Anemia -

Vitamin B12-Deficiency Anemia

Vitamin B12-Deficiency Anemia. Vitamin B12, also known as cobalamin, serves as a cofactor for two important reactions in humans. It is essential for DNA synthesis and nuclear maturation, which in turn leads to normal red cell maturation and division. 5,20 Vitamin B12 is also involved in a reaction that prevents abnormal fatty acids from being incorporated into neuronal lipids. This abnormality may predispose to myelin breakdown and produce some of the neurologic complications of vitamin B12 deficiency.5 Vitamin B12 is found in all foods of animal origin. Dietary deficiency is rare and usually found only in strict vegetarians who avoid all dairy products as well as meat and fish. Vitamin B12 is absorbed by a unique process. After release from the animal protein, it is bound to intrinsic factor, a protein secreted by the gastric parietal cells (Fig. 13-11). The vitamin B12-intrinsic factor com- plex protects vitamin B12 from digestion by intestinal enzymes. The complex travels to the ileum, where it binds to membrane receptors on the epithelial cells. Vitamin B12 is then separated from intrinsic factor and transported across the membrane into the circulation. There it is bound to its carrier protein, transcobalamin II, which transports vitamin B12 to its storage and tissue sites. An important cause of vitamin B12 deficiency is perni- cious anemia, resulting from an atrophic gastritis (see Chapter 29). Pernicious anemia is believed to result from immunologically mediated, possibly autoimmune, destruc- tion of the gastric mucosa. The resultant chronic atrophic gastritis is marked by loss of parietal cells and production of antibodies that interfere with binding of vitamin B12 to intrinsic factor. Other causes of vitamin B12 deficiency anemia include gastrectomy, ileal resection, inflamma- tion or neoplasms in the terminal ileum, and malabsorp- tion syndromes in which vitamin B12 and other B-vitamin compounds are poorly absorbed. Dietary vitamin B12 The hallmark of vitamin B12 deficiency is megaloblastic anemia. When vitamin B12 is deficient, the red cells that are produced are abnormally large because of excess cytoplasmic growth and structural proteins (see Fig. 13- 8). The cells have immature nuclei and show evidence of cellular destruction. They have flimsy membranes and are oval rather than biconcave. These oddly shaped cells have a short life span that can be measured in weeks rather than months. The loss of red cells results in a mod- erate to severe anemia and mild jaundice. The MCV is elevated, and the MCHC is normal. As with other ane- mias, there is pallor, easy fatigability, and in severe cases dyspnea. The megaloblastic state also produces changes in mucosal cells, leading to glossitis (sore tongue), as well as other vague gastrointestinal disturbances such as anorexia and diarrhea. Vitamin B12 deficiency also leads to a complex neurologic syndrome caused by deranged methylation of myelin protein. Demyelination of the dorsal and lateral columns of the spinal cord causes symmetric paresthesias of the feet and fingers, loss of vibratory and position sense, and eventual spastic ataxia. In more advanced cases, cerebral function may be altered. In some cases, dementia and other neuropsychiatric changes may precede hematologic changes. Diagnosis of vitamin B12 deficiency is made by finding an abnormally low serum vitamin B12 level. The diagnosis of pernicious anemia is usually made by the detection of parietal cell and intrinsic factor antibodies.19 Lifelong treatment consisting of intramuscular injections or high oral doses of vitamin B12 reverses the anemia and pre- vents the neurologic changes.

Overview

Anemia is a condition that develops when your blood lacks enough healthy red blood cells or hemoglobin. Hemoglobin is a main part of red blood cells and binds oxygen. If you have too few or abnormal red blood cells, or your hemoglobin is abnormal or low, the cells in your body will not get enough oxygen. Symptoms of anemia -- like fatigue -- occur because organs aren't getting what they need to function properly.

