult. Consistent with homeostatic properties, no toxicity was seen in a repeat-dose 28-day non-GLP safety study in rats dosed up to 100-fold above the efficacious range. Histopathology assessment revealed no tissue abnormalities, no increase in bone marrow reticulin and no hyperplasia of myeloid precursors. Clinical chemistry and hematology parameters were in the normal range with a modest increase in platelet counts, as anticipated in animals with normal platelet levels. Our in vitro data suggest that ATYR0030 may play a role in megakaryopoiesis by facilitating cell migration and adhesion to the vasculature. In contrast to TPO, ATYR0030 does not directly signal through the TPO receptor and does not activate the JAK/STAT pathway but rather appears to engage specific G-protein coupled receptors. In vitro, ATYR0030 does not stimulate proliferation of cultured M07e human megakaryoblasts or primary bone marrow cells isolated from AML patients (Figure 2). The parent synthetase is present in human platelets and is secreted in response to platelet activation, perhaps providing a feedback mechanism to stimulate the release of new platelets. In an effort to link the biological activity of ATYR0030 and the role that the parent synthetase plays in human physiology, we have begun to analyze samples from patients with abnormal platelets counts to determine circulating levels of the parent synthetase. The unique thrombopoietic activity of ATYR0030 may lead to an orthogonal approach to restoring normal platelet levels in thrombocytopenic patients who currently have limited treatment options. For example, in the myelodysplastic syndrome population, TPO-receptor agonists carry a risk of stimulating blast proliferation and accelerating disease progression to acute myeloid leukemia (AML). The distinct proliferation profile of ATYR0030 may translate into important safety benefits by reducing the risk of progression to AML. In addition, the potential role of ATYR0030 in regulating platelet homeostasis may provide a greater safety margin in the normalization of platelet levels, thereby also limiting the risk of thrombosis. Leveraging the therapeutic potential of this thrombopoietic physiocrine may lead to the development of a novel treatment option with a favorable safety profile. Disclosures: Do: aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Zhang:aTyr Pharma: Employment, Equity Ownership. Chiang:aTyr Pharma: Employment, Equity Ownership. Wu:aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Park:aTyr Pharma: Equity Ownership. Yang:aTyr Pharma: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Kunkel:aTyr Pharma: Consultancy, Stock Ownership. Ashlock:aTyr Pharma: Employment, Equity Ownership. Mendlein:aTyr Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Belani:Atyr Pahrma: Consultancy, Equity Ownership, Patents & Royalties. Vasserot:aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Watkins:aTyr Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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44

Murai, Kazunori, Shugo Kowata, Yasuhiko Tsukushi, Mamiko Ishiguro, Tatsuo Oyake, Takeshi Sugawara, and Yoji Ishida. "Thrombocytopoiesis Is Not Regulated by Thrombopoietin (TPO) but Proplatelet Formation (PPF) Stimulating Factor." Blood 108, no. 11 (November 16, 2006): 1112. http://dx.doi.org/10.1182/blood.v108.11.1112.1112.

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Abstract TPO is believed to be the physiological humoral hematopoietic factor in megakaryopoiesis and thrombopoiesis. Some investigators reported the inverted relationship between platelet mass and serum TPO levels, resulting in the conclusion that the platelet mass may directly play a role of regulating the circulating TPO levels. In the previous ASH meeting, we reported that serum TPO levels were not elevated in Immune thrombocytopenic purpura (ITP) patients. In this study, we measured platelet count, the serum TPO level, % reticulated platelet (%RP) and megakaryocytes mass in patients with refractory anemia in myelodysplastic syndrome (MDS-RCMD). The mean plasma TPO level in 20 healthy persons was 57.3±15.2 pg/ ml, the percentage of RPs was 1.51±0.71%. Plasma TPO levels were widely distributed (799.9±883.0 pg/ ml, n=35) in MDS-RCMD, while they were less than 131.0 pg/ml in ITP (48.5±37.0 pg/ ml, n=37). There were no significant relationship between platelet counts and plasma TPO levels in MDS-RCMD or ITP. These results indicated that plasma TPO level was not regulated by the platelet mass at least in thrombocytopenic patient with MDS-RCMD or ITP. We evaluated the thrombopoiesis in thrombocytopenic patients with MDS-RCMD or ITP. %RPs were 1.9±0.2 % in MDS-RCMD (n=34), indicating that increased thrombopoiesis was not observed in MDS-RCMD, in which serum TPO levels were increased. While %RPs were 6.6±4.9 % in ITP (n=45), indicating that thrombopoiesis was observed in ITP, in which serum TPO levels were not increased. These results indicated that thrombopoiesis was not regulated by plasma TPO levels but some thrombopoiesis stimulating factor(s). Therefore, we evaluated the thrombopoiesis stimulating activity in plasma of patients with MDS-RCMD or ITP as the indicator of PPF stimulating activity of murine megakaryocytes. PPF stimulating activity was measured as the ratio of PPF bearing megakaryocytes/ viable megakaryocytes after 48 hrs serum-free culture of murine megakaryocytes. As the plasma have some inhibitory effects of PPF activiy, the HDL fraction, isolated from plasma, was used as the methods described previously in Ishida Y et al. (Thrombosis and Haemostasis, 2001; 85:349–55). The higher PPF stimulating activity was observed in patients with ITP (n=15) or MDS-RCMD (n=15) than that with healthy donors (n=10) {healthy donors 26.1±5.4 % versus ITP 38.0± 6.0% (p<0.01), MDS-RCMD 41.9±5.3%(p<0.01)}. There was a significant correlation between the PPF activity and platelet counts (R=0.68; p<0.01) in these thrombopenic patients. These data strongly suggest that thrombopoiesis may not be regulated by TPO but some PPF stimulating factor(s).

