ANEMIA

Definition Clinical manifestations Diagnosis Classifications Treatment

Anemias are a group of diseases characterized by a decrease in hemoglobin(Hb) or the volume of red blood cells (RBCs) , resulting in decreased oxygen-carrying capacity of blood.

Anemias are generally a sign of underlying pathology; therefore, determining the cause of the anemia is important

Possible consequences of chronic anemia include reduced quality-of-life, decreased survival, and increased risk of cardiac complications, neurologic dysfunction, and surgical complications. Awareness of anemia, its detection, investigation, and management must be raised.

Clinical presentation of anemia

■Patients may be asymptomatic or have vague complaints.

■Patients with vitamin B12 deficiency may develop neurologic consequences.

■In anemia of chronic disease, signs and symptoms of the underlying disorder often overshadow those of the anemia .

Symptoms■Decreased exercise tolerance■Fatigue■Dizziness■Irritability■Weakness■Palpitations■Vertigo■Shortness of breath■Chest pain■Neurologic symptoms in vitamin B12 deficiency

Signs■Tachycardia■Pale appearance (most prominent in conjunctivae)■Decreased mental acuity■Increased intensity of some cardiac valvular murmurs■Diminished vibratory sense or gait abnormality in vitamin B1

Classification system of anemia

I. MorphologyMacrocytic anemias Megaloblastic anemias Vitamin B12 deficiency Folic acid deficiency anemiaMicrocytic hypochromic anemias Iron-deficiency anemia Genetic anomaly Sickle cell anemia Thalassemia Other hemoglobinopathies (abnormal hemoglobins)Normocytic anemias Recent blood loss Hemolysis Bone marrow failure Anemia of chronic disease Renal failureEndocrine disorders Myelodysplastic anemias

II. Etiology

Deficiency Iron Vitamin B12 Folic acid PyridoxineCentral, caused by impaired bone marrow function Anemia of chronic disease Anemia of the elderly Malignant bone marrow disordersPeripheral Bleeding (hemorrhage) Hemolysis (hemolytic anemias)

III. Pathophysiology

Excessive blood loss Recent hemorrhage

Peptic ulcer GastritisHemorrhoidsChronic hemorrhageVaginal bleedingPeptic ulcerIntestinal parasitesAspirin and other NSAIDExcessive RBC destructionDrugsExcessive sequestration in the spleenHeredityDisorders of hemoglobin synthesis

Inadequate production of mature RBCs

Deficiency of nutrients (B12 ,folic acid, iron, protein)

Deficiency of erythroblastsAplastic anemiaFolic acid antagonistsAntibodiesLeukemiaCarcinomaEndocrine abnormalities

Hypothyroidism Adrenal insufficiencyPituitary insufficiencyChronic renal diseaseChronic inflammatory diseaseCollagen vascular diseasesHepatic disease

DIAGNOSIS OF ANEMIA

History, physical examination and laboratory testing are used in the evaluation of anemia

LABORATORY EVALUATION

1. RBC production failure (hypoproliferative)2. Cell maturation ineffectiveness3. Increase in RBC destruction

Hemoglobin

Hb represent the amount of Hb per volume of whole blood. The higher values seen in males are due to stimulationof RBC production by androgenic steroids, whereas the lower values in females are due to decrease in Hb as a result of blood loss during menstruation. The Hb estimate of the oxygen-carrying capacity of blood. Hb levels may be diminished because of a decreased quantity of Hb per RBC or because of a decrease in the actual number of RBCs. In pregnancy Hb may not reflect red cell mass changes.

HematocritExpressed as a percentage. hematocrit (Hct) is the actual volume of RBCs in a unit volume of whole blood .abnormal cell size or shape and indicates the pathology. A low Hct indicates a reduction in either the number or the size of RBCs or an increase in plasma volume.The RBC count is an indirect estimate of the Hb content of the blood; it is an actual count of RBCs per unit of blood.

Red Blood Cell Indices

indices describe the size and Hb content of the RBCs and are calculated from the Hb, Hct, and RBC count. RBC indices, such as mean corpuscular volume (MCV) and mean corpuscular Hb (MCH), are single mean values that do not express the variation that can occur in cells.