Sickle cell complications

Complications By Mayo Clinic Staff Sickle cell anemia can lead to a host of complications, including: Stroke. A stroke can occur if sickle cells block blood flow to an area of your brain. Signs of stroke include seizures, weakness or numbness of your arms and legs, sudden speech difficulties, and loss of consciousness. If your baby or child has any of these signs and symptoms, seek medical treatment immediately. A stroke can be fatal. Acute chest syndrome. This life-threatening complication of sickle cell anemia causes chest pain, fever and difficulty breathing. Acute chest syndrome can be caused by a lung infection or by sickle cells blocking blood vessels in your lungs. It may require emergency medical treatment with antibiotics and other treatments. Pulmonary hypertension. People with sickle cell anemia can also develop high blood pressure in their lungs (pulmonary hypertension). This complication usually affects adults rather than children. Shortness of breath and fatigue are common symptoms of this condition, which can be fatal. Organ damage. Sickle cells can block blood flow through blood vessels, immediately depriving an organ of blood and oxygen. In sickle cell anemia, blood is also chronically low on oxygen. Chronic deprivation of oxygen-rich blood can damage nerves and organs in your body, including your kidneys, liver and spleen. Organ damage can be fatal. Blindness. Tiny blood vessels that supply your eyes can get blocked by sickle cells. Over time, this can damage the portion of the eye that processes visual images (retina) and lead to blindness. Skin ulcers. Sickle cell anemia can cause open sores, called ulcers, on your legs. Gallstones. The breakdown of red blood cells produces a substance called bilirubin. A high level of bilirubin in your body can lead to gallstones. Priapism. Men with sickle cell anemia may experience painful, long-lasting erections, a condition called priapism. As occurs in other parts of the body, sickle cells can block the blood vessels in the penis. This can damage the penis and eventually lead to impotence.

Blood loss

Red blood cells can be lost through bleeding, which can occur slowly over a long period of time, and can often go undetected. This kind of chronic bleeding commonly results from the following: Gastrointestinal conditions such as ulcers, hemorrhoids, gastritis (inflammation of the stomach), and cancer Use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirinor ibuprofen, which can cause ulcers and gastritis Menstruation and childbirth in women, especially if menstrual bleeding is excessive and if there are multiple pregnancies

Sickle Cell Causes

Sickle cell anemia is caused by a mutation in the gene that tells your body to make hemoglobin — the red, iron-rich compound that gives blood its red color. Hemoglobin allows red blood cells to carry oxygen from your lungs to all parts of your body. In sickle cell anemia, the abnormal hemoglobin causes red blood cells to become rigid, sticky and misshapen. The sickle cell gene is passed from generation to generation in a pattern of inheritance called autosomal recessive inheritance. This means that both the mother and the father must pass on the defective form of the gene for a child to be affected. If only one parent passes the sickle cell gene to the child, that child will have the sickle cell trait. With one normal hemoglobin gene and one defective form of the gene, people with the sickle cell trait make both normal hemoglobin and sickle cell hemoglobin. Their blood may contain some sickle cells, but they generally don't experience symptoms. However, they are carriers of the disease, which means they can pass the defective gene on to their children. With each pregnancy, two people with sickle cell traits have: A 25 percent chance of having an unaffected child with normal hemoglobin A 50 percent chance of having a child who also is a carrier A 25 percent chance of having a child with sickle cell anemia

