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Blood Reviews Jan 2017Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required... (Review)
Review
Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1). The persistence of MYH10 expression in platelets is a surrogate marker for FLI1 and RUNX1 defects. Characterisation of the transcription factor defects that give rise to platelet function disorders, and of the genes that are differentially regulated as a result, are yielding insights into the roles of these genes in platelet formation and function.
Topics: Blood Platelet Disorders; Blood Platelets; Disease Susceptibility; Gene Expression Regulation; Germ-Line Mutation; Hemostasis; Humans; Structure-Activity Relationship; Thrombopoiesis; Transcription Factors
PubMed: 27450272
DOI: 10.1016/j.blre.2016.07.002 -
Internal Medicine (Tokyo, Japan) Aug 2003
Topics: Blood Platelets; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Thrombocytosis; Thrombopoiesis; Thrombopoietin
PubMed: 12924482
DOI: 10.2169/internalmedicine.42.632 -
Blood Jan 2023
Topics: Humans; Glycosylation; Thrombopoiesis; Mutation; Thrombocytopenia
PubMed: 36701170
DOI: 10.1182/blood.2022019021 -
Frontiers in Immunology 2022Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex,... (Review)
Review
Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex, regulated by multiple factors, and related to many cellular events including apoptosis. However, the role of apoptosis in thrombopoiesis has been controversial for many years. Some researchers believe that apoptosis is an ally of thrombopoiesis and platelets production is apoptosis-dependent, while others have suggested that apoptosis is dispensable for thrombopoiesis, and is even inhibited during this process. In this review, we will focus on this conflict, discuss the relationship between megakaryocytopoiesis, thrombopoiesis and apoptosis. In addition, we also consider why such a vast number of studies draw opposite conclusions of the role of apoptosis in thrombopoiesis, and try to figure out the truth behind the mystery. This review provides more comprehensive insights into the relationship between megakaryocytopoiesis, thrombopoiesis, and apoptosis and finds some clues for the possible pathological mechanisms of platelet disorders caused by abnormal apoptosis.
Topics: Megakaryocytes; Thrombopoiesis; Blood Platelets; Hemostasis; Apoptosis; Fenbendazole
PubMed: 36685543
DOI: 10.3389/fimmu.2022.1025945 -
Blood Jun 2022Fetal and neonatal megakaryocyte progenitors are hyperproliferative compared with adult progenitors and generate a large number of small, low-ploidy megakaryocytes....
Fetal and neonatal megakaryocyte progenitors are hyperproliferative compared with adult progenitors and generate a large number of small, low-ploidy megakaryocytes. Historically, these developmental differences have been interpreted as "immaturity." However, more recent studies have demonstrated that the small, low-ploidy fetal and neonatal megakaryocytes have all the characteristics of adult polyploid megakaryocytes, including the presence of granules, a well-developed demarcation membrane system, and proplatelet formation. Thus, rather than immaturity, the features of fetal and neonatal megakaryopoiesis reflect a developmentally unique uncoupling of proliferation, polyploidization, and cytoplasmic maturation, which allows fetuses and neonates to populate their rapidly expanding bone marrow and blood volume. At the molecular level, the features of fetal and neonatal megakaryopoiesis are the result of a complex interplay of developmentally regulated pathways and environmental signals from the different hematopoietic niches. Over the past few years, studies have challenged traditional paradigms about the origin of the megakaryocyte lineage in both fetal and adult life, and the application of single-cell RNA sequencing has led to a better characterization of embryonic, fetal, and adult megakaryocytes. In particular, a growing body of data suggests that at all stages of development, the various functions of megakaryocytes are not fulfilled by the megakaryocyte population as a whole, but rather by distinct megakaryocyte subpopulations with dedicated roles. Finally, recent studies have provided novel insights into the mechanisms underlying developmental disorders of megakaryopoiesis, which either uniquely affect fetuses and neonates or have different clinical presentations in neonatal compared with adult life.
Topics: Adult; Bone Marrow; Fetus; Humans; Infant, Newborn; Megakaryocyte Progenitor Cells; Megakaryocytes; Thrombopoiesis
PubMed: 35108353
DOI: 10.1182/blood.2020009301 -
Blood Apr 2016Hypercholesterolemia is a risk factor for atherothrombotic disease, largely attributed to its impact on atherosclerotic lesional cells such as macrophages. Platelets are... (Review)
Review
Hypercholesterolemia is a risk factor for atherothrombotic disease, largely attributed to its impact on atherosclerotic lesional cells such as macrophages. Platelets are involved in immunity and inflammation and impact atherogenesis, primarily by modulating immune and inflammatory effector cells. There is evidence that hypercholesterolemia increases the risk of atherosclerosis and thrombosis by modulating platelet biogenesis and activity. This review highlights recent findings on the impact of aberrant cholesterol metabolism on platelet biogenesis and activity and their relevance in atherosclerosis and thrombosis.
Topics: Animals; Atherosclerosis; Blood Platelets; Cholesterol; Humans; Lipid Metabolism; Platelet Activation; Thrombopoiesis
PubMed: 26929273
DOI: 10.1182/blood-2016-01-631259 -
Current Opinion in Hematology Nov 2021This review highlights recent advancements in understanding the regulation of platelet numbers, focusing on mechanisms by which carbohydrates (glycans) link platelet... (Review)
Review
PURPOSE OF THE REVIEW
This review highlights recent advancements in understanding the regulation of platelet numbers, focusing on mechanisms by which carbohydrates (glycans) link platelet removal with platelet production in the bone marrow in health and disease.
