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Cancer Treatment and Research 2011Megakaryopoiesis and thrombopoiesis are the central biological processes of platelet generation. Severe thrombocytopenia is a major morbidity and mortality factor in... (Review)
Review
Megakaryopoiesis and thrombopoiesis are the central biological processes of platelet generation. Severe thrombocytopenia is a major morbidity and mortality factor in several diseases and represents a significant unmet medical need. Since the discovery of thrombopoietin (TPO) as the primary physiological regulator of megakaryopoiesis, a number of therapeutics have been developed for thrombocytopenia and been tested in preclinical models and human clinical trials. The TPO mimetics romiplostim (Nplate(®) or AMG531) and eltrombopag (Promacta(®)) have recently been approved for the treatment of adult chronic idiopathic (immune) thrombocytopenic purpura (ITP) and are successful examples of these endeavors. This chapter will review scientific progress over the last 20 years on various thrombopoietic factors with an emphasis on the biology, physiology, and pharmacology of TPO, its cognate receptor, c-Mpl, and various TPO mimetics.
Topics: Animals; Humans; Thrombopoiesis; Thrombopoietin
PubMed: 21052951
DOI: 10.1007/978-1-4419-7073-2_5 -
Seminars in Thrombosis and Hemostasis Feb 2013Platelets are formed by giant precursor cells called megakaryocytes that reside within the bone marrow. The generation of platelets, and their release into the... (Review)
Review
Platelets are formed by giant precursor cells called megakaryocytes that reside within the bone marrow. The generation of platelets, and their release into the bloodstream by megakaryocytes, requires a complex series of remodeling events powered by the cytoskeleton to result in the release of many platelets from a single megakaryocyte. Abnormalities in this process can result in thrombocytopenia (low platelet count) and can lead to increased risk of bleeding. This review describes the process of platelet production in detail and discusses new insights into novel platelet biology.
Topics: Blood Platelet Disorders; Blood Platelets; Cytoskeleton; Humans; Megakaryocytes; Models, Biological; Platelet Count; Thrombocytopenia; Thrombopoiesis
PubMed: 23266965
DOI: 10.1055/s-0032-1331157 -
Thrombosis Research Mar 2012Circulating platelets are highly specialized cells produced by megakaryocytes (Mks) that participate in hemostatic and inflammatory functions. Despite their critical... (Review)
Review
Circulating platelets are highly specialized cells produced by megakaryocytes (Mks) that participate in hemostatic and inflammatory functions. Despite their critical role little is known about the molecular mechanisms involved in their production from megakaryocytes, or about the pathogenesis of platelet disorders. Megakaryopoiesis occurs in a complex microenvironment within the bone marrow. The underlying relationships between Mk maturation and bone marrow components are key factors in this process. Mk interactions with extracellular matrices (ECM) via specific surface receptors control many functions, with chemistry, physical parameters and membrane elasticity as fundamental elements of the processes involved. Alteration of Mk-ECM interactions in the bone marrow environment may lead to pathophysiologic situations, such as myelofibrosis and congenital thrombocytopenia. Searching the mechanisms related to Mks-bone marrow environment interactions, will provide novel insight into fundamental control of Mk function, leading to new concepts in the study of Mk-related disease states and future modes for therapeutic inquiry.
Topics: Animals; Blood Platelets; Cell Shape; Hematopoietic Stem Cells; Humans; Signal Transduction; Stem Cell Niche; Thrombopoiesis
PubMed: 22226434
DOI: 10.1016/j.thromres.2011.11.042 -
The Journal of Endocrinology Jul 2018Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose... (Review)
Review
Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications.
Topics: Animals; Aspirin; Atherosclerosis; Blood Platelets; Bone Marrow Cells; Hepatitis; Humans; Infant, Newborn; Liver; Myelopoiesis; Risk Factors; Thrombopoiesis; Treatment Outcome
PubMed: 29720539
DOI: 10.1530/JOE-18-0082 -
Thrombosis and Haemostasis Jan 2016Platelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical... (Review)
Review
Platelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells.