Sickle Cell symptoms

Signs and symptoms of sickle cell anemia often don't appear until an infant is at least 4 months old and may include: Anemia. Sickle cells are fragile. They break apart easily and die, leaving you without a good supply of red blood cells. Red blood cells usually live for about 120 days before they die and need to be replaced. But sickle cells die after an average of less than 20 days. This results in a lasting shortage of red blood cells (anemia). Without enough red blood cells in circulation, your body can't get the oxygen it needs to feel energized. That's why anemia causes fatigue. Episodes of pain. Periodic episodes of pain, called crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones. The pain may vary in intensity and can last for a few hours to a few weeks. Some people experience only a few episodes of pain. Others experience a dozen or more crises a year. If a crisis is severe enough, you may need to be hospitalized. Hand-foot syndrome. Swollen hands and feet may be the first signs of sickle cell anemia in babies. The swelling is caused by sickle-shaped red blood cells blocking blood flow out of their hands and feet. Frequent infections. Sickle cells can damage your spleen, an organ that fights infection. This may make you more vulnerable to infections. Doctors commonly give infants and children with sickle cell anemia vaccinations and antibiotics to prevent potentially life-threatening infections, such as pneumonia. Delayed growth. Red blood cells provide your body with the oxygen and nutrients you need for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers. Vision problems. Some people with sickle cell anemia experience vision problems. Tiny blood vessels that supply your eyes may become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images.

Folic Acid-Deficiency Anemia

Folic Acid-Deficiency Anemia. Folic acid is also required for DNA synthesis and red cell maturation, and its deficiency produces the same type of megaloblastic red cell changes that occur in vitamin B12-deficiency ane- mia (i.e., increased MCV and normal MCHC). Folic acid is readily absorbed from the intestine. It is found in vegetables (particularly the green leafy types), fruits, cereals, and meats. Much of the vitamin, however, is lost in cooking. The most common causes of folic acid deficiency are malnutrition or dietary lack, especially in the elderly or in association with alcoholism. Total body stores of folic acid amount to 2000 to 5000 g, and 50 g is required in the daily diet.6 A dietary deficiency may result in anemia in a few months. Malabsorption of folic acid may be due to syndromes such as celiac disease or other intestinal disorders. Some drugs used to treat seizure disorders (e.g., primidone, phenytoin, phenobar- bital) and triamterene, a diuretic, predispose to a deficiency by interfering with folic acid absorption. In neoplastic disease, tumor cells compete for folate, and deficiency is common. Methotrexate, a folic acid analog used in the treatment of cancer, impairs the action of folic acid by blocking its conversion to the active form. Because pregnancy increases the need for folic acid 5- to 10-fold, a deficiency commonly occurs. Poor dietary habits, anorexia, and nausea are other reasons for folic acid deficiency during pregnancy. Studies also show an association between folate deficiency and neural tube defects The features of folic acid deficiency are similar to those of vitamin B12 deficiency, with megaloblastic ane- mia and symptoms referable to changes in the mucosal surface of the gastrointestinal tract. However, there are none of the neurologic abnormalities associated with B12 deficiency.

Hemolytic

Hemolytic anemia is characterized by the premature destruction of red cells, the retention in the body of iron and the other products of hemoglobin destruction, and a compensatory increase in erythropoiesis. 5,6 Almost all types of hemolytic anemia are distinguished by normo- cytic and normochromic red cells. Because of the red blood cell's shortened life span, the bone marrow usually is hyperactive, resulting in an increased number of reticu- locytes in the circulating blood. As with other types of anemia, the person experiences easy fatigability, dyspnea, and other signs and symptoms of impaired oxygen transport. Hemolytic anemias are commonly classified according to whether the defect is intrinsic to the red cell or due to some external factor.5 Intrinsic factors have been described for all components of the red cell, including the cell membrane, enzyme systems, and hemoglobin, most of which are hereditary. Extrinsic or acquired factors include immune mechanisms, mechanical trauma, and infections. Destruction of red cells can occur within the vascular compartment (intravascular) or within the phagocytic cells of the reticuloendothelial system (extravascular) Intravascular hemolysis is less common and occurs as a result of mechanical injury caused by defective cardiac valves, complement fixation in transfusion reactions, or exogenous toxic factors. Regardless of cause, intravascu- lar hemolysis leads to hemoglobinemia, hemoglobinuria, and hemosiderinuria.

