System erythropoiesis

About 70% of the total body store of iron (-5 g) is contained within erythrocytes. When these are degraded by macrophages of the reticuloendothelial (mononuclear phagocyte) system, iron is liberated from hemoglobin. Fe can be stored as ferritin (= protein apoferri-tin + Fe ) or returned to erythropoiesis sites via transferrin. 

Haematologic system Mild polycythaemia Stimulation of erythropoiesis... 

Hematopoietic system Increased erythropoiesis anemia1 Decreased erythropoiesis anemia1... 

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]. 

The hematopoietic system is affected by both short- and long-term arsenic exposure. Arsenic is known to cause a wide variety of hematological abnormalities like anemia, absolute neutropenia, leucopenia, thrombocytopenia, and relative eosinophilia - more common than absolute esino-philia, basophilic stippling, increased bone marrow vascularity, and rouleau formation (Rezuke et al, 1991). These effects may be due to a direct hemolytic or cytotoxic effect on the blood cells and a suppression of erythropoiesis. The mechanism of hemolysis involves depletion of intracellular GSH, resulting in the oxidation of hemoglobin (Saha et al, 1999). Arsenic exposure is also known to influence the activity of several enzymes of heme biosynthesis. Arsenic produces a decrease in ferrochelatase, and decrease in COPRO-OX and increase in hepatic 5-aminolevulinic acid synthetase activity (Woods and Southern, 1989). Subchronic... 

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... 

This chapter will provide an overview of anemia. This first section will present definitions and classification systems. A review of basic aspects of erythropoiesis, followed by laboratory evaluation of the anemia patient will then be discussed. The general similarities in the clinical presentation of the anemic patient will be presented in the text. 

Most patients who require dialysis have a normocytic normochronic anemia and a hypoproliferative bone marrow. As erythropoiesis decreases with advancing renal disease, iron shifts from circulating red cells to the reticuloendothelial system, leading to high serum ferritin levels. Repeated blood transfusion is also a common cause of iron overload and hyperferritinemia. Clearly the most important cause of the anemia of chronic renal failure is decreased erythropoietin production by the kidneys uremic patients have much lower plasma erythropoietin levels than comparably anemic patients with normal renal function (E8). Less important causes are shortened red cell survival, iron or folate deficiency, aluminum intoxication, and osteitis fibrosa cystica (E8). Uremic retention products such as methylguanidine (G10) and spermidine (R2) may also have an adverse effect on erythropoiesis. 

A mathematical model of the control system for erythropoiesis is presented. It is postulated that the rate of erythropoiesis is controlled by a hormone, erythropoietin, which is released from the kidney in response to reduced renal oxygen supply. Equations are developed relating erythropoietin release to arterial oxyhemoglobin concentration, and hemoglobin production to plasma erythropoietin concentration, with appropriate time delays. Effects of plasma volume changes during hypoxia are included. The model simulates the dynamic response of the erythropoietic system to a step decrease in the pOt of inspired air. Contributions of the parameters and relationships to the predicted response are analyzed. The model response compares favorably with experimental data obtained from mice subjected to different degrees of hypoxia. 

The balance of this paper will be devoted to a model that has been used to facilitate the understanding of a complex biological control system. The erythropoietic system is relatively simple. However, when the interactions of associated physiological systems are considered, the control of erythropoiesis becomes highly interactive and complex. 

While this concept for the control of erythropoiesis is generally accepted, there are at present insufficient data to determine quantitative relationships among the variables involved. In addition, some auxiliary systems must be included to describe fully the erythropoietic response to stress such as hypoxia. The performance of the respiratory system and the relationships expressed by the oxyhemoglobin dissociation curve affect the oxygenation state of the blood. Blood volume, and in particular plasma volume, affect hemoglobin concentration which limits the amount... 

In summary, a mathematical model has been used to investigate the role of parameters and relationships in producing a response similar to available experimental data. As a result of this work, several questions have been raised concerning the behavior of various components of the system. Thus the model has successfully served as a tool to allow confirming some ideas, questioning of others, and stimulating thought on the various relationships and interaction of the components and subsystems involved in the control of erythropoiesis. 

Cobalt inhibits cellular respiration and enzymes of the citric acid cycle, and thus generates a type of systemic hypoxia against which the organism responds with an increase of erythropoietin biosynthesis. Erythropoietin - a lipoprotein produced primarily in the kidneys and liver - in turn triggers erythropoiesis in bone marrow (Bern etal. 1986). 

Hematopoietic system Increased erythropoiesis anemia Decreased erythropoiesis anemia ... 

The molecular pattern of iron deposition in tissues determines its accessibility to chelation, and depends upon the source of iron. Excessive intestinal absorption increases circulating levels of diferric transferrin, which deposits iron in hepatocytes and the parenchymal cells of other organs. Deposition in the reticuloendothelial system (RES) occurs only in advanced disease. On the other hand, transfused red cells are turned over in the RES and iron accumulates initially in the bone marrow, spleen, and Kupffer cells of the liver. In patients with aplastic anemia, loading is purely transfusional. However, in thalassemics with ineffective erythropoiesis there is a compensatory increase in intestinal iron absorption, and iron overload can occur even in the absence of transfusion (Ellis et al. 1954 Olivieri et al. 1992b). Therefore, even initial iron deposition in transfused thalassemics affects both RES and parenchymal cells, for example both the Kupffer cells and hepatocytes of the liver. 

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