Defective erythropoiesis

Defective erythropoiesis (dyserythropoiesis) impaired hemoglobin synthesis leading to lack of utilization and consequent accumulation of iron in mitochondria, e.g., from inhibition of ALA synthase activity by dietary vitamin 85 deficiency inhibition of heme synthesis by lead impairment of pyridoxine metabolism in alcoholic patients familial sideroblastic anemias and Cooley s anemia. 

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,... 

Most patients with Al intoxication develop an erythropoietin-resistant microcytic anemia in the absence of iron deficiency, and this may be a useful early indication of Al toxicity [41,93,254,255]. The chemical similarity between Fe3+ and Al3+ suggest that both elements will have similar metabolic effects, suggesting that iron and Al compete during erythropoiesis, resulting from a reversible block in heme synthesis due either to a defect in porphyrin synthesis or to impaired iron utilization. It was also suggested that the main mechanisms for Al toxicity in the erythropoietic system are the interference of Al in the uptake and utilization of iron and an interaction of Al with cellular membrane components, affecting not only their structures but also their functions [256]. 

Iron deficiency is the most common cause of resistance to erythropoietic therapy. Evaluation and treatment of iron deficiency should occur prior to initiation of erythropoietic therapy as previously discussed (see Figs. 44—1 and 44—2). Inflammation (localized or systemic infection, active inflammatory disease, or surgical trauma) is associated with defective iron utilization known as reticuloendothelial block. Reticuloendothelial block is characterized by a reduction in iron delivery from body stores to the bone marrow, and is generally refractory to iron therapy. Failure to respond to erythropoietic therapy requires evaluation of other factors causing resistance, such as infection, inflammation, chronic blood loss, aluminum toxicity, hemoglobinopathies, malnutrition, and hyperparathyroidism. Erythropoietic therapy may be continued in the infected or postoperative patient, although increased doses are often required to maintain or slow the rate of decline in Hgb/Hct. Deficiencies in folate and vitamin Bi2 should also be considered as potential causes of resistance to erythropoietic therapy, as both are essential for optimal erythropoiesis. Patients on hemodialysis or peritoneal dialysis should be routinely... 

Suboptimal erythropoiesis can be classified by changes in the size of RBCs noted on examination of the peripheral blood. Because the excretory and endocrine functions of the kidney usually mirror each other, renal dysfunction can lead to anemia by reduction in EPO production, resulting in a normochromic, normocytic pattern. Other causes of insufficient erythropoiesis include replacement of bone marrow by fibrosis, solid tumors, or leukemia, as well as defects in erythroid maturation. Relative deficiencies in the cofactors required for heme-RBC synthesis such as iron, folate, and vitamin B may also be important contributors. Structurally, RBC macrocytosis denotes defects in the maturation of the nucleus, whereas microcytosis is indicative of cytoplasmic defects (reduced hemoglobin synthesis). (A detailed description regarding the pathogenesis and treatment of anemic disorders is found in Chap. 99.)... 

A severe decrease in P-globin levels leads to the precipitation of the a-chain, which in turn causes a defect in the maturation of the erythroid precursor, and erythropoiesis thus reducing red cell survival. The profound anemia in the affected individual stimulates the production of erythropoietin leading to the expansion of bone marrow and subsequent skeletal deformities. The hyperplasia of the bone marrow induces increased iron absorption leading to the deposition of iron in tissues. If the concentration of iron in the tissues becomes too high, it can lead to organ failure and death if appropriate therapeutic steps are not taken. 

Exogenous folate is required for nucleoprotein synthesis and maintenance of normal erythropoiesis. Folic acid stimulates production of red and white blood cells and platelets in certain megaloblastic anemias. Folic acid is the precursor of tetrahy-drofolic acid, which is involved as a cofactor for transform-ylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to mega-loblast formation and megaloblastic and macrocytic anemias. 

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