Iron deficiency anemia

Iron deficiency is a common worldwide cause of anemia affecting persons of all ages. The anemia results from dietary deficiency, loss of iron through bleeding, or increased demands. Because iron is a component of heme, a deficiency leads to decreased hemoglobin syn- thesis and consequent impairment of oxygen delivery. Body iron is used repeatedly. When red cells become senescent and are broken down, their iron is released and reused in the production of new red cells. Despite this efficiency, small amounts of iron are lost in the feces and need to be replaced by dietary uptake. Iron balance is maintained by the absorption of 0.5 to 1.5 mg daily to replace the 1 mg lost in the feces. The average Western diet supplies about 20 mg.6 The absorbed iron is more than sufficient to supply the needs of most individuals, but may be barely adequate in toddlers, adolescents, and women of child-bearing age. The usual reason for iron deficiency in adults in the Western world is chronic blood loss because iron cannot be recycled to the pool. In men and postmenopausal women, blood loss may occur from gastrointestinal bleeding because of peptic ulcer, intestinal polyps, hemor- rhoids, or cancer. Excessive aspirin intake may cause undetected gastrointestinal bleeding. In women, menstru- ation may account for an average of 1.5 mg of iron lost per day, causing a deficiency.15 Although cessation of menstruation removes a major source of iron loss in the pregnant woman, iron requirements increase at this time, and deficiency is common. The expansion of the mother's blood volume requires approximately 500 mg of addi- tional iron, and the growing fetus requires approximately 360 mg during pregnancy. In the postnatal period, lacta- tion requires approximately 1 mg of iron daily.15 A child's growth places extra demands on the body. Blood volume increases, with a greater need for iron. Iron requirements are proportionally higher in infancy (3 to 24 months) than at any other age, although they are also increased in childhood and adolescence. In infancy, the two main causes of iron-deficiency anemia are low iron levels at birth because of maternal deficiency and a diet consisting mainly of cow's milk, which is low in absorbable iron. Adolescents are also susceptible to iron deficiency because of high requirements due to growth spurts, dietary deficiencies, and menstrual loss.16 Iron-deficiency anemia is characterized by low hemo- globin and hematocrit, decreased iron stores, and low serum iron and ferritin levels. The red cells are decreased in number and are microcytic and hypochromic (see Fig. 13-8). Poikilocytosis (irregular shape) and anisocytosis (irregular size) are also present. Laboratory values indi- cate reduced MCHC and MCV. Membrane changes may predispose to hemolysis, causing further loss of red cells. The manifestations of iron-deficiency anemia are related to impaired oxygen transport and lack of hemoglobin. Depending on the severity of the anemia, pallor, easy fati- gability, dyspnea, and tachycardia may occur. Epithelial atrophy is common and results in waxy pallor, brittle hair and nails, sometimes a spoon-shaped deformity of the fin- gernails, smooth tongue, sores in the corners of the mouth, and sometimes dysphagia and decreased acid secretion. A poorly understood symptom occasionally seen is pica, the bizarre, compulsive eating of ice, dirt, or other abnormal substances. Iron deficiency in infants may also result in long-term manifestations such as poor cognitive, motor, and emotional function that may be related to effects on brain development or neurotransmitter function.17 Prevention of iron deficiency is a primary concern in infants and children. Avoidance of cow's milk, iron sup- plementation at 4 to 6 months of age in breast-fed infants, and use of iron-fortified formulas and cereals are recom- mended for infants younger than 1 year of age.18 In the sec- ond year, a diet rich in iron-containing foods and use of iron-fortified vitamins will help prevent iron deficiency. The treatment of iron-deficiency anemia in children and adults is directed toward controlling chronic blood loss, increas- ing dietary intake of iron, and administering supplemental iron. Ferrous sulfate, which is the usual oral replacement therapy, replenishes iron stores in several months. Par- enteral iron therapy may be used when oral forms are not tolerated or are ineffective. Caution is required because of the possibility of severe hypersensitivity reactions.

