Erythropoietin marrow

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. 

Erythropoietin is a growth factor produced by interstitial cells of the kidney in response to hypoxia. Erythropoietin stimulates haematopoiesis in the bone marrow. Recombinant human erythropoietin is used to treat anemias, e.g. anemia caused by chronic renal failure and anemia in AIDS and cancer patients. 

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... 

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... 

Bone marrow suppression ZDV Onset Few weeks to months Symptoms Fatigue, risk of T bacterial infections due to neutropenia anemia, neutropenia 1. Advanced HIV 2. High dose ZDV 3. Preexisting anemia or neutropenia 4. Concomitant use of bone marrow suppressants Avoid in patients with high risk for bone marrow suppression avoid other suppressing agents monitor CBC with differential at least every 3 months Switch to another NRTI D/C concomitant bone marrow suppressant, if possible for anemia Identify and treat other causes consider erythropoietin treatment or blood transfusion, if indicated for neutropenia Identify and treat other causes consider filgrastim treatment, if indicated... 

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. 

Erythropoietin A hormone primarily produced by the progenitor cells of the kidney that stimulates red blood cell production in the bone marrow. Lack of this hormone leads to anemia. 

Although the kidneys are not considered endocrine glands per se, they are involved in hormone production. Erythropoietin is a peptide hormone that stimulates red blood cell production in bone marrow. Its primary source is the kidneys. Erythropoietin is secreted in response to renal hypoxia. Chronic renal disease may impair the secretion of erythropoietin, leading to development of anemia. The kidneys also produce enzymes. The enzyme renin is part of the renin-angiotensin-aldosterone system. As will be discussed, these substances play an important role in the regulation of plasma volume and therefore blood pressure. Other renal enzymes are needed for the conversion of vitamin D into its active form, 1,25-d i hyd ro xyv itamin D3, which is involved with calcium balance. 

Erythropoietin Erythropoietin (EPO) (Fig. 4.8) is a glycoprotein produced by specialized cells in the kidneys. It has 166 amino acids and a molecular weight of approximately 36kDa.EPO stimulates the stem cells of bone marrow to produce red blood cells. It is used to treat anemia and chronic infections such as HIV and cancer treatment with chemotherapy where anemia is induced. Patients feel tired and breathless owing to the low level of red blood cells. EPO can be prescribed instead of blood transfusion. 

Erythropoietin is a peptide hormone that is formed predominantly by the kidneys, but also by the liver. Together with other factors known as colony-stimulating factors" (CSF see p.392), it regulates the differentiation of stem cells in the bone marrow. 

Erythropoietin release is stimulated by hypoxia (low PO2). Within hours, the hormone ensures that erythrocyte precursor cells in the bone marrow are converted to erythrocytes, so that their numbers in the blood increase. Renal damage leads to reduced erythropoietin release, which in turn results in anemia. Forms of anemia with renal causes can now be successfully treated using erythropoietin produced by genetic engineering techniques. The hormone is also administered to dialysis patients. Among athletes and sports professionals, there have been repeated cases of erythropoietin being misused for doping purposes. 

Pharmacology Erythropoietin is a glycoprotein that stimulates red blood cell production. It is produced in the kidney and stimulates the division and differentiation of erythroid progenitors in bone marrow. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis. In patients with CRF, erythropoietin production is impaired this deficiency is the primary cause of their anemia. Epoetin alfa stimulates erythropoiesis in anemic patients on dialysis and those who do not require regular dialysis. 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

Criswell, K.A., Sulkanen, A.P., Hochbaum, A.F. and Bleavins, M.R. (2000) Effects of phenylhydrazine or phlebotomy on peripheral blood, bone marrow and erythropoietin in wistar rats. Journal of Applied Toxicology, 20, 25—34. 

The kidney normally manufactures erythropoietin, the growth factor for the production of red blood cells. In fact, erythropoietin was first isolated from the urine of patients with anemia, a condition characterized by too few red blood cells. Red cells carry oxygen to the body s tissues, and if too little oxygen is delivered to them, certain kidney cells produce erythropoietin. Most of this substance goes into the blood, where it circulates to the bone marrow and other tissues and triggers increased production of red cells from immature cells. Some erythropoietin spills into the urine. The concentration of erythropoietin in the blood is very low. The concentration is even lower in urine, but urine is easy, safe, and cheap to collect, and it does not contain a large number of other proteins. 

Many cytokines play a regulatory role in processes other that immunity and inflammation. Neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) regulate growth, development and maintenance of various neural populations in the central and peripheral nervous system. Erythropoietin stimulates the production of red blood cells from erythroid precursors in the bone marrow. 

