Megakaryocytes

XIII hver, megakaryocytes 95-120 1-2 1-2 factor XIII deficiency, <0.5 AR ... 

Thrombopoietic factors (no recombinant TPO product in clinical use at this time IL-11 [recombinant product oprelvekin] has marketing approval) stimulate the production of megakaryocyte precursors, megakaryocytes, and platelets [8]. Interleukin-11 has many effects on multiple tissues, and can interact with IL-3, TPO, and SCF. AMG 531, a recombinant peptibody in that binds to the thrombopoetin receptor Mpl and stimulates the production of platelets, is in phase 1 and 2 studies and has been shown to safely increase platelet counts in patients with immune thrombocytopenic purpura [9]. 

Platelets are the formed elements of the blood which participate in hemostasis. Platelets are enucleated, discoid fragments which arise from mature megakaryocytes in the bone marrow. Under normal circumstances, platelets do not adhere to endothelial surfaces of blood vessels. However, platelets can adhere to damaged areas of blood vessels and become activated in such a way that they can also bind fibrinogen. 

The von Willebrand factor (vWf) is a heterogeneous multimeric plasma glycoprotein produced by megakaryocytes and endothelial cells which is found in platelets, plasma and the subendothelium. Subendothelial vWf facilitates platelet adhesion, especially under high shear stress, by binding to glycoprotein GPIb-V-IX, a complex of four leucine-rich repeat proteins on platelets. 

Blood platelets are key players in the blood-clotting mechanism. These tiny fragments of cytoplasm are shed into the circulation from the surface of megakaryocytes located in the bone marrow. When the lining of a blood vessel is injured, activated platelets release clotting factors, adhere to each other and to damaged surfaces, and send out numerous filopodia. The shape changes that occur in activated platelets are the result of actin polymerization. Before activation, there are no microfilaments because profilin binds to G-actin and prevents its polymerization. After activation, profilin dissociates from G-actin, and bundles and networks of F-actin filaments rapidly appear within the platelet. 

IgG autoantibody-coated platelets induce Fey receptor-mediated phagocytosis by mononuclear macrophages, predominantly in the spleen and liver. Thrombocytopenia develops as a consequence of megakaryocyte inability to increase platelet production and maintain a normal number of circulating platelets. Currently used treatments are directed at different aspects of the antibody production, platelet sensitization, and the clearance and production cycle.30... 

Hematopoiesis is defined as the development and maturation of blood cells and their precursors. In utero, hematopoiesis may occur in the liver, spleen, and bone marrow. However, after birth, it occurs exclusively in the bone marrow. All blood cells are generated from a common hematopoietic precursor, or stem cell. These stem cells are self-renewing and pluripotent and thus are able to commit to any one of the different lines of maturation that give rise to platelet-producing megakaryocytes, lymphoid, erythroid, and myeloid cells. The myeloid cell line produces monocytes, basophils, neutrophils, and eosinophils, whereas the lymphoid stem cell differentiates to form circulating B and T lymphocytes. In contrast to the ordered development of normal cells, the development of leukemia seems to represent an arrest in differentiation at an early phase in the continuum of stem cell to mature cell.1... 

CML arises from a defect in an early progenitor cell. Several cell lines may be affected, including myeloid, erythroid, megakaryocyte, and rarely, lymphoid lineages. These cells remain functional in chronic-phase CML, which is why patients in this phase are at low risk for developing infectious complications. 

PLATELETS. Platelets are nonnucleated discoid or elliptical cells that originate from the fragmentation of giant polyploid megakaryocytes located in the bone marrow. The average diameter of the platelet is 1.5 pm. Each platelet is surrounded by a trilaminar membrane, and its cytoplasm contains a dense body (delta granule), a surface-connected canalicular system,... 

The third of the cellular elements within the blood are the platelets (thrombocytes). Platelets are actually small, round or oval cell fragments. They are about 2 to 4 pm in diameter and have no nuclei. Platelets are formed in the red bone marrow as pinched-off portions of the very large megakaryocytes. Each megakaryocyte, which is confined to the bone marrow, can produce... 

CSFs, which play a major role in the differentiation of stem-derived cells into neutrophils, macrophages, megakaryocytes (from which platelets are derived), eosinophils and basophils ... 

Main target cells Neutrophils. Also other haemopoietic progenitors and endothelial cells Macrophages and their precursor cells Haematopoietic progenitor cells Granulocytes Monocytes Endothelial cells Megakaryocytes T-lymphocytes Erythroid cells... 

Figure 10.6 Simplified representation of the production of platelets from stem cells. CFU-megakaryocytes and in particular, mature megakaryocytes, are most sensitive to the stimulatory actions of TPO. These two cell types also display a limited response to IL-6, IL-11 and LIF...

P2Y receptors are activated by adenine and uridine nucleotides. Most of the known P2Y receptors have been detected in the nervous system [21]. The majority of P2Y receptors inhibit neuronal N-type Ca2+ channels and M-type K+ channels. P2Y1 receptors are found exclusively on platelets, on their precursor megakaryocyte cells and on certain other cultured hematopoietic cells, such as K562 leukemia cells. They can be distinguished from other P2 receptors in that ADP is the most potent natural agonist and ATP is a competitive antagonist. ADP acts via a G protein to inhibit cyclic AMP accumulation, mobilize intracellular Ca2+ and stimulate granule secretion. ADP... 

The first site of myelopoiesis75 in the mouse embryo is the fetal liver, where the common myeloid progenitor, the megakaryocyte-erythrocyte-restricted progenitors and granulocyte-monocyte restricted progenitors are present. Myelopoiesis occurs in the fetal liver in the same manner as in adult bone marrow.81 However, the proliferation capacity, colony forming activity and differentiation capacity is different between the fetal liver and adult bone marrow.81... 

IL-3 multi-CSF 20 14.6 stem cells, BFU-E, neutrophil/monocytes, megakaryocytes 5q23-31 T-lymphocytes, keratinocytes... 

Figure 2.2. Role of cytokines in blood-cell development. Abbreviations CFU, colony-forming unit CFU-GEMM, granulocyte-erythroid-monocyte-megakaryocyte CFU CFU-GM, granulocyte-macrophage CFU CFU-M, macrophage CFU CFU-G, granulocyte CFU CFU-Eos, eosinophil CFU IL, Interleukin. See text for details.

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