Aplastic anemia

Aplastic anemia describes a disorder of pluripotential bone marrow stem cells that results in a reduction of all three hematopoietic cell lines—red blood cells, white blood cells, and platelets. Pure red cell aplasia, in which only the red cells are affected, rarely occurs. Anemia results from the failure of the marrow to replace senescent red cells that are destroyed and leave the circulation, although the cells that remain are of normal size and color. At the same time, because the leukocytes, particularly the neutrophils, and the thrombocytes have a short life span, a deficiency of these cells usually is apparent before the anemia becomes severe. The onset of aplastic anemia may be insidious, or it may strike with suddenness and great severity. It can occur at any age. The initial presenting symptoms include weakness, fatigability, and pallor caused by anemia. Petechiae (i.e., small, punctate skin hemorrhages) and ecchymoses (i.e., bruises) often occur on the skin, and bleeding from the nose, gums, vagina, or gastroin- testinal tract may occur because of decreased platelet lev- els. The decrease in the number of neutrophils increases susceptibility to infection. Among the causes of aplastic anemia are exposure to high doses of radiation, chemicals, and toxins that suppress hematopoiesis directly or through immune mecha- nisms. Chemotherapy and irradiation commonly result in bone marrow depression, which causes anemia, thrombocytopenia, and neutropenia. Identified toxic agents include benzene, the antibiotic chloramphenicol, and the alkylating agents and antimetabolites used in the treatment of cancer (see Chapter 7). Aplastic anemia caused by exposure to chemical agents may be an idiosyncratic reaction because it affects only certain susceptible persons. It typically occurs weeks after a drug is initiated. Such reactions often are severe and sometimes irreversible and fatal. It can also develop in the course of many infections and has been reported most often as a complication of viral hepatitis, mononucleosis, and other viral illnesses, including acquired immunodeficiency syndrome (AIDS). In two thirds of cases, the cause is unknown, a condition referred to as idiopathic aplastic anemia. The mechanisms underlying the pathogenesis of aplastic anemia are unknown. It is suggested that exposure to the chemicals, infectious agents, and other insults generates a cellular immune response resulting in production of cytokines by activated T cells. These cytokines (e.g., interferon, tumor necrosis factor [TNF]) then suppress hematopoietic stem cell growth and development.5 T herapy for aplastic anemia in the young and severely affected includes stem cell replacement by bone marrow or peripheral blood transplantation. Histocompatible donors supply the stem cells to replace the patient's destroyed marrow cells. Graft-versus-host disease, rejection, and infection are major risks of the procedure, yet 75% or more survive.22 For those who are not transplantation can- didates, immunosuppressive therapy with lymphocyte immune globulin (i.e., antithymocyte globulin) prevents suppression of proliferating stem cells, producing remis- sion in up to 50% of patients.21,22 Persons with aplastic anemia should avoid the offending agents and be treated with antibiotics for infection. Red cell transfusions to cor- rect the anemia and platelets and corticosteroid therapy to minimize bleeding may also be required.

