Erythropoiesis

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... 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

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... 

Require between 150 and 200 mg elemental iron per day for adequate erythropoiesis (e.g., ferrous sulfate 325 mg enterally TID provides 195 mg of elemental iron)... 

Patients with CKD should be evaluated for anemia when the GFR falls below 60 mL/minute or if the serum creatinine rises above 2 mg/dL (176.8 mmol/L). If the Hgb is less than 11 g/dL (6.8 mmol/L), an anemia work-up should be performed. The work-up for anemia should rule out other potential causes for anemia (see Chapter 63). Abnormalities found during the anemia work-up should be corrected before initiating erythropoiesis-stimulating agents (ESA),... 

The first-line treatment for anemia of CKD involves replacement of erythropoietin with erythropoiesis-stimulating agents (ESAs). Use of ESAs increases the iron demand for RBC production and iron deficiency is common, requiring iron supplementation to correct and maintain adequate iron stores to promote RBC production. Androgens were used extensively... 

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... 

Anemia from vitamin BI2 or folic acid deficiency is treated effectively by replacing the missing nutrient. Both folic acid and vitamin B12 are essential for erythrocyte production and maturation. Replacing these factors allows for normal DNA synthesis and, consequently, normal erythropoiesis. 

Folic acid supplementation with 1 mg daily generally is recommended in adult SCD patients, women considering pregnancy, and any SCD patient with chronic hemolysis.6 Because of accelerated erythropoiesis, these patients have an increased need for folic acid. There are conflicting studies in the SCD population, especially among infants and children, but if the child has chronic hemolysis, supplementation is recommended.21... 

Erythropoiesis-stimulating agents Agents developed by recombinant DNA technology that have the same biologic activity as endogenous erythropoietin to stimulate erythropoiesis (red blood cell production) in the bone marrow. 

Bogden JD, Kemp FW, Han S, et al. 1995. Dietary calcium and lead interact to modify maternal blood pressure, erythropoiesis, and fetal and neonatal growth in rats during pregnancy and lactation. J Nutr 125 990-1002. 

Fluxes of iron from the plasma towards BM and other tissues can be quantified by ferrokinetic studies, using 59Fe and sophisticated computer models (Ricketts et ah, 1975 Ricketts and Cavill, 1978 Barosi et ah, 1978 Stefanelli et ah, 1980). Plasma iron turnover (PIT), erythroid iron turnover (EIT), non-erythroid iron turnover (NEIT), marrow iron turnover (MIT), and tissue iron turnover (TIT) could be calculated in many disorders of iron metabolism and in all kinds of anaemias. Iron is rapidly cleared from the plasma in iron deficiency and in haemolytic anaemias. If more iron is needed for erythropoiesis, more transferrin receptors (TfR) are expressed on erythroblasts, resulting in an increased flux of iron from intestinal mucosal cells towards the plasma. In haemolytic anaemias MPS, and subsequently hepatocytes, are overloaded. In hereditary haemochromatosis too much iron is absorbed by an intrinsic defect of gut mucosal cells. As this iron is not needed for erythropoiesis,... 

Body iron content is the principal factor in the regulation of iron absorption (Marx,1979a,b). However, other physiological variables, such as erythropoietic rate (Bothwell, 1968), hypoxia (Raja et ah, 1988) and inflammation (Weber et ah, 1988) also influence iron absorption. In normal individuals, if the rate of erythropoiesis is stimulated by blood loss, dyserythropoiesis or acute haemolysis, iron absorption is increased. Conversely, if erythropoiesis is inhibited by hypertransfusion, starvation or descent from high altitude to sea level, then iron absorption decreases. The adaptive response of iron absorption to increased erythropoiesis, stimulated... 

Wang Q, Khillan J, Gadue P, Nishi-kura K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 2000 290[5497] 1765—1768. 

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