Disease relevance of Thrombopoiesis

• It is concluded that heavy ethanol ingestion induces, augments, or sustains thrombocytopenia by impairing megakaryocytopoiesis in man [1].
• IL-1 beta by itself did not stimulate megakaryocytopoiesis in vitro, suggesting that the thrombocytosis is attributed to other factor(s) via IL-1 beta stimulation [2].
• Besides its well-recognized role in hemostasis and thrombosis, thromboxane A(2) synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation [3].
• Surprisingly, TPO treatment of GATA-1(low) mice restored the GATA-1 content in Mks and halted both defective thrombocytopoiesis and fibrosis [4].
• The influence of antiplatelet glycoprotein (GP) antibodies on megakaryocytopoiesis in patients with idiopathic or immune thrombocytopenic purpura (ITP) has been well studied [5].

High impact information on Thrombopoiesis

• Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis [6].
• cMpl ligand is a humoral regulator of megakaryocytopoiesis [7].
• The isolated Mpl ligand shares homology with erythropoietin and stimulates both megakaryocytopoiesis and thrombopoiesis [8].
• Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand [8].
• To further investigate the role and specificity of this receptor in regulating megakaryocytopoiesis, c-mpl-deficient mice were generated by gene targeting [9].

Chemical compound and disease context of Thrombopoiesis

• In particular, thrombopoiesis has been proven to be stimulated by melatonin, and the pineal indole has been shown to be effective in the treatment of thrombocytopenia resulting from different causes [10].
• Flow cytometry can also be used in the following clinical settings: monitoring of GPIIb-IIIa antagonist therapy, diagnosis of inherited deficiencies of platelet surface glycoproteins, diagnosis of storage pool disease, diagnosis of heparin-induced thrombocytopenia, and measurement of the rate of thrombopoiesis [11].
• CONCLUSIONS: This study demonstrated a minimal effect (statistically significant in the first cycle only) on thrombopoiesis in women undergoing paclitaxel and carboplatin therapy of ovarian cancer [12].
• Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20 [13].
• We concluded that although the platelet destruction mechanism in the reticuloendothelial system shows a primary role in thrombocytopenia, the impaired rate of effective thrombopoiesis may also contribute to the severity of ITP [14].

Biological context of Thrombopoiesis

• Interaction of thrombopoietin (TPO) with its receptor, c-Mpl, triggers cell growth and differentiation responses controlling primitive haemopoietic cell production and megakaryocytopoiesis [15].
• Megakaryocyte-specific expression of the platelet-adhesion receptor, integrin alphaIIbbeta3, is caused by the presence of regulatory elements of the alphaIIb promoter that direct high-level, selective gene transcription early in megakaryocytopoiesis [16].
• This in vivo system shows that a relationship between erythropoiesis and thrombopoiesis can exist at the level of the Epo-EpoR signaling pathway [17].
• Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis through binding to the cytokine receptor c-Mpl (the product of the c-mpl proto-oncogene) [18].
• Megakaryocyte growth and development factor (MGDF) is a potent inducer of megakaryopoiesis in vitro and thrombopoiesis in vivo [19].

Anatomical context of Thrombopoiesis

• These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis [6].
• Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl [20].
• Local production of early-acting cytokines and TPO by stromal cells may be relevant to the regulation of hematopoietic stem cell self-renewal and megakaryocytopoiesis in the bone marrow microenvironment [21].
• In studying the role of Tie-2 and Ang-1 in megakaryocytopoiesis, 3 alternatively spliced species of Ang-1 mRNA (Ang-1.3 kb, Ang-0.9 kb, and Ang-0.7 kb) were identified in addition to the full-length Ang-1 (Ang-1.5 kb), in the megakaryocyte cell line CHRF by reverse transcription-polymerase chain reaction (RT-PCR), and then cloned and sequenced [22].
• These findings provide critical mechanistic links between NF-E2, platelet formation, and selected microtubule proteins, and they also provide novel molecular insights into thrombopoiesis [23].

Associations of Thrombopoiesis with chemical compounds

• In view of previous reports on the effect of acetylcholine analogs and ChoEase inhibitors in the induction of megakaryocytopoiesis and production of platelets in the mouse, we further searched for such phenomena in nonleukemic patients with platelet production disorders [24].
• These results provide in vivo insights into the structural elements of the GP Ibalpha subunit that contribute to normal megakaryocyte maturation and thrombopoiesis [25].
• Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway [26].
• They may be responsible for the enhanced megakaryocytopoiesis seen in the marrow of mice 7 days after the injection of 5-FU [27].
• Lithium enhancement of megakaryocytopoiesis in culture: mediation via accessory marrow cells [28].

Gene context of Thrombopoiesis

• These results show that c-mpl specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO [9].
• We conclude that both COX-isoforms contribute to prostanoid formation during human megakaryocytopoiesis and that COX-2-derived PGE(2) and TXA(2) may play an unrecognized role in inflammatory and hemostatic responses in clinical syndromes associated with high platelet turnover [29].
• We have investigated the expression and activity of COX-1 and -2 during human megakaryocytopoiesis [29].
• Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand [30].
• Megakaryocytopoiesis is also enhanced by other colony-stimulating factors (CSFs), including IL-3, IL-6, and Steel factor (SLF) [31].

Analytical, diagnostic and therapeutic context of Thrombopoiesis

• Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use [32].
• In contrast, the spleens of irradiated mice 12 days after transplantation with mutant bone marrow contained abundant megakaryocyte progenitor cells, suggesting that altered c-Myb activity skews differentiation commitment in spleen colony-forming units (CFU-S) in favor of excess megakaryocytopoiesis [33].
• The pronounced elevation of erythropoietin after apheresis suggests a role for this primarily erythropoietic cytokine in thrombopoiesis, too [34].
• Since thrombopoietin (TPO) is the primary regulator of thrombopoiesis, we have investigated whether levels of TPO and/or its receptor, c-mpl, are of value in the differential diagnosis of ET [35].
• Castration decreases thrombocytopoiesis and testosterone restores platelet production in castrated BALB/c mice: evidence that testosterone acts on a bipotential hematopoietic precursor cell [36].

References