Sickle Cell Treatment

Bone marrow transplant offers the only potential cure for sickle cell anemia. But finding a donor is difficult and the procedure has serious risks associated with it, including death. As a result, treatment for sickle cell anemia is usually aimed at avoiding crises, relieving symptoms and preventing complications. If you have sickle cell anemia, you'll need to make regular visits to your doctor to check your red blood cell count and monitor your health. Treatments may include medications to reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as a bone marrow transplant. Medications Medications used to treat sickle cell anemia include: Antibiotics. Children with sickle cell anemia may begin taking the antibiotic penicillin when they're about 2 months of age and continue taking it until they're at least 5 years old. Doing so helps prevent infections, such as pneumonia, which can be life-threatening to an infant or child with sickle cell anemia. Antibiotics may also help adults with sickle cell anemia fight certain infections. Pain-relieving medications. To relieve pain during a sickle crisis, your doctor may advise over-the-counter pain relievers and application of heat to the affected area. You may also need stronger prescription pain medication. Hydroxyurea (Droxia, Hydrea). When taken daily, hydroxyurea reduces the frequency of painful crises and may reduce the need for blood transfusions. Hydroxyurea seems to work by stimulating production of fetal hemoglobin — a type of hemoglobin found in newborns that helps prevent the formation of sickle cells. Hydroxyurea increases your risk of infections, and there is some concern that long-term use of this drug may cause tumors or leukemia in certain people. However, this hasn't yet been seen in studies of the drug. Hydroxyurea was initially used just for adults with severe sickle cell anemia. Studies on children have shown that the drug may prevent some of the serious complications associated with sickle cell anemia. But the long-term effects of the drug on children are still unknown. Your doctor can help you determine if this drug may be beneficial for you or your child. Assessing stroke risk Using a special ultrasound machine (transcranial), doctors can learn which children have a higher risk of stroke. This test can be used on children as young as 2 years, and those who are found to have a high risk of stroke are then treated with regular blood transfusions. Vaccinations to prevent infections Childhood vaccinations are important for preventing disease in all children. But, these vaccinations are even more important for children with sickle cell anemia, because infections can be severe in children with sickle cell anemia. Your doctor will make sure your child receives all of the recommended childhood vaccinations. Vaccinations, such as the pneumococcal vaccine and the annual flu shot, are also important for adults with sickle cell anemia. Blood transfusions In a red blood cell transfusion, red blood cells are removed from a supply of donated blood. These donated cells are then given intravenously to a person with sickle cell anemia. Blood transfusions increase the number of normal red blood cells in circulation, helping to relieve anemia. In children with sickle cell anemia at high risk of stroke, regular blood transfusions can decrease their risk of stroke. Blood transfusions carry some risk. Blood contains iron. Regular blood transfusions cause an excess amount of iron to build up in your body. Because excess iron can damage your heart, liver and other organs, people who undergo regular transfusions may need treatment to reduce iron levels. Deferasirox (Exjade) is an oral medication that can reduce excess iron levels. Supplemental oxygen Breathing supplemental oxygen through a breathing mask adds oxygen to your blood and helps you breathe easier. It may be helpful if you have acute chest syndrome or a sickle cell crisis. Stem cell transplant A stem cell transplant, also called a bone marrow transplant, involves replacing bone marrow affected by sickle cell anemia with healthy bone marrow from a donor. Because of the risks associated with a stem cell transplant, the procedure is recommended only for people who have significant symptoms and problems from sickle cell anemia. If a donor is found, the diseased bone marrow in the person with sickle cell anemia is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected intravenously into the bloodstream of the person with sickle cell anemia, where they migrate to the bone marrow cavities and begin generating new blood cells. The procedure requires a lengthy hospital stay. After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells. A stem cell transplant carries risks. There's a chance that your body may reject the transplant, leading to life-threatening complications. In addition, not everyone is a candidate for transplantation or can find a suitable donor. Treating complications Doctors treat most complications of sickle cell anemia as they occur. Treatment may include antibiotics, vitamins, blood transfusions, pain-relieving medicines, other medications and possibly surgery, such as to correct vision problems or to remove a damaged spleen. Experimental treatments Scientists are studying new treatments for sickle cell anemia, including: Gene therapy. Because sickle cell anemia is caused by a defective gene, researchers are exploring whether inserting a normal gene into the bone marrow of people with sickle cell anemia will result in the production of normal hemoglobin. Scientists are also exploring the possibility of turning off the defective gene while reactivating another gene responsible for the production of fetal hemoglobin — a type of hemoglobin found in newborns that prevents sickle cells from forming. Potential treatments using gene therapy are still a long way off, however. No human trials using genes specifically for sickle cell have yet been done. Nitric oxide. People with sickle cell anemia have low levels of nitric oxide in their blood. Nitric oxide is a gas that helps keep blood vessels open and reduces the stickiness of red blood cells. Treatment with nitric oxide may prevent sickle cells from clumping together. Studies on nitric oxide have had mixed results so far. Drugs to boost fetal hemoglobin production. Researchers are studying various drugs to devise a way to boost the production of fetal hemoglobin. This is a type of hemoglobin that stops sickle cells from forming. Statins. These medications, which are normally used to lower cholesterol, may also help reduce inflammation. In sickle cell anemia, statins may help blood flow better through blood vessels.