Topics: Animals; Biocompatible Materials; Bioengineering; Bioreactors; Blood Platelets; Bone Marrow; Bone Marrow Cells; Humans; Inflammation; Megakaryocytes; Phenotype; Stem Cells; Thrombopoiesis; Translational Research, Biomedical; Treatment Outcome
PubMed: 26353819
DOI: 10.1160/TH15-07-0570 -
Thrombosis Research Jan 2003Thrombospondin-1 (TSP-1) is an inhibitor of angiogenesis, inducing apoptosis of the endothelial cells via CD36 signaling mechanism. We investigated CD36 expression and...
Thrombospondin-1 (TSP-1) is an inhibitor of angiogenesis, inducing apoptosis of the endothelial cells via CD36 signaling mechanism. We investigated CD36 expression and the effect of TSP-1 on megakaryocytopoiesis, with and without pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), and with and without blocking TSP-1 binding with receptor CD36 on megakaryocytic cells. Our data showed that TSP-1 induced a dose-dependent growth inhibition in both murine and human colony forming unit-megakaryocyte (CFU-MK) assays and significantly counteracted the mitogenic effect from PEG-rHuMGDF. Moreover, the growth suppression induced by TSP-1 was correlated with CD36 expression in megakaryocytic cell lines, where growth inhibition was demonstrated in CD36 positive (Meg-01, Dami and CHRF-288-11) but not in CD36 negative (M-07e) cell lines. More importantly, the inhibitory effect of TSP-1 on both human CFU-MK and Meg-01 cells was partially but significantly reversed by the addition of FA6-152 (anti-CD36), a blocking antibody which blocks the access of TSP-1 to CD36 receptor, suggesting that the TSP-1-induced inhibition of megakaryocytopoiesis is probably mediated in part by the binding of TSP-1 to CD36 expressed on the megakaryocytic progenitors. Thus, our findings represent the first demonstration that TSP-1 inhibits in vitro megakaryocytopoiesis via interaction with CD36.
Topics: Animals; Antibodies, Monoclonal; CD36 Antigens; Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Hematopoietic Stem Cells; Humans; Mice; Platelet Factor 4; Polyethylene Glycols; Protein Binding; Recombinant Proteins; Thrombopoiesis; Thrombopoietin; Thrombospondin 1
PubMed: 12679131
DOI: 10.1016/s0049-3848(03)00142-7 -
Seminars in Hematology Jan 2015Myelodysplastic syndromes (MDS) are clinically, genetically, and molecularly heterogeneous neoplastic diseases characterized by ineffective hematopoiesis leading to... (Review)
Review
Myelodysplastic syndromes (MDS) are clinically, genetically, and molecularly heterogeneous neoplastic diseases characterized by ineffective hematopoiesis leading to peripheral cytopenias. The severity of cytopenias influences oucome and is considered in prognostic scoring systems; thrombocytopenia, although not the most frequently observed at disease onset, is estimated to affect 40%-80% of MDS patients. As thrombocytopenia in MDS is determined by premature marrow destruction and programmed cell death, the use of thrombomimetic agents has been proposed in order to stimulate megakaryocyte differentation and proliferation. After early attempts of therapy of thrombocytopenic MDS patients with thrombopoietin and interleukin (IL)-11, clinical trials testing the activity of romiplostim and eltrombopag have been recently designed and have demonstrated good tolerability and efficacy in re-inducing megakaryocytopoiesis and in lowering the number of hemorragic events. The number of MDS patients receiving such treatments is still limited and a broader evaluation of the long-term effects and safety of these agents is ongoing.
Topics: Bone Marrow; Clinical Trials as Topic; Humans; Megakaryocytes; Myelodysplastic Syndromes; Prognosis; Thrombocytopenia; Thrombopoiesis
PubMed: 25578418
DOI: 10.1053/j.seminhematol.2014.10.005 -
Blood Oct 2015The human body produces and removes 10(11) platelets daily to maintain a normal steady state platelet count. Platelet production must be regulated to avoid spontaneous... (Review)
Review
The human body produces and removes 10(11) platelets daily to maintain a normal steady state platelet count. Platelet production must be regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. Multifaceted and complex mechanisms control platelet production and removal in physiological and pathological conditions. This review will focus on different mechanisms of platelet senescence and clearance with specific emphasis on the role of posttranslational modifications. It will also briefly address platelet transfusion and the role of glycans in the clearance of stored platelets.