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Mean Corpuscular Volume (Hct/RBC Count)MCV

represents the average volume of RBCs. It may reflect changes in MCH, but it can be confounded. Cells are considered macrocytic if they are larger than normal, microcytic if they are smaller than normal, and normocytic if their size falls within normal limits. Folic acid and vitamin B12 deficiency anemias yield macrocytic morphology, whereas iron deficiency and thalassemia are examples of microcytic anemias.

MCV is falsely elevated in the presence of cold agglutinins and hyperglycemia. When IDA (decreased MCV) is accompanied by folate deficiency (increased MCV), failure to understand that the MCV represents an average RBC size creates the potential for overlooking the real cause of the anemia.

Mean Corpuscular Hemoglobin (Hb/RBC Count)MCH

Is defined as the volume of Hb in an RBC. It reflects the adequacy of iron supply to developing erythron. Two morphologic changes, microcytosis and hypochromia, can reduce MCH .

Mean Corpuscular Hemoglobin Concentration (Hb/Hct)

The weight of Hb per volume of cells is the mean corpuscular Hb concentration (MCHC). Because MCHC is independent of cell size, it is more useful than MCH in distinguishing between microcytosis and hypochromia. A low MCHC always indicates hypochromia; a microcyte with a normal Hb concentration will have a low MCH but a normal MCHC. A decreased MCHC is seen most often in association with IDA.

Total Reticulocyte Count

Although an indirect assessment, the total reticulocyte count is an indication of new RBC production. It measures how quickly immature RBCs (reticulocytes) are produced by bone marrow and released into the blood. the reticulocyte count usually are low. Reticulocytes circulate in the blood approximately 2 days before maturing into RBCs

Red Blood Cell Distribution Width

The higher the red blood cell distribution width (RDW), the more variable the size of the RBCs. The RDW increases in early IDA because of the release of large, immature, nucleated RBCs to compensate for the anemia, but this change is not specific for IDA.The RDW also can be helpful in the diagnosis of a mixed anemia. A patient can have a normal MCV yet have a wide RDW. This finding indicates the presence of microcytes and macrocytes, which would yield a “normal” average RBC size.

Serum IronThe level of serum iron is the concentration of iron bound totransferrin. Normally, transferrin is approximately one-third bound (saturated) to iron.Total Iron-Binding CapacityAn indirect measurement of the iron-binding capacity of serumtransferrin, TIBC evaluation is performed by adding an excess of iron to plasma to saturate all transferrin with iron .Folic AcidThe results of folic acid measurements vary depending on the assay method used.

Vitamin B12Low levels of vitamin B12(cyanocobalamin) indicate vitamin B12 deficiency.

Coombs TestAntiglobulin tests, also called Coombs tests , indicate hemolytic anemia caused by an immune response.

Schilling TestThe purpose of the rarely used Schilling urinary excretion test is to diagnose vitamin B12 deficiency anemia caused by a B12 absorption defect resulting from a lack of intrinsic factor (pernicious anemia) .

Erythropoietin LevelsHealthy individuals require 10 to 30 milliunits/mL of EPO to maintain normal Hb and Hct concentrations

Homocysteine

Vitamin B12 and folate both are required for conversion of homocysteine to methionine. Increased serum homocysteine may suggest vitamin B12 or folate deficiency.Homocysteine levels also can be elevated in patients with vitamin B6 deficiency, renal failure and hypothyroidism .

Methylmalonic Acid

A vitamin B12 coenzyme is needed to convert methylmalonyl coenzyme A to succinyl coenzyme A. Patients with vitamin B12Deficiency may have increased concentrations of serum methylmalonic acid (MMA), which is a more specific marker for vitamin B12 deficiency .

■Hb, hematocrit (Hct), and RBC indices may remain normal early in the disease and then decrease as the anemia progresses .■Serum iron is low in IDA and ACD .■Ferritin levels are low in IDA and normal to increased in ACD■TIBC is high in IDA and is low or normal in ACD .■Mean corpuscular volume is elevated in vitamin B12 deficiency and folate deficiency .■Vitamin B12 and folate levels are low in their respective types of anemia .■Homocysteine is elevated in vitamin B12 deficiency and folate deficiency .■Methylmalonic acid is elevated in vitamin B12 deficiency .