Recombinant erythropoietin, a hormone normally secreted by the kidney, which stimulates the production of red blood corpuscles, also shows interesting clearance mechanisms. Arguing from the G-CSF case you might guess that it will be taken up by the cells of the bone marrow which is its site of action. This is the case, and up to half of the clearance of erythropoietin is through the marrow itself. 

Physiologically, oxygen transport to metabolising tissues is provided by haemoglobin contained within erythrocytes. This pathway starts in the bone marrow with immunohaematopoietic stem cells that differentiate to progenitors which proliferate to yield the recognisable normoblasts. The latter mature to reticulocytes, which are then released into the circulation. Overall regulation is primarily mediated by the renal hormone called erythropoietin. 

Studies indieate that the erythrocytosis is mediated by an inereased renal produetion of erythropoietin. Erythropoietin is a protein produced by the kidney, which enhances erythropoiesis by stimulating the formation of proerythrocytes and the release of retieulocytes from the bone marrow. Overall, the results indicate that niekel exposure results in hematological effects in both humans and... 

Clinical pharmacology Erythropoietin is instrumental in the production of red cells from the erythroid tissues in the bone marrow. The majority of this hormone is produced in the kidney in response to hypoxia, with an additional 10% to 15% of synthesis occurring in the hver. Erythropoietin functions as a growth factor, stimulating the mitotic activity of the erythroid progenitor cells and early precursor cells. Chronic renal failure patients often manifest the sequelae of renal dysfunction, including anemia. Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents. 

These studies demonstrating a protective effect of sialic acid residues on serum glycoproteins provide an explanation for earlier, conflicting observations about the biological effect of, for example, desialylated erythropoietin, which stimulates erythropoiesis only after direct application to bone-marrow cell-cultures, and not after injection into the blood stream.469 In the latter experiment, only the native, sialylated hormone was active. Rapid clearance and inactivation of follicle-stimulating hormone,470 or interferon,471 after treatment with sialidase may be explained by uptake into liver cells. 

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Stimulates erythroid proliferation and differentiation, and induces the release of reticulocytes from the bone marrow Treatment of anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity prevention of the need for transfusion in patients undergoing certain types of elective surgery IV or SC administration 1-3 times per week Toxicity Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia to reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL... 

Anemia. Testosterone and similar compounds are potent stimulators of erythropoietin synthesis from the kidneys and other tissues.109 Erythropoietin, in turn, stimulates production of red blood cell synthesis in bone marrow. Human erythropoietin, however, can now be synthesized using recombinant DNA techniques. Hence, various types of anemia that occur secondary to renal disease, cancer chemotherapy, and so forth are usually treated directly with recombinant erythropoietin.109 Nonetheless, androgens may be used as an adjunct to erythropoietin and other drugs to stimulate red blood cell production in certain patients with severe or recalcitrant anemia.10... 

In selected patients, erythropoietin may also be useful for the treatment of anemia due to primary bone marrow disorders and secondary anemias. This includes patients with aplastic anemia and other bone marrow failure states, myeloproliferative and myelodysplastic disorders, multiple myeloma and perhaps other chronic bone marrow malignancies, and the anemias associated with chronic inflammation, AIDS, and cancer. Patients with these disorders who have disproportionately low serum erythropoietin levels for their degree of anemia are most likely to respond to treatment with this growth factor. Patients with endogenous erythropoietin levels of less than 100 IU/L have the best chance of response, though patients with erythropoietin levels between 100 and 500 IU/L respond occasionally. These patients generally require higher erythropoietin doses (150-300 IU/kg three times a week) to achieve a response, and responses are often incomplete. 

Epoetin-oc (recombinant human erythropoietin) is approved for the treatment of anemia in hemodialysis patients and those receiving chemotherapy. A hyperglyco-sylated analogue of erythropoietin (darbepoetin-oc) that has a lower clearance rate and can be dosed less frequently has also been approved. Erythropoietin stimulates the proliferation of erythrocyte progenitor cells in bone marrow and increases peripheral red blood cell (RBC) counts. 

The formed elements of blood are red blood cells, platelets, and leukocytes. Red blood cells, or erythrocytes (Figure 9.2), are flexible biconcave disk-shaped bodies whose main function is to carry oxygen to tissue bound to the hemoglobin that they contain. They are generated in the marrow of various bones by the action of stem cells. The hormone erythropoietin stimulates erythrocyte production in response to tissue needs for oxygen. Marrow stem cells also produce platelets, tiny cell fragments that contain the biochemicals necessary for blood clotting. The third kind of formed elements consists of leukocytes, which are defensive white blood cells. 

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