Topics: Blood Platelets; Cellular Senescence; Humans; Polysaccharides; Protein Processing, Post-Translational; Thrombopoiesis
PubMed: 26330242
DOI: 10.1182/blood-2015-01-569129 -
Infectious Disorders Drug Targets 2018Hematopoiesis is the process which generates all the mature blood cells from the rare pool of Hematopoietic stem cells (HSCs). Asymmetric cell division of HSCs provide... (Review)
Review
Hematopoiesis is the process which generates all the mature blood cells from the rare pool of Hematopoietic stem cells (HSCs). Asymmetric cell division of HSCs provide it dual capacity for self-renewal and multi-potent differentiation. Hematopoiesis is a steady state process in which mature blood cells are produced at the same rate at which they are lost, establishing a homeostasis. HSCs are regulated through their environmental niche, cytokine signalling, and the orchestrated activities of various transcription factors. However, there is very little information available about the signal transduction events that regulate HSC function; in particular, the effects of bioactive lipids and lipid mediators are not well understood. Recent studies have added an important aspect of this process, introducing the role of lipids in cell fate decisions during hematopoiesis. The mechanisms of bioactive lipids and their derivatives have been studied extensively in signal transduction and various other cellular processes. This review focuses on various categories of lipids and their regulatory mechanisms in HSCs and their comment into different blood cells. Moreover, we also discuss the role of lipid signalling specifically in megakaryocyte and platelets.
Topics: Blood Platelets; Cell Differentiation; Ceramides; Eicosanoids; Hematopoiesis; Hematopoietic Stem Cells; Humans; Megakaryocytes; Phosphatidylinositols; Thrombopoiesis
PubMed: 29621967
DOI: 10.2174/1871526518666180405155015 -
Clinical Lymphoma & Myeloma 2009Thrombopoietin (TPO) is the physiologic regulator of platelet production and works by binding to its receptor on megakaryocyte precursor cells, thereby activating a... (Review)
Review
Thrombopoietin (TPO) is the physiologic regulator of platelet production and works by binding to its receptor on megakaryocyte precursor cells, thereby activating a large number of antiapoptotic and cell maturation pathways. "First-generation" recombinant forms of TPO were developed over a decade ago and were found to increase the platelet count in patients undergoing nonmyeloablative chemotherapy, in patients with immune thrombocytopenic purpura (ITP) and myelodysplasia, as well as in platelet apheresis donors. Thrombopoietin did not improve platelet counts in patients undergoing stem cell transplantation or acute leukemia induction. Further development ended when antibodies formed against one of the recombinant proteins. Subsequently, 2 "second-generation" TPO mimetics have been developed and are entering clinical practice: romiplostim and eltrombopag. Romiplostim is an injectable peptide TPO mimetic that activates the TPO receptor just like native TPO. Eltrombopag is an oral nonpeptide TPO mimetic that activates the TPO receptor by binding to a different region of the TPO receptor that does not compete with TPO binding. Both increased the platelet counts in healthy subjects and in over two thirds of patients with ITP both before and after splenectomy; responses were maintained for at least 1 year. Romiplostim and eltrombopag are now US Food and Drug Administration approved for the second-line treatment of patients with ITP. Adverse events have been few, but long-term assessment for reticulin formation, increased bone marrow blasts, and thromboembolism is ongoing. Studies are under way to assess the efficacy of these drugs in the treatment of other thrombocytopenic disorders associated with chemotherapy, myelodysplasia, and chronic hepatitis.
Topics: Benzoates; Clinical Trials as Topic; Hematology; Humans; Hydrazines; Intercellular Signaling Peptides and Proteins; Models, Biological; Models, Chemical; Peptides; Platelet Count; Pyrazoles; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; Time Factors; Treatment Outcome
PubMed: 19778863
DOI: 10.3816/CLM.2009.s.034