Anemia therapeutics

IRON-DEFICIENCY ANEMIA

• Oral iron therapy with soluble ferrous iron salts, which are not enteric coated and not slow- or sustained-release, is recommended at a daily dosage of 200 mg elemental iron in two or three divided doses .

Slow-release or sustained-release iron preparations do not undergo sufficient dissolution until they reach the small intestines, which significantly reduces iron absorption and can attenuate the hematinic effects .

• Diet plays a significant role because iron is poorly absorbed from vegetables, grain products, dairy products, and eggs; iron is best absorbed from meat, fish, and poultry. Meat, orange juice, and other ascorbic acid–rich foods should be included with meals, whereas milk and tea should be consumed in moderation between meal

Adverse reactions dark discoloration of feces, constipation or diarrhea, nausea, and vomiting .

• Parenteral iron may be required for patients with iron malabsorption, intolerance of oral iron therapy, or noncompliance. The replacement dose depends on etiology of anemia and Hb concentration• Available parenteral iron preparations have similar efficacy but different pharmacologic, pharmacokinetic, and safety profile. The newer products, sodium ferric gluconateand iron sucrose, appear to be better tolerated than iron dextran.

Comparison of Parenteral Iron Preparations

Equations for Calculating Doses of Parenteral Iron

Drugs That Decrease Iron Absorption Al-, Mg-, and Ca+2 -containing antacids Tetracycline and doxycycline Histamine2 antagonists Proton pump inhibitors Cholestyramine Object Drugs Affected by Iron

Levodopa↓ (chelates with iron)Methyldopa↓ (decreases efficacy of methyldopa) Levothyroxine↓(decreased efficacy of Levothyroxine)Fluoroquinolones↓(forms ferric ion– quinolone complex)Tetracycline and doxycycline ↓(when administered within 2 hours of iron salt)

TRANSFUSIONS

indicated in acute situations of blood loss when hemodynamic support is needed.

Once Hct decreases to <30%, the oxygen-carrying capacity in patients with coronary disease is dangerously compromised, and ischemia can occur.

patients who have developed low Hct values over extended time periods, These patients often demonstrate cardiac compromise after transfusion despite Hct levels in the 20% range. These patients should receive iron therapy , followed by transfusion only if necessary.

VITAMIN B12-DEFICIENCY ANEMIA

The goals of treatment for vitamin B12 deficiency include reversal of hematologic manifestations, replacement of body stores, and prevention or resolution of neurologic manifestations .

Oral cobalaminis initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily.• Oral vitamin B12 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B 12 absorption pathway is independent of intrinsic factor, but in much larger doses than those used to treat other causes of vitamin B 12 deficiency .

• Parenteral therapy is more rapid acting than oral therapy and should be used if neurologic symptoms are present. A popular regimen is cyanocobalamin 1,000 mcg daily for 1 week, then weekly for 1 month, and then monthly.When symptoms resolve, daily oral administration can be initiated.

• Adverse events are rare with vitamin B 12 therapy, Uncommon side effects include hyperuricemia and hypokalemia due to marked increase in potassium utilization during production of new hematopoietic cells.

FOLATE-DEFICIENCY ANEMIA

folic acid deficiency include inadequate intake, decreased absorption, hyperutilization, and inadequate utilization .

Hyperutilization of folic acid may occur when the rate of cellular division is increased, as seen in pregnant women; patients with hemolytic anemia, myelofibrosis, malignancy, chronic inflammatory disorders such as Crohn disease, rheumatoid arthritis, or psoriasis; patients undergoing long-term dialysis; burn patients; andin adolescents and infants during their growth spurts .

Dose: Oral folate1 mg daily for 4 months is usually sufficient for treatment of folate-deficiency anemia, unless the etiology cannot be corrected. If malabsorption is present, the daily dose should be increased to 5 mg.