RECENT FINDINGS
This review is focused on the role of carbohydrates, specifically sialic acid moieties, as a central mediator of platelet clearance. We discuss recently identified novel mechanisms of carbohydrate-mediated platelet removal and carbohydrate-binding receptors that mediate platelet removal.
SUMMARY
The platelet production rate by megakaryocytes and removal kinetics controls the circulating platelet count. Alterations in either process can lead to thrombocytopenia (low platelet count) or thrombocytosis (high platelet count) are associated with the risk of bleeding or overt thrombus formation and serious complications. Thus, regulation of a steady-state platelet count is vital in preventing adverse events. There are few mechanisms delineated that shed light on carbohydrates' role in the complex and massive platelet removal process. This review focuses on carbohydrate-related mechanisms that contribute to the control of platelet numbers.
Topics: Blood Platelets; Humans; Megakaryocytes; Platelet Count; Polysaccharides; Thrombopoiesis
PubMed: 34605444
DOI: 10.1097/MOH.0000000000000682 -
Current Opinion in Hematology Nov 2021Platelet transfusion can be life-saving but carries a risk of infection or alloimmunization and is limited by insufficient donor sources and restricted unit shelf life.... (Review)
Review
PURPOSE OF REVIEW
Platelet transfusion can be life-saving but carries a risk of infection or alloimmunization and is limited by insufficient donor sources and restricted unit shelf life. Generating sufficient platelets in vitro to replace a unit of collected blood remains a challenge. Here, we examine the latest advances in the regulation of megakaryocyte maturation and expansion along with platelet formation and survival. We also discuss alternative therapies investigated to induce platelet production.
RECENT FINDINGS
Recent studies examined candidate niche cells in the bone marrow microenvironment for promoting platelet formation and developed an explant-based bioreactor to enhance platelet production ex vivo. Chemical inhibitors were examined for their ability to promote megakaryocyte maturation and expansion. Microparticles from megakaryocytes or platelets were found to improve megakaryocyte maturation and platelet formation. Membrane budding was identified as a novel mode of platelet formation. Lastly, a chemical inhibitor to improve cold-stored platelets was identified.
SUMMARY
Recent advances in the regulation of megakaryocyte expansion and platelet production provide exciting promise for the development of improved approaches to generate platelets in vitro. These findings bring the field one step closer to achieving the ultimate goal of creating a unit of platelets without the need for donation.
Topics: Blood Platelets; Bone Marrow; Humans; Megakaryocytes; Platelet Transfusion; Thrombopoiesis
PubMed: 34232141
DOI: 10.1097/MOH.0000000000000662 -
Molecular Medicine Reports Jan 2021Platelets are small pieces of cytoplasm that have become detached from the cytoplasm of mature megakaryocytes (MKs) in the bone marrow. Platelets modulate vascular... (Review)
Review
Platelets are small pieces of cytoplasm that have become detached from the cytoplasm of mature megakaryocytes (MKs) in the bone marrow. Platelets modulate vascular system integrity and serve important role, particularly in hemostasis. With the rapid development of clinical medicine, the demand for platelet transfusion as a life‑saving intervention increases continuously. Stem cell technology appears to be highly promising for transfusion medicine, and the generation of platelets from stem cells would be of great value in the clinical setting. Furthermore, several studies have been undertaken to investigate the potential of producing platelets from stem cells. Initial success has been achieved in terms of the yields and function of platelets generated from stem cells. However, the requirements of clinical practice remain unmet. The aim of the present review was to focus on several sources of stem cells and factors that induce MK differentiation. Updated information on current research into the genetic regulation of megakaryocytopoiesis and platelet generation was summarized. Additionally, advanced strategies of platelet generation were reviewed and the progress made in this field was discussed.
Topics: Blood Platelets; Cell Culture Techniques; Cell Differentiation; Culture Media; Gene Expression Regulation; Humans; Stem Cells; Thrombopoiesis
PubMed: 33179095
DOI: 10.3892/mmr.2020.11645 -
Haematologica Aug 2020Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia... (Review)
Review
Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia was recognized as a cause of bleeding, first through an acquired immune disorder; then, since 1948, when Bernard-Soulier syndrome was first described, inherited thrombocytopenia became a fascinating example of Mendelian disease. The platelet count is often severely decreased and platelet size variable; associated platelet function defects frequently aggravate bleeding. Macrothrombocytopenia with variable proportions of enlarged platelets is common. The number of circulating platelets will depend on platelet production, consumption and lifespan. The bulk of macrothrombocytopenias arise from defects in megakaryopoiesis with causal variants in transcription factor genes giving rise to altered stem cell differentiation and changes in early megakaryocyte development and maturation. Genes encoding surface receptors, cytoskeletal and signaling proteins also feature prominently and Sanger sequencing associated with careful phenotyping has allowed their early classification. It quickly became apparent that many inherited thrombocytopenias are syndromic while others are linked to an increased risk of hematologic malignancies. In the last decade, the application of next-generation sequencing, including whole exome sequencing, and the use of gene platforms for rapid testing have greatly accelerated the discovery of causal genes and extended the list of variants in more common disorders. Genes linked to an increased platelet turnover and apoptosis have also been identified. The current challenges are now to use next-generation sequencing in first-step screening and to define bleeding risk and treatment better.
Topics: Bernard-Soulier Syndrome; Blood Platelets; Humans; Megakaryocytes; Thrombocytopenia; Thrombopoiesis
PubMed: 32527953
DOI: 10.3324/haematol.2019.233197