Ineffective erythropoiesis

Partial or total deficiency, or inhibition of bilirubin UDP-glucuronyltransferase may cause unconjugated hyperbilirubinemia. Increased production (hemolysis, ineffective erythropoiesis) should be excluded by investigating hematologic parameters. Determination in vitro of bilirubin UDP-glycosyltransferase activities can contribute to a differential diagnosis. To minimize the effect of cytoplasmic carrier proteins, in in vitro... 

Examination of these people revealed disruptions in bone marrow function, including cases of hypoplastic, acellular, hyperplastic, or normoblastic bone marrow. The continuing assessment further identified that ineffective erythropoiesis or increased hemolysis may have been responsible for the reticulocytosis, hyperbilirubinemia, erythroblastemia, increase in quantitative osmotic fragility, and elevated serum lactate dehydrogenase levels observed in some patients. 

Daily bilirubin production averages 4 mg/kg, and 70-80% is derived from haemoglobin degradation from senescent erythrocytes (which occurs in macrophages in the spleen, liver and bone marrow) a small amount arises from the destruction of developing erythrocytes (ineffective erythropoiesis). The remaining 20-30% of bilirubin production occurs in the liver. 

Another major use of G-CSF is for patients with neutropenia as a result of cytotoxic chemotherapy, to shorten the duration of neutropenia and reduce morbidity due to infection. It is also used for the same purpose after autologous and allogeneic bone marrow transplantation, in aplastic anaemia, AIDS, and congenital, cyclical and idiopathic neutropenia. In combination with epoetin, G-CSF can be effective in the management of some patients with myelo-dysplastic syndromes. G-CSF not only improves the neutrophil count, but dramatically improves the proportion of patients with a raised haemoglobin in response to epoetin possibly by reduction of erythroid apoptosis (the cause of ineffective erythropoiesis). 

Decreased Plasma Levels. Decreased levels of Hp are seen with genetic deficiency, hemolytic disease, ineffective erythropoiesis, estrogens, and hepatocellular disease and in neonates. 

Hemolysis, if sufficiently severe, produces an LD isoenzyme pattern similar to that in myocardial infarction. Megaloblastic anemias, usually resulting from the deficiency of folate or vitamin cause the erythrocyte precursor cell to break down in the bone marrow (ineffective erythropoiesis), resulting in the release of large quantities of LD-1 and LD-2 isoenzymes. Marked elevations of the total LD activity in serum— up to 50 times the upper reference limit—have been observed in the megaloblastic anemias. These elevations rapidly return to normal after appropriate treatment. 

Characteristics of the more common /3-thalassemia syndromes are summarized in Table 28-4. Not included are two different abnormal heterozygotes. Anemia results from precipitation of excess a-globin chains, premature red cell destruction in bone marrow and the circulation, and deficiency of functional hemoglobin tetramer. /S-Thalassemia major, or Cooley s anemia, occurs when /3-globin synthesis is markedly depressed or absent. The ineffective erythropoiesis causes massive erythroid proliferation, skeletal deformities, and extramedullary erythropoiesis. The usual treatment is frequent blood transfusion. 

The demand for folate is increased in people with thalassemia because of a more rapid cell turnover due to ineffective erythropoiesis. Where this demand cannot be met, a megaloblastic anemia may be superimposed on the thalassemia (R14, G8). This may be difficult to recognize because the abnormal synthesis of the globin moiety of hemoglobin may prevent the development of characteristic megaloblasts. A similar situation may occur in iron-deficiency anemia where characteristic megaloblasts will not develop until... 

Autohemolysis in bone marrow (ineffective erythropoiesis) will cause increased bilirubin and lactate dehydrogenase (LDH). 

In humans, hemoglobin concentration and hematocrit provide information about iron utilization in erythropoiesis. These parameters, however, can be confounded by inflammation, pregnancy, dehydration, polycythemia, hemoglobinopathies, and by deficiencies of vitamin B12 or folic acid (Gibson 1990). Plasma ferritin reflects body iron stores, but is also confounded by inflammation, liver diseases, leukemia, Hodgkin s disease, or alcohol intake. Transferrin saturation and plasma transferrin receptor are valuable parameters to support the diagnosis of iron deficiency and ineffective erythropoiesis (Thorstensen and... 

These hematopoietic precursor cells when exposed to too little folate and/or vitamin B12 show slowed cell division, but cytoplasmic development occurs at a normal rate. Hence, the megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors are usually destroyed in the bone marrow (although some reach the circulation). Thus, marrow cellularity is often increased but production of red blood cells is decreased, a condition called "ineffective erythropoiesis."... 

Jean Ann Tonich s megaloblastic anemia was treated, in part, with folate supplements (see Clinical Comments). Within 48 hours of the initiation of folate therapy, megaloblastic or "ineffective" erythropoiesis usually subsides, and effective erythropoiesis begins. 

GNT-II HEMPAS Substantially reduced activity of GNT-II responsible for ineffective erythropoiesis, multinucleated erythroblasts, anemia... 

The transient elevations in plasma activity observed in normal subjects and in pathological conditions indicate a feedback of radioiron to the plasma from other compartments, i.e. from bone marrow because of ineffective erythropoiesis and from circulating red cells because of peripheral haemolysis. The recognition of these radioiron refluxes allowed us to describe iron kinetics by a seven-compartment model (Barosi, et ai., 1978). 

A proper definition of radioiron reflux from red cells to the plasma proved to be essential for an accurate estimate of effective and ineffective erythropoiesis in severe haemolytic conditions (Stefanelli et al., 1979). Red cell death probability function is required for such definition. LSC of Cr and Fe allows one to obtain simultaenously accurate experimental data for estimating red cell death probability function and red cell iron turnover in these patients. 

Intravascular hemolysis Ineffective erythropoiesis Estrogens/pregnancy Hepatocellular disease Nephrotic syndrome (Hp 1-1) Childhood... 

Recently this type of study has been undertaken in order to quantitate ineffective erythropoiesis in normal subjects [393] and in patients with a variety of haematological disorders [387]. In these investigations the incorporation of [ N]glycine into early labelled bilirubin and haemoglobin haem was measured. [ Cj Bilirubin clearance was used to estimate total bilirubin production rate [394], and hepatic haem turnover was calculated from the incorporation of a-amino [ N]laevulinic acid into early labelled bilirubin. The relative contribution of ineffective erythropoiesis in the production of anaemia found in these... 

Figure 1.8. The role of ineffective erythropoiesis in the production of various anaemias. The actual haemo obin (Hb), , is compared to the potential Hb, which would be achieved if...

A third small fraction of ELB but of erythropoietic origin appears in several days after a glycine tracer is administered. It may be derived from ineffective erythropoiesis or from the developing normoblast at the time of red cell maturation, perhaps at the time the nucleus is lost. In contrast to all these early fractions of bilirubin, the major fraction of bilirubin is derived from hemoglobin which is released when the red cell dies— that is, in about 120 days in humans. 

B vitamins also play important roles in haematopoiesis (Fishman et al. 2000). For example, folate deficiency by impairing DNA synthesis leads to ineffective erythropoiesis, and as a result a macrocytic anaemia develops. Deficiency of vitamin B12, by impairing functions of folic acid, leads to ineffective ery-thropoeisis and in turn to macrocytic anaemia. Vitamin Bg is also required in synthesis of haem, a component of haemoglobin and perhaps for mobilization of iron from stores. Vitamin B2 is known to mobilize stored iron from the liver and its deficiency is associated with anaemia. 

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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