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Kenneth Kaushansky
Thrombopoietin was posited to exist in 1958 and cloned in 1994, and in the ensuing two decades we have learned a great deal about the physiology and pathology of the primary regulator of thrombopoiesis. This paper will review the role of the hormone and its receptor, the product of the c-Mpl proto-oncogene, in health and disease, including many unexpected effects in both normal and neoplastic hematopoiesis. Amongst these unexpected properties are a non-redundant effect on hematopoietic stem cells, a critical role in all three of the acquired, chronic myeloproliferative neoplasms, as well as both gain-of-function and loss-of-function mutations in congenital and acquired states of thrombocytopenia and thrombocythemia...
2016: Thrombosis Journal
C Du, Y Xu, K Yang, S Chen, X Wang, S Wang, C Wang, M Shen, F Chen, M Chen, D Zeng, F Li, T Wang, F Wang, J Zhao, G Ai, T Cheng, Y Su, J Wang
Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte differentiation and its deficiency will lead to megakaryoblastic leukemia. Here, we show that estrogen can dose-dependently promote megakaryocyte polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant up-regulation of GATA1...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
K-H Lim, Y-C Chang, Y-H Chiang, H-C Lin, C-Y Chang, C-S Lin, L Huang, W-T Wang, C Gon-Shen Chen, W-C Chou, Y-Y Kuo
CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b...
October 7, 2016: Blood Cancer Journal
Y Jamilloux, E Bourdonnay, M Gerfaud-Valentin, B F Py, L Lefeuvre, T Barba, C Broussolle, T Henry, P Sève
Interleukin-1 is a major cytokine of innate immunity and inflammation. It exerts various systemic effects during the inflammatory response, such as fever induction, thrombopoiesis and granulopoiesis, or leukocyte recruitment. Its involvement has been demonstrated in many inflammatory-mediated diseases, such as diabetes or gout. Moreover, interleukin-1 plays a pivotal role in some autoinflammatory diseases, such as cryopyrinopathies or familial Mediterranean fever. In these diseases, a constitutional defect of the inflammasome, a protein complex responsible for the activation of interleukin-1, explains the hypersecretion of interleukin-1...
September 14, 2016: La Revue de Médecine Interne
Wasiluk Alicja, Polewko Agnieszka, Laudanski Piotr, Redzko Slawomir, Kicel-Wesolowska Barbara, Dabrowska Milena, Milewski Robert
BACKGROUND: The current study objective was to compare blood platelet indices in late preterm newborns (LPN) and full term newborns (FTN). MATERIALS AND METHODS: We recruited 58 LPN and 71 FTN. Platelet indices were estimated in blood samples collected from the umbilical artery. RESULTS: LPN demonstrated a decreased count of blood platelets (249 × 10³/μL) as compared to FTN (295 × 10³/μL), p < 0.001. Platelet hematocrit (PCT) also showed substantial differences in both groups (LPN = 0...
October 6, 2016: Journal of Maternal-fetal & Neonatal Medicine
P J Vinholt, A M Hvas, H Frederiksen, L Bathum, M K Jørgensen, M Nybo
INTRODUCTION: Platelet count is used to determine bleeding risk and monitoring thrombopoiesis. While abnormal platelet counts are associated with mortality and morbidity, it is unclear whether it also apply to platelet counts within reference range. We investigated the relationship between platelet count (100-450×10(9)/L) and mortality, development of future cardiovascular disease (myocardial infarction, ischaemic stroke, or peripheral vascular disease), venous thromboembolism, bleeding or cancer in the general population...
August 20, 2016: Thrombosis Research
Qi Wang, Tao You, Hongqiong Fan, Yinyan Wang, Tinatian Chu, Mortimer Poncz, Li Zhu
Autophagy is an effective strategy for cell development by recycling cytoplasmic constituents. Genetic deletion of autophagy mediator Atg7 in hematopoietic stem cells (HSCs) can lead to failure of megakaryopoiesis and enhanced autophagy has been implicated in various hematological disorders such as immune thrombocytopenia and myelodysplastic syndrome. Here, we examined the hypothesis that optimal autophagy is essential for megakaryopoiesis and thrombopoiesis by altering autophagy using pharmacological approaches...
