Anemias, Pathophysiology, Clinical presentation, Diagnosis & Treatment.

• Anemias are a group of diseases characterized by a decrease in hemoglobin (Hb) or red blood cells (RBCs), resulting in decreased oxygen-carrying capacity of blood. The World Health Organization defines anemia as Hb less than 13 g/dL (<130 g/L, <8.07 mmol/L) in men or less than 12 g/dL (<120 g/L; <7.45 mmol/L) in women.

PATHOPHYSIOLOGY

• The functional classification of anemias is found. The most common anemias are included in this chapter. 

• Morphologic classifications are based on cell size. Macrocytic cells are larger than normal and are associated with deficiencies of vitamin B12 or folic acid. Microcytic cells are smaller than normal and are associated with iron deficiency, whereas normocytic anemia may be associated with recent blood loss or chronic disease.

• Iron-deficiency anemia (IDA) can be caused by inadequate dietary intake, inadequate gastrointestinal (GI) absorption, increased iron demand (eg, pregnancy), blood loss, and chronic diseases.

• Vitamin B12– and folic acid–deficiency anemias can be caused by inadequate dietary intake, decreased absorption, and inadequate utilization. Deficiency of intrinsic factor causes decreased absorption of vitamin B12 (ie, pernicious anemia). Folic acid–deficiency anemia can be caused by hyperutilization due to pregnancy, hemolytic anemia, myelofibrosis, malignancy, chronic inflammatory disorders, long-term dialysis, or growth spurt. Drugs can cause anemia by reducing absorption of folate (eg, phenytoin) or through folate antagonