Erythropoiesis A

Blood corpuscles develop from stem cells through several cell divisions (n = 17 ). Hemoglobin is then synthesized and the cell nucleus is extruded. Erythropoiesis is stimulated by the hormone erythropoietin (a glycoprotein), which is released from the kidneys when renal oxygen tension declines. A nephrogenic anemia can be ameliorated by parenteral administration of recombinant erythropoietin (epoetin alfa) or hyperglyco-sylated erythropoietin (darbepoetin longer half-life than epoetin). 

Given adequate production of erythropoietin, a disturbance of erythropoiesis is due to two principal causes. (1) Cell multiplication is inhibited because DNA synthesis is insuf cient. This occurs in deficiencies of vitamin B12 or folic acid (macrocytic hyper-chromic anemia). (2) Hemoglobin synthesis is impaired. This situation arises in iron deficiency, since Fe2+ is a constituent of hemoglobin (microcytic hypochromic anemia). 

Vitamin B12 (cyanocobalamin) is produced by bacteria vitamin B12 generated in the colon, however, is unavailable for absorption. Liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 pg/day. Enteral absorption of vitamin B12 requires the so-called intrinsic factor from parietal cells of the 

Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 is required for the conversion of methyltetrahydro-FA to tetra-hydro-FA, which is important for DNA-syn-thesis (B). Inhibition of this reaction due to vitamin B12 deficiency can be compensated by increased FA intake. The anemia is readily corrected however, nerve degeneration progresses unchecked and its cause is made more dif cult to diagnose by the absence of hematological changes. Indiscriminate use of FA-containing multivitamin preparations 

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Silver, L. and Palis, J. Initiation of murine embryonic erythropoiesis a spatial analysis, Blood, 89, 1154, 1997. 

Significant ribavirin side effects include anemia and hyperbilirubinemia due to mild hemolysis and a reversible block of erythropoiesis. A published study in Sierra Leone and unpublished limited trials in West Africa reported that none of the patients with anemia required transfusions. Although ribavirin is contraindicated in pregnancy, pregnant women with confirmed Lassa fever should receive ribavirin because fetal death is nearly inevitable (95%) and because evacuation of uterine contents significantly increases the pregnant patient s chances of survival (48,56). Safety of ribavirin for children and infants is not well established (48). 

There are undifferentiated stem cells of the blood elements in the bone marrow that differentiate and mature into erythrocytes, (red blood cells), thrombocytes (platelets), and white blood cells (leukocytes and lymphocytes). The production of erythrocytes is regulated by a hormone, erythropoietin (see the section on kidney toxicity), that is synthetized and excreted by the kidney. An increase in the number of premature erythrocytes is an indication of stimulation of erythropoiesis, i.e., increased production of erythrocytes in anemia due to continuous bleeding. 

Macdougall IC (2005) CERA (Continuous Erythropoietin Receptor Activator) a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4 436-440... 

Human erythropoietin is a glycoprotein of 166 amino acids (molecular mass about 34 kDa). Its amount in plasma can be measured by radioimmunoassay. It is the major regulator of human erythropoiesis. Erythropoietin is synthesized mainly by the kidney and is released in response to hypoxia into the bloodstream, in which it travels to the bone marrow. There it interacts with progenitors of red blood cells via a specific receptor. The receptor is a transmembrane protein consisting of two different subunits and a number of domains. It is not a tyrosine kinase, but it stimulates the activities of specific... 

Dideoxyeytidine (DDC, zaleitabine), a nueleoside analogue that also inhibits reverse transeriptase, is more active than zidovudine in vitro, and (unlike zidovudine) does not suppress erythropoiesis. DDC is not without toxieity, however, and a severe peripheral neiuotoxicity, which is dose-related, has been reported. The chemical... 

Erythropoiesis is a process that starts with a pluripotent stem cell in the bone marrow that eventually differentiates into an erythroid colony-forming unit (CFU-E)4 (Fig. 63-1). The development of these cells depends on stimulation from the appropriate growth factors, primarily erythropoietin. Other cytokines involved include granulocyte-monocyte colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Eventually, the CFU-Es differentiate into reticulocytes and cross from the bone marrow into the peripheral blood. Finally, these reticulocytes mature into erythrocytes after 1 to 2 days in the bloodstream. Throughout this process, the cells gradually accumulate more hemoglobin and lose their nuclei.4... 

Since HU needs to be taken lifelong in the treatment of non-neoplastic conditions such as SCA (since the inhibition of ribonucleotide reductase is reversible) a major concern is its long term secondary effects. Several studies have shown the potential leukomegenic effect of HU in myeloproliferative disorders [22], [23]. Such concern becomes quite legitimate in sickle cell patients with permanently expanded erythropoiesis in whom the use of HU is at the limit of marrow toxicity. Hence alternative therapies must be sought for. 

A number of clinical circumstances have been identified which are characterized by an often profoundly depressed rate of erythropoiesis (Table 10.7). Many, if not all, such conditions could... 

Administration of EPO doses ranging from 50 to 150 IU kg-1 three times weekly is normally sufficient to elevate the patient s haematocrit values to a desired 32-35 per cent. (Haematocrit refers to packed cell volume , i.e. the percentage of the total volume of whole blood that is composed of erythrocytes.) Plasma EPO concentrations generally vary between 5 and 25 IU U1 in healthy individuals. One IU (international unit) of EPO activity is defined as the activity that promotes the same level of stimulation of erythropoiesis as 5 mmol of cobalt. 

In addition to enhancing erythropoiesis, EPO treatment also improves tolerance to exercise, as well as a patient s sense of well-being. Furthermore, reducing/eliminating the necessity for blood transfusions also reduces/eliminates the associated risk of accidental transmission of blood-borne infectious agents, as well as the risk of precipitating adverse transfusion reactions in recipients. The therapeutic spotlight upon EPO has now shifted to additional (non-renal) applications (Table 10.8). 

Oskarsson, A., M.C. Reid, and F.W. Sunderman, Jr. 1981. Effects of cobalt chloride, nickel chloride, and nickel subsulfide upon erythropoiesis in rats. Ann. Clin. Lab. Sci. 11 165-172. 

Niimi, G., et al. A light and electron microscopic study of the mouse visceral yolk sac endodermal cells in the middle and late embryonic periods, showing the possibility of definitive erythropoiesis, Ann. Anat., 184,425, 2002. 

About a quarter of the total body iron is stored in macrophages and hepatocytes as a reserve, which can be readily mobilized for red blood cell formation (erythropoiesis). This storage iron is mostly in the form of ferritin, like bacterioferritin a 24-subunit protein in the form of a spherical protein shell enclosing a cavity within which up to 4500 atoms of iron can be stored, essentially as the mineral ferrihydrite. Despite the water insolubility of ferrihydrite, it is kept in a solution within the protein shell, such that one can easily prepare mammalian ferritin solutions that contain 1 M ferric iron (i.e. 56 mg/ml). Mammalian ferritins, unlike most bacterial and plant ferritins, have the particularity that they are heteropolymers, made up of two subunit types, H and L. Whereas H-subunits have a ferroxidase activity, catalysing the oxidation of two Fe2+ atoms to Fe3+, L-subunits appear to be involved in the nucleation of the mineral iron core once this has formed an initial critical mass, further iron oxidation and deposition in the biomineral takes place on the surface of the ferrihydrite crystallite itself (see a further discussion in Chapter 19). 

All tissues except mature red blood cells are able to manufacture haem for use in the respiratory cytochrome proteins of the electron transport chain. However, the liver is an especially important site of haem synthesis because it (a) is a major organ of erythropoiesis in utero and (b) haem-containing cytochrome-P450 (CYP-450) enzymes play significant roles in hepatic detoxification of drugs, toxins and endogenous waste products (Section 6.4). 

Phenol is a tumor promoter in laboratory animals. In mice, dermal exposure to phenol in benzene (Boutwell and Bosch 1959) or in acetone (Salaman and Glendenning 1957 Wynder and Hoffmann 1961) increased the incidence of tumors resulting from dermal exposure to the tumor initiator, DMBA. When injected with mixtures of phenol and hydroquinone, a hydrolyzed metabolite of phenol, mice exhibited significantly depressed bone marrow erythropoiesis compared to injection with phenol alone (Chen and Eastmond 1995a). The involvement of peripheral acetylcholine in phenol-induced tremors was implicated by studies in which mice were injected with phenol and pentobarbital, an inhibitor of acetylcholine release (Itoh 1995). 

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