August 18, 2016: Platelets
Christian A Di Buduo, Manuela Currao, Alessandro Pecci, David L Kaplan, Carlo L Balduini, Alessandra Balduini
Eltrombopag is a small non-peptide thrombopoietin mimetic that has been approved for increasing platelet count not only in immune thrombocytopenia and HCV-related thrombocytopenia, but also in aplastic anemia. Moreover, this drug is under investigation for increasing platelet count in myelodysplastic syndromes. Despite current clinical practice, the mechanisms governing Eltrombopag's impact on human hematopoiesis are largely unknown in part due to the impossibility of using traditional in vivo models. To investigate Eltrombopag's impact on megakaryocyte functions, we employed our established in vitro model for studying hematopoietic stem cell differentiation combined with our latest 3D silk-based bone marrow tissue model...
August 11, 2016: Haematologica
Ayano Yurino, Katsuto Takenaka, Takuji Yamauchi, Takuya Nunomura, Yasufumi Uehara, Fumiaki Jinnouchi, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Toshihiro Miyamoto, Hiromi Iwasaki, Yuya Kunisaki, Koichi Akashi
In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice...
September 13, 2016: Stem Cell Reports
Bing Zhang, James L Zehnder
No abstract text is available yet for this article.
August 4, 2016: Blood
B Pedersen
During the least 10 years a growing number of case reports arid small patient series have demonstrated an association between certain structural changes of the q arm of chromosom'e no. 3 (insertion, inversion, translocation (3; 3) or translocation with other chromosomes) and signs of increased platelet production and morphologic megakaryocyte abnormalitieis. Analysis of published data on 64 such patients now demonstrate that rearrangements between the two chromosomes 3 are associated with significantly higher platelet counts and higher frequencies of megakaryocytes in the marrow than are translocations between no...
1990: Leukemia & Lymphoma
Dana E Oellers, Natali Bauer, Melanie Ginder, Sigrid Johannes, Iris Pernecker, Andreas Moritz
BACKGROUND: Canine reticulated platelets (r-PLTs) i.e., juvenile PLTs reflecting thrombopoiesis can be measured automatically with the hematology analyzer Sysmex XT-2000iV using manual gating options. However, the impact of interferences on r-PLT measurements performed with the gates published previously (Pankraz et al., Vet Clin Path 38:30-38, 2009; Gelain et al., High fluorescent platelets fraction in macrothrombocytopenic Norfolk terrier, 2010) is largely unknown. The aim was to compare different published gates for measurement of r-PLTs with the Sysmex XT-2000iV with an own, optimized gate ("Oellers-gate") and to establish reference intervals (RIs) in > 120 dogs...
2016: BMC Veterinary Research
M Dominis, D Ivanković, V Kuŝec, R Kuŝec, S Dẑebro
In a group of 102 patients with myelodysplastic syndrome an evaluation of bone marrow biopsy was performed in order to assess prognostic impact on survival. The following characteristics were included in the analysis: cellularity, erythropoiesis, granulopoiesis, thrombopoiesis, lymphatic nodules, mastocytes, dyserythropoiesis, dysgranulopoiesis, dysthrombopoiesis, blasts, atypical localisation of immature precursor cells, fibrosis, osteoblasts and osteoclasts on bone surfaces. Data were statistically analysed by stepwise Cox proportional hazards regression...
1998: Hematology (Amsterdam, Netherlands)
Aaron C Petrey, Dana R Obery, Sean P Kessler, Bruno Flamion, Carol A de la Motte
Hyaluronan is the predominant glycosaminoglycan component of the extracellular matrix with an emerging role in hematopoiesis. Modulation of hyaluronan polymer size is responsible for its control over cellular functions, and the balance of hyaluronan synthesis and degradation determines its molecular size. Although two active somatic hyaluronidases are expressed in mammals, only deficiency in hyaluronidase-2 (Hyal-2) results in thrombocytopenia of unknown mechanism. Our results reveal that Hyal-2 knockout mice accumulate hyaluronan within their bone marrow and within megakaryocytes, the cells responsible for platelet generation...