Several drugs have been reported to cause a folic acid deficiency megaloblastic anemia. Some drugs (e.g., azathioprine, 6-mercaptopurine, 5-fluorouracil, hydroxyurea, and zidovudine) directly inhibit DNA synthesis.

Other drugs are folate antagonists; the most toxic is methotrexate (other examples include trimethoprim, and triamterene).

A number of drugs (e.g., phenytoin and phenobarbital ) antagonize folate via poorly understood mechanisms but are thought to reduce vitamin absorption by the intestine

humans are unable to synthesize sufficient folate to meet total daily requirements, they depend on dietary sources. Major dietary sources of folate include fresh, green, leafy vegetables, citrus fruits, yeast, mushrooms, dairy products, and animal organs such as liver and kidney

Because the body stores approximately 5 to 10 mg of folate, primarily in the liver, cessation of dietary folate intake can result in megaloblastosis within 4 to 5 months.

Periconceptional folic acid supplementation isrecommended to decrease the occurrence and recurrence of neural tube defects, specifically anencephaly and spina bifida.

Hemolytic anemia

Hemolytic anemia results in decreased survival time of RBCs secondary to destruction in the spleen or circulation.

Hemolytic anemias usually are normocytic and normochromic, with increased levels of reticulocytes, lactate dehydrogenase, and indirect bilirubin.

Treatment is directed toward correcting or controlling the underlying pathology.

Common classes of hemolytic anemia

• Treatment of hemolytic anemia should focus on correcting the underlying cause.

There is no specific therapy for G6PD deficiency, so treatment consists of avoiding oxidant medications and chemicals.

Steroids, other immunosuppressants, and even splenectomy can be indicated to reduce RBC destruction.

Patients with sickle cell disease( SCD) require lifelong multidisciplinary care. All patients should receive regularly scheduled comprehensive medical evaluations. The goal of comprehensive care is to reduce hospitalizations, complications, and mortality. Because of the complexity of the disease, a multidisciplinary team is needed to provide medical care, education, counseling, and psychosocial support.

Appropriate comprehensive care can have a positive impact on both longevity and general quality of life. This care includes the use of traditional prophylactic and general symptomatic supportive care and the use of newer, more specific therapies aimed at altering hematologic capacity and function.

Treatment for patients with SCD involves the use of general measures to meet the unique demands for increased erythropoiesis.

Additional interventions can be aimed at preventing or treating complications of the disease. When crises occur, the type and severity of the crisis determine the appropriate therapeutic plan .

Hemolysis and Vaso-occlusion

Vaso-occlusion:Occurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs.

Hemolysis:The anemia in SCD is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction.

Hemolysis and Vaso-occlusionAcute Manifestations: Bacterial Sepsis or

meningitis* Recurrent vaso-occlusive

pain (dactylitis, muscoskeletal or abdominal pain)

Splenic Sequestration* Aplastic Crisis* Acute Chest Syndrome* Stroke* Priapism Hematuria, including

papillary necrosis

Chronic Manifestations: Anemia Jaundice Splenomegaly Cardiomegaly and

functional murmurs Proteinemia Cholelithiasis Delayed growth and sexual

maturation Restrictive lung disease* Pulmonary Hypertension* Avascular necrosis Proliferative retinopathy Leg ulcers Transfusional

hemosiderosis**Potential cause of mortality

TREATMENTGENERAL PRINCIPLES

• Patients with SCD require lifelong multidisciplinary care. Interventions include general measures, preventive strategies, and treatment of complications and acute crises.• Patients with SCD should receive routine immunizations plus influenza, meningococcal, and pneumococcal vaccinations.• Prophylactic penicillinis recommended for children with SCD until they are 5 years old. Beginning at age 2 months or earlier, the dosage is penicillin V potassium, 125 mg orally twice daily until 3 years of age and then 250 mg twice daily until age 5 years, or benzathine penicillin, 600,000 units intramuscularly every 4 weeks from age 6 months to 6 years.• Folic acid, 1 mg daily, is recommended in adult patients.