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45

Kostyak, John C., and Ulhas P. Naik. "Dual Role for CIB1 in Thrombopoiesis: CIB1 Suppresses Megakaryocyte Quantities but Supports Adhesion, Migration, and Proplatelet Formation." Blood 118, no. 21 (November 18, 2011): 2384. http://dx.doi.org/10.1182/blood.v118.21.2384.2384.

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Abstract Abstract 2384 Megakaryocytes (MKs) are large polyploid cells that produce platelets through a process known as thrombopoiesis. Thrombopoietin (Tpo) is the major cytokine that regulates a variety of steps in this process, including hematopoietic stem cell (HSC) differentiation to MKs, proplatelet formation, and platelet release into the circulation. However, the molecular mechanism of thrombopoiesis is poorly understood. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in thrombopoiesis, we utilized a Cib1−/− mouse model. We observed that Cib1−/− mice have a slightly elevated number of platelets and bone marrow (BM)-derived MKs than wild-type (WT) controls (p<0.05). Rate of platelet clearance was comparable in Cib1−/− and WT mice, suggesting that the defective clearance is not the cause of the observed elevated platelet number. In order to determine if the HSC differentiation is dysregulated by the ablation of Cib1, we analyzed MK-colony forming unit production, which revealed an increase in the colony forming cells with Cib1 deletion compared to WT (p<0.05). Additionally, BM from Cib1−/− mice, cultured with Tpo for 24 hours, produced more highly polyploid MKs than WT BM (p<0.05). These results suggest that Cib1 may negatively regulate initial steps of megakaryopoiesis. Subsequent analysis of Tpo signaling revealed that activation of FAK, a known suppresser of Tpo signaling, is attenuated, as indicated by reduced FAKY925 phosphorylation in Cib1−/− BM-derived MKs treated with Tpo. Consequently, Akt and ERK1/2 activation downstream of Tpo was enhanced. These results suggested that Cib1 inhibits Tpo signaling by augmenting FAK activation. Interestingly, platelet recovery in Cib1−/− mice following platelet depletion by experimental immunothrombocytopenia was attenuated compared to WT (p<0.05). This could be due to impaired adhesion and migration of MKs on the extracellular matrix. Consistent with this notion, adhesion to fibrinogen and fibronectin and migration towards an SDF-1α gradient were significantly reduced in Cib1−/− MKs compared to WT (p<0.05). Additionally, Cib1−/− MKs formed fewer proplatelets compared to WT (p<0.05), when plated on fibrinogen. These data suggest that CIB1 plays a dual role in thrombopoiesis, initially by negatively regulating Tpo signaling, and later by supporting MK migration and proplatelet production. Disclosures: No relevant conflicts of interest to declare.

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46

Perreault, Sarah, and Julianna Burzynski. "Romiplostim: A novel thrombopoiesis-stimulating agent." American Journal of Health-System Pharmacy 66, no. 9 (May 1, 2009): 817–24. http://dx.doi.org/10.2146/ajhp080524.

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47

FUJITA, Rie, Hozumi MOTOHASHI, and Masayuki YAMAMOTO. "Transcriptional regulation of megakaryopoiesis and thrombopoiesis." Japanese Journal of Thrombosis and Hemostasis 23, no. 6 (2012): 539–43. http://dx.doi.org/10.2491/jjsth.23.539.

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48

SAKATA, Asuka, and Satoshi NISHIMURA. "Imaging for thrombopoiesis and thrombus formation." Japanese Journal of Thrombosis and Hemostasis 27, no. 5 (2016): 526–31. http://dx.doi.org/10.2491/jjsth.27.526.

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49

Brierley, Charlotte K., and David P. Steensma. "Thrombopoiesis-stimulating agents and myelodysplastic syndromes." British Journal of Haematology 169, no. 3 (February 6, 2015): 309–23. http://dx.doi.org/10.1111/bjh.13285.

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50

Kaushansky, K. "The molecular mechanisms that control thrombopoiesis." Journal of Clinical Investigation 115, no. 12 (December 1, 2005): 3339–47. http://dx.doi.org/10.1172/jci26674.

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