PCOL 301.6Nov. 2004

Hematopoesis and Anemia

Pluripotent stem cells give rise to different types of blood cells such as erythrocytes, leukocytes and platelets. These stem cells differentiate under the influence of various cellular and humoral growth factors. One colony of such cells forms the erythrocytes under the influence of erythropoietin and other growth factors.Erythropoetin, a glycoprotein, is a major growth factor for red cell production. In its absence severe anemia is present. Erythropoesis is controlled by a feedback system in the kidney which responds to changes in oxygen delivery and secretes erythropoietin from peritubular interstitial cells, which then stimulates the marrow cells to produce erythrocytes. This feedback can be disrupted by kidney disease, marrow damage or a deficiency in iron or an essential vitamin.

Recombinant erythropoietin (epoetin alfa- EPOGEN and PROCRIT) is similar and is supplied in vials of from 2000 to 10,000 U/ml for iv or sc administration. It is normally given three times a week (t1/2 10 h). No significant allergy reported.

Uses of epoetin alfa:It is useful in anemia associated with a poor erythropoetic response – especially anemia of chronic renal failure. Subcutaneous route is preferred over iv route since it reduces the required dose by 20% to 40% due to slower absorption. Iron stores should be sufficient, if not, iron dextran is given.

Recommended starting dose is 80 – 120 U/kg of epoetin alfa, given sc three times a week. The dose is progressively increased if the response is poor. The maintenance dose can vary from 10 U/kg to 300 U/kg with an average of 75 U/kg, three times a week in most patients. Children under the age 5 generally require a higher dose. Resistance to therapy is seen if the patient develops an inflammatory disease or becomes iron deficient.

The most common side effect to epoetin alfa is aggravation of hypertension, seen in 20% to 30% of patients and most often associated with a too rapid rise in hematocrit.

Epoetin is also used in:

- anemias associated with surgery, such as orthopedic and cardiac surgery – it reduces the need for blood transfusion. E.g. 150 – 300 U/kg epoetin alfa once daily for the 10 days preceding surgery andon the day and 4 days after surgery.

- AIDS patients, especially those treated with zidovudine. E.g. 100 – 300 U/kg, sc three times a week.

- Cancer chemotherapy – e.g. 150 U/kg three times a week or 450 – 600 U/kg once a week.

Anemia of prematurity and certain chronic inflammatory illnesses.

Highly competitive athletes use epoetin alfa to increase their hemoglobin level (“blood doping”). Misuse can cause death.

Iron deficiency anemia

Iron deficiency anemia is the most common cause of anemia. It can result from inadequate iron intake (nutritional), malabsorption, pathological blood loss (in men and post-menopausal women especially that from the gastrointestinal tract), or an increased requirement in women (pregnancy, menstruation, lactation) and for growth in infants and children.

When severe it causes a characteristic microcytic, hypochromic anemia.

Iron deficiency also affects iron-dependent enzymes such as cytochromes, catalase, peroxidase, xanthine oxidase and mitochondrial enzyme α-glycerophosphate oxidase.

Iron deficiency has also been associated with learning problems in children.

Although the total dietary intake of elemental iron in human beings usually exceeds requirements, the bioavailability of the iron in diet is limited.

Metabolism of iron: The body store of iron consists of essential iron-containing compounds (hemoglobin, myoglobin and iron-dependent enzymes) and excess iron in storage form (ferritin – an iron storage protein). Aggregated ferritin, known as hemosiderin, constitutes about one third of iron stores. The two predominant sites of iron storage are the reticuloendothelial system and hepatocytes. Internal exchange of iron is accomplished by transferrin.

Foods high in iron (greater than 5 mg/100 g) include organ meats such liver and heart, brewer’s yeast, wheat germ, egg yolks, oysters and certain dried beans and fruits; foods low in iron (less than 1 mg/100 g) include milk and milk products and most non-green vegetables.

In the diet heme iron is far more available. It constitutes about 6% of the dietary iron and represents 30% of iron absorbed. Nonheme iron is the major fraction of dietary iron. In the vegetarian diet nonheme iron is poorly absorbed because of the inhibitory action of a variety of dietary components, particularly phosphates.

Two substances that facilitate absorption of nonheme iron are ascorbic acid and meat. Ascorbate forms complexes with and /or reduces ferric iron to ferrous iron. Meat stimulates gastric acid production.

In developing countries as many as 20% to 40% of infants and pregnant women are iron-deficient. In the US 0.2 % to 3% of adult men and women are iron-deficient. Iron fortified flour, iron-fortified formulas for infants and medicinal iron supplements during pregnancy have helped.

Therapy: The ability of the patient to tolerate and absorb medicinal iron is important. Gastrointestinal tolerance to oral iron is limited.It is mainly absorbed only in the upper small intestinal. Complicating illness (e.g. disease of the marrow) can affect the response by decreasing the number of red cell precursors. Inflammatory illnesses can suppress the rate of red cell production by reducing iron absorption and reticuloendothelial release and by inhibition of erythropoietin and erythroid precursors.

Ferrous sulfate –least expensive – treatment of choice. Ferrous salts are absorbed about three times as well as ferric salts. Sulfate, fumarate, gluconate, succinate and others are absorbed to approximately the same extent.

Ferrous sulfate (FEOSOL) – 20% iron

Dried ferrous sulfate – 32% elemental iron

Ferrous fumarate (FEOSTAT) – 33% iron

Ferrous gluconate – (FERGON) – 12% iron

Polysaccharide iron complex (NIFEREX) – a compound of ferrihydrite and carbohydrate.

Coating of tablets should dissolve rapidly in the stomach. Effectiveness of delayed-release preparations is questionable.

Iron compounds used in food fortification: Reduced iron (metallic iron, elemental iron) is as effective as ferrous sulfate, provided that the material employed has a small particle size.

Ferrum reductum (large particle), iron phosphate salts have a lower bioavailability. Ferric edetate – has good bioavailability.

Surface-acting agents, carbohydrates, inorganic salts, amino acids and vitamins have been used to enhance absorption.Ascorbic acid, 200 mg or more, increases absorption by at least 30% (with increased incidence of side effects too).

Average dose – 200 mg of iron per day (2-3 mg/kg) given in three equal doses of 65 mg. children weighing 15 to 30 kg can take half the average adult dose, while small children and infants can tolerate relatively large doses – e.g 5 mg/kg.

When the object is prevention in pregnant women, doses of 15 to 30 mg of iron per day are adequate to meet the 3-6 mg mg daily requirement of the last two trimesters. When the purpose is to treat iron-deficiency anemia, without haste, a total dose of about 100 mg (35 mg three times daily) may be used.

Parenteral iron: May be an effective alternative when oral therapy fails.

Indications: malabsorption, severe oral iron intolerance, as a routine supplement to total parenteral nutrition and in patients with renal disease who are receiving erythrpoietin. Parenteral iron therapy should only be used when clearly indicated, since acute hypersensitivity, including anaphylactoid reactiosn, can occur in from 0.2% to 3% of patients.

Iron dextran injection (INFED, DEXFERRUM) – colloidal solution of ferric oxyhdroxide complexed with polymerized dextran – contains 50 mg/ml of elemental iron. Adminsitered by im or iv injection. Iv is preferred – gives a more reliable response. Im route – more local side effects – skin discoloration, long-term discomfort, concern about malignant change at injection site.

Sodium ferric gluconate complex in sucrose (FERRILECIT) – used in treatment of iron deficiency in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy.

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