FETAL HEMOGLOBIN (HbF) INDUCERS

Increases in HbF correlate with decreased RBC sickling and adhesion. Patients with low HbF levels have more frequent crises and higher mortality.

• Hydroxyurea, a chemotherapeutic agent, has many effects on blood cells, including the stimulation of HbF production. It is indicated for patients with frequent painful episodes, severe symptomatic anemia, acute chest syndrome, or other severe vasoocclusive complications.

The dosage should be individualized based on response and toxicity.

TREATMENT OF COMPLICATIONS

• Patients should be educated to recognize conditions that require urgent evaluation. To avoid exacerbation during acute illness, patients should maintain balanced fluid status and oxygen saturation of at least 92%.

• RBC transfusions are indicated for acute exacerbation of baseline anemia (e.g., aplastic crisis, hepatic or splenic sequestration, severe hemolysis), severe vasoocclusive episodes, and procedures requiring general anesthesia or ionic contrast .

Fever of 38.5°C (101.3°F) or higher should be evaluated promptly. A low threshold for empiric antibiotic therapy with coverage against encapsulated organisms is recommended (e.g., ceftriaxonefor outpatients and cefotaximefor inpatients).

• Patients with acute chest syndrome should receive incentive spirometry; appropriate fluid therapy; broad-spectrum antibiotics including a macrolideor quinolone; and, for hypoxia or acute distress, oxygen therapy.Steroids and nitric oxide are being evaluated.

• Priapism has been treated with analgesics, antianxiety agents, and vasoconstrictors to force blood out of the corpus cavernosum (e.g., epinephrine), and vasodilators to relax smooth muscle (e.g., hydralazine).

TREATMENT OF SICKLE CELL CRISIS

• Treatment is primarily supportive. Blood transfusions may be indicated for severe or symptomatic anemia. Antibiotic therapy is not warranted because the most common etiology is viral, not bacterial, infection.

• Treatment options for splenic sequestrationinclude observation alone, especially for adults because they tend to have milder episodes; chronic transfusion to delay splenectomy; and splenectomy after a life-threatening crisis, after repetitive episodes, or for chronic hypersplenism.

• Hydration and analgesics are the mainstays of treatment for vasoocclusive (painful) crisis. Fluid replacement should be 1.5 times the maintenance requirement, can be administered IV or orally, and should be monitored to avoid volume overload. An infectious etiology should be considered; if appropriate, empiric therapy should be initiated.

• Mild to moderate pain should be treated with nonsteroidal antiinflammatory drugs or acetaminophen.• Severe pain should be treated aggressively with an opioid, such as morphine, hydromorphone, fentanyl,and methadone. Moderate pain should be treated with a weak opioid, such as codeineor hydrocodone. • Severe pain should be treated with an IV opioid titrated to pain relief and then administered on a scheduled basis with as-needed dosing for breakthrough pain. Patient-controlled analgesia is commonly utilized.• Suspicion of addiction commonly leads to suboptimal pain control.

Factors that minimize dependence include aggressive pain control, frequent monitoring, and tapering medication according to response.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A hereditary condition, drug-induced oxidative hemolytic anemia, most often accompanies a glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency, but it can occur because of other enzyme defects .

A G6PD deficiency is a disorder of the hexose monophosphate shunt, which is responsible for producing NADPH in RBCs, which in turn keeps glutathione in a reduced state. Reduced glutathione is a substrate for glutathione peroxidase, an enzyme that removes peroxide from RBCs, thus protecting them from oxidative stress.

Without reduced glutathione, oxidative drugs can oxidizethe sulfhydryl groups of hemoglobin, removing them prematurely from the circulation (i.e., causing hemolysis).

Although severe hemolysis is rare, any drug that places oxidative stress on RBCs can cause drug-induced oxidative hemolytic anemia. One case of drug-induced oxidative hemolytic anemia has been reported in a child when dapsone (an oxidizing agent) was transferred through the breast milk of the mother, who was taking the drug.

ANEMIA OF CHRONIC DISEASE

Anemia of chronic disease is a diagnosis of exclusion, It resultsfrom chronic inflammation, infection, or malignancy and can occur as early as 1 to 2 months after the onset of these processes.

