Article

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

ABSTRACT

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.

Full-text preview

Available from: ncbi.nlm.nih.gov
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2014 · Hematology Reports
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2013 · Translational Proteomics
  • Source
    • "We observed endomitosing megakaryoblasts in MPP, CMP and MEP cultures. In the MKC culture, we observed mature MKCs with red nuclei exhibiting hallmark features of proplatelets (supplementary material Fig. S6C, arrowhead) (Patel et al., 2005). We also examined nuclear structures during endomitosis in MKCs (Fig. 5C). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The majority of mammalian somatic cells maintain a diploid genome. However, some mammalian cell types undergo multiple rounds of genome replication (endoreplication) as part of normal development and differentiation. For example, trophoblast giant cells (TGCs) in the placenta become polyploid through endoreduplication (bypassed mitosis), and megakaryocytes (MKCs) in the bone marrow become polyploid through endomitosis (abortive mitosis). During the normal mitotic cell cycle, geminin and Cdt1 are involved in 'licensing' of replication origins, which ensures that replication occurs only once in a cell cycle. Their protein accumulation is directly regulated by two E3 ubiquitin ligase activities, APC(Cdh1) and SCF(Skp2), which oscillate reciprocally during the cell cycle. Although proteolysis-mediated, oscillatory accumulation of proteins has been documented in endoreplicating Drosophila cells, it is not known whether the ubiquitin oscillators that control normal cell cycle transitions also function during mammalian endoreplication. In this study, we used transgenic mice expressing Fucci fluorescent cell-cycle probes that report the activity of APC(Cdh1) and SCF(Skp2). By performing long-term, high temporal-resolution Fucci imaging, we were able to visualize reciprocal activation of APC(Cdh1) and SCF(Skp2) in differentiating TGCs and MKCs grown in our custom-designed culture wells. We found that TGCs and MKCs both skip cytokinesis, but in different ways, and that the reciprocal activation of the ubiquitin oscillators in MKCs varies with the polyploidy level. We also obtained three-dimensional reconstructions of highly polyploid TGCs in whole, fixed mouse placentas. Thus, the Fucci technique is able to reveal the spatiotemporal regulation of the endoreplicative cell cycle during differentiation.
    Preview · Article · Oct 2013 · Development
Show more