The biogenesis of platelets from megakaryocyte proplatelets

Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2006; 115(12):3348-54. DOI: 10.1172/JCI26891
Source: PubMed


Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/microl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/microl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production.

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    • "Megakaryopoiesis is a multistep process driving the proliferation, differentiation and maturation of hematopoietic stem cells to the generation of platelets, anucleate blood components with a fundamental role in the hemostatic process.1 "
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    ABSTRACT: The relationship between thrombopoietin (TPO) and its receptor cMpl in thrombocytopenic conditions has not been entirely clarified. To elucidate this interplay may expand the spectrum of indications of TPO mimetics. In this study we have explored the relationship between TPO and cMpl in platelets and megakaryocytes of 43 patients with thrombocytopenia due to idiopathic thrombocytopenic purpura (ITP), bone marrow hypoplasia, myelodysplastic syndromes (MDS), and familial thrombocytopenia. Data were compared to cMpl and TPO in patients with a normal platelet count and in patients with thrombocytosis due to essential thrombocythemia (ET). All but familial patients showed higher TPO compared to controls. All thrombocytopenic states were invariably associated with increased expression of platelet cMPL compared to healthy controls. ET patients showed normal TPO and a trend toward a reduced cMpl expression. Immunofluorescence of bone marrow sections from patients with ITP and MDS failed to show a peculiar pattern compared to controls. Multiple mechanisms regulate TPO and cMpl in thrombocytopenic conditions.
    Hematology Reports 01/2014; 6(1):4996. DOI:10.4081/hr.2014.4996
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    • "They become polyploid (4–64 N) through several cycles of endomitosis [6] [7] [8]. In addition, a cytoplasmic maturation occurs involving the formation of a demarcation membrane system (DMS) and the accumulation of cytoplasmic proteins and secretory granules [6] [9]. "
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    ABSTRACT: Platelets play an important role in the pathogenesis and the ischemic complications of atherosclerosis. Platelets may be activated by several different agonists, promoting the release of their granule contents and subsequent aggregation and thrombus formation; this leads to ischemic events such as myocardial infarction or stroke. Aspirin, the most popular antiplatelet agent, is a cornerstone in the treatment and prevention of ischemic events in cardiovascular patients. It inhibits a particular amplification pathway of platelet activation, based on thromboxane A2 (TxA2) generation. However, despite a consistent inhibition of TxA2 production, a substantial proportion of patients display preserved platelet function. This phenotype is defined as “high on-treatment platelet reactivity”. It is a risk factor for the recurrence of ischemic events, particularly in acute vessel injury settings. The determinants of platelet reactivity in these patients remain unclear, but previous studies, including healthy subjects, suggested that it is genetically determined. Over the last decade, technological improvements have led to the development of highly efficient omics strategies. High-throughput genomics, transcriptomics and proteomics have the potential to dissect fine metabolic modulations. However, the bioinformatics management of these large data sets remains a challenging issue. Network biology approaches permit the integration of different omics data sets and the identification of mutual interactions between gene products and/or molecules. The inherent topology of the network can be then explored at a pathway level rather than at a gene level. Network biology constitutes an efficient tool to further explore platelet metabolism and defects, such as modulators of platelet reactivity in cardiovascular patients.
    Translational Proteomics 12/2013; 1(1):25-37. DOI:10.1016/j.trprot.2013.04.002
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    • "In addition, apoptosis is likely involved in LT-mediated cellular changes as compared with PA controls (Figure 3C–3E and Figure S1C–1E). Since platelet biogenesis also involves apoptotic processes [30],[31], and the R2-population contained a high percentage staining patterns of platelet-marker CD61 (68% CD61+ in the R2 region, unpublished results), these R2 cells may still possible be platelet-like fragments instead of death cells. Platelets isolated from human cord blood were used as normal controls to verify this conjecture. "
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    ABSTRACT: Anthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis. LT challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. LT inhibits cellular mitogen-activated protein kinases (MAPKs), which are vital pathways responsible for cell survival, differentiation, and maturation. One of the MAPKs, the MEK1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. This study evaluates the hypothesis that LT may suppress the progenitor cells of platelets, thereby inducing thrombocytopenic responses. Using cord blood-derived CD34(+) cells and mouse bone marrow mononuclear cells to perform in vitro differentiation, this work shows that LT suppresses megakaryopoiesis by reducing the survival of megakaryocytes. Thrombopoietin treatments can reduce thrombocytopenia, megakaryocytic suppression, and the quick onset of lethality in LT-challenged mice. These results suggest that megakaryocytic suppression is one of the mechanisms by which LT induces thrombocytopenia. These findings may provide new insights for developing feasible approaches against anthrax.
    PLoS ONE 03/2013; 8(3):e59512. DOI:10.1371/journal.pone.0059512 · 3.23 Impact Factor
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