The serum iron level usually is decreased, but in contrast to IDA , the serum ferritin concentration is normal or increased and TIBC is normal or decreased.

• Treatment of anemia of chronic disease is less specific than that of other anemias and should focus on correcting reversible causes

. Iron therapy is not effective when inflammation is present. RBC transfusions are effective but should be limited to episodes of inadequate oxygen transport and Hb of 8 to 10 g/dL .

• Epoetin alfa (recompinant human erythropoitin)can be considered, especially if cardiovascular status is compromised, but the response can be impaired in patients with anemia of chronic disease (off-label use).

The initial dosage is 50 to 100 units/kg three times weekly. If Hb does not increase after 6 to 8 weeks, the dosage can beincreased to 150 units/kg three times weekly.

• Epoetin alfa is usually well tolerated. The hypertension seen in patients with end-stage kidney disease is less common in patients with acquired immune deficiency syndrome.

Diseases Causing Anemia of Chronic Disease

Less common causes

Alcoholic liver diseaseCongestive heart failureThrombophlebitisChronic obstructive pulmonary diseaseIschemic heart disease

Common causes

Chronic infectionsTuberculosisHIVSubacute bacterial endocarditisOsteomyelitisChronic UTIChronic inflammationRheumatoid arthritisSLEInflammatory bowel diseaseInflammatory osteoarthritisGoutChronic inflammatory liver diseasesMalignancies

OTHER TYPES OF ANEMIAS

• Patients with other types of anemias require appropriate supplementation depending on the etiology of anemia.

• In patients with anemia of critical illness, parenteral iron is often utilized but is associated with a theoretical risk of infection. Routine use of epoetin alfa or RBC transfusions is not supported by clinical studies.• Anemia of prematurity is usually treated with RBC transfusions. The use of epoetin is controversial.

• In the pediatric population, the daily dose of elemental iron, administered as iron sulfate, is 3 mg/kg for infants and 6 mg/kg for older children for 4 weeks. If response is seen, iron should be continued for 2 to 3 months. The dose and schedule of vitamin B 12 should be titrated according to clinical and laboratory response. The daily dose of folate is 1 to 3 mg.

EVALUATION OF THERAPEUTIC OUTCOMES

In iron-deficiency anemia, iron therapy should cause reticulocytosis in 5 to 7 days and raise Hb by 2 to 4 g/dL every 3 weeks. The patient should be reevaluated if reticulocytosis does not occur or if Hb does not increase by 2 g/dL within 3 weeks.

Iron therapy is continued until iron stores are replenished, which usually requires at least 3 to 6 months.

bleeding may require iron replacement therapyfor only 1 month after correction of the underlying lesion.

In megaloblastic anemia, signs and symptoms usually improve within a few days after starting vitamin B12 or folate therapy.

Neurologic symptoms can take longer to improve or can be irreversible, but they should not progress during therapy.

Reticulocytosis should occur within 2 to 5 days.

A week after starting vitamin B12 therapy, Hb should rise and leukocyte and platelet counts should normalize .

A CBC count and serum cobalamin level usually are drawn 1 to 2 months after initiation of therapy and 3 to 6 months thereafter for surveillance monitoring .

Slow response to therapy or failure to observe normalization of laboratory results may suggest the presence of an additional abnormality such as iron deficiency, thalassemia trait, infection, malignancy, or misdiagnosis .

Folic acid Symptomatic improvement, as evidenced by increased alertness, appetite, and cooperation, often occurs early during the course of treatment.

Reticulocytosis occurs within 2 to 3 days and peakswithin 5 to 8 days after beginning therapy. Hct begins to rise within 2 weeks and should reach normal levels within 2 months.

MCV initially increases because of an increase in reticulocytes but gradually decreases to normal .

In anemia of chronic disease, reticulocytosis should occur a few days after starting epoetin alfa therapy.

Iron, TIBC, transferrin saturation, or ferritin levels should be monitored periodically because iron depletion is a major reason for treatment failure.

If clinical response does not occur by 8 weeks, epoetin should be discontinued.