September 2016: American Journal of Pathology
Cih-En Huang, Yi-Yang Chen, Jung-Jung Chang, Feng-Che Kuan, Kuan-Der Lee, Chang-Hsien Lu, Jrhau Lung, Chien-Heng Shen, Chih-Cheng Chen
OBJECTIVES: Complex and multiple mechanisms are involved in the etiology of Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP). Many hematopoietic growth factors affect the thrombopoiesis. The aim of this study was to clarify the interaction of the thrombopoietic factors in patients with HCV-ITP. METHODS: We selected 33 patients with HCV-ITP and 17 normal individuals. We compare serum interleukin (IL)-3, IL-6, IL-11, thrombopoietin (Tpo), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-α (TNFα), and spleen size between these two groups...
July 9, 2016: Hematology (Amsterdam, Netherlands)
Biao Wang, Jiansheng Zheng
Platelet (PLT) transfusion, which is the primary cell therapy for thrombocytopenia, has been a source of concern in recent years due to its limitations of donor-dependent supply and soaring costs. In vitro platelet generation on an industrial scale is a possible solution requiring exploration. The technology of platelet generation ex vivo has been widely studied across the world, though the mechanisms of physiological thrombopoiesis and platelet biology function in vivo still remain elusive today. Various culture systems have been studied, most of which proved quite inefficient in generating functional platelets ex vivo, so there is still a long way to reach our ultimate goal of generating a fully functional platelet in vitro on an industrial scale...
2016: SpringerPlus
Tomohiro Muronoi, Kansuke Koyama, Shin Nunomiya, Alan Kawarai Lefor, Masahiko Wada, Toshitaka Koinuma, Jun Shima, Masayuki Suzukawa
INTRODUCTION: The diagnostic and prognostic value of immature platelet fraction (IPF) in sepsis has not been determined. This study aimed to assess whether IPF is an early predictor of platelet decline due to coagulopathy and is associated with mortality in patients with sepsis. MATERIALS AND METHODS: In total, 149 patients with a platelet count of ≥80×10(3)/μL on intensive care unit admission (101 with sepsis, 48 controls without sepsis) were prospectively evaluated...
August 2016: Thrombosis Research
M Lebois, M R Dowling, P Gangatirkar, P D Hodgkin, B T Kile, W S Alexander, E C Josefsson
UNLABELLED: Essentials We examined platelet survival in models of absent or enhanced thrombopoietin (TPO) signaling. Platelet lifespan is normal in transgenic mice with chronically enhanced TPO signaling. Mpl deficiency does not negatively affect platelet lifespan in the absence of thrombocytopenia. We conclude that TPO and its receptor Mpl are dispensable for platelet survival in adult mice. SUMMARY: Background It is well established that thrombopoietin (TPO), acting via its receptor Mpl, is the major cytokine regulator of platelet biogenesis...
September 2016: Journal of Thrombosis and Haemostasis: JTH
Song Wu, Zongdong Li, Dmitri V Gnatenko, Beibei Zhang, Lu Zhao, Lisa E Malone, Nedialka Markova, Timothy J Mantle, Natasha M Nesbitt, Wadie F Bahou
Human blood cell counts are tightly maintained within narrow physiologic ranges, largely controlled by cytokine-integrated signaling and transcriptional circuits that regulate multilineage hematopoietic specification. Known genetic loci influencing blood cell production account for <10% of platelet and red blood cell variability, and thrombopoietin/cellular myeloproliferative leukemia virus liganding is dispensable for definitive thrombopoiesis, establishing that fundamentally important modifier loci remain unelucidated...
August 4, 2016: Blood
Tao You, Qi Wang, Li Zhu
Autophagy is a conserved biological process for digestion and recycling of cytoplasmic constituents in eukaryotic cells. Autophagy may trigger cell death or promote cell survival following various forms of stress. The emerging roles of autophagy in megakaryopoiesis, thrombopoiesis, and platelet function have been uncovered using not only in vitro and in vivo genetic models, but also in clinical observations of autophagic structure in patients with thrombocytopenic disorders. Inhibition of autophagy in early stage of megakaryocyte differentiation appears to impede megakaryocyte maturation, reduce platelet formation, and affect platelet function, whereas autophagic deficiency in mature megakaryocytes gives rise to abnormal platelet activation and function without changing platelet size and number...
2016: International Journal of Physiology, Pathophysiology and Pharmacology
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