Decreased or Faulty Red Blood Cell Production

Decreased or Faulty Red Blood Cell Production With this type of anemia, the body may produce too few blood cells or the blood cells may not function correctly. In either case, anemia can result. Red blood cells may be faulty or decreased due to abnormal red blood cells or a lack of minerals and vitamins needed for red blood cells to work properly. Conditions associated with these causes of anemia include the following: Sickle cell anemia Iron-deficiency anemia Vitamin deficiency Bone marrow and stem cell problems Other health conditions Sickle cell anemia is an inherited disorder that affects African-Americans. Red blood cells become crescent-shaped because of a genetic defect. They break down rapidly, so oxygen does not get to the body's organs, causing anemia. The crescent-shaped red blood can cells also get stuck in tiny blood vessels, causing pain.

Life span and destruction of RBCs

Mature red blood cells have a life span of approximately 4 months, or 120 days. Even though mature red cells do not have a nucleus, mitochondria, or endoplasmic retic- ulum, they have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of adenosine triphosphate (ATP). These enzymes also help to preserve the pliability of the cell membrane, maintain transmembrane transport of ions, keep the iron of the cell's hemoglobin in the reduced ferrous form that binds oxygen, and prevent oxidation of the proteins in the red cells. Even so, the metabolic activity in the cell decreases as the red cell ages, and the cell membrane becomes more and more fragile, causing it to rupture as it passes through tight places in the circulation. Many of the aged red cells self-destruct in the spleen as they squeeze through spaces between the trabeculae of the red pulp, which are only about 3 mm wide, in comparison with the 8 mm width of the red cell.3 The rate of red cell destruction (1% per day) normally is equal to the rate of red cell production, but in conditions such as hemolytic anemia, the cell's life span may be shorter. The destruction of red blood cells is facilitated by a group of large phagocytic macrophages found in the spleen, liver, bone marrow, and lymph nodes. These phagocytic cells recognize old and defective red cells and then ingest and destroy them in a series of enzymatic reactions. During these reactions, the amino acids from the globulin chains and iron from the heme units are salvaged and reused (Fig. 13-6). The bulk of the heme unit is converted to bilirubin, the pigment of bile, which is insoluble in plasma and attaches to plasma proteins for transport. Bilirubin is removed from the blood by the liver and conjugated with glucuronide to render it water soluble so that it can be excreted in the bile. The plasma- insoluble form of bilirubin is referred to as unconjugated bilirubin and the water-soluble form as conjugated biliru- bin. Serum levels of conjugated and unconjugated bilirubin can be measured in the laboratory and are reported as direct and indirect, respectively. If the rate of red cell destruction and consequent bilirubin production exceed the liver's ability to remove it from the blood, unconjugated bilirubin accumulates in the blood. This results in a yellow discoloration of the skin, called jaundice. When red blood cell destruction takes place in the circulation, as in hemolytic anemia, the hemoglobin remains in the plasma where it binds to a hemoglobin- binding protein called haptoglobin.1 Other plasma pro- teins, such as albumin, can also bind hemoglobin. With extensive intravascular destruction of red blood cells, hemoglobin levels may exceed the hemoglobin-binding capacity of haptoglobin and other plasma proteins. When this occurs, free hemoglobin appears in the blood (i.e., hemoglobinemia) and is excreted in the urine (i.e., hemoglobinuria). Because excessive red blood cell destruction can occur in hemolytic transfusion reactions, urine samples are tested for free hemoglobin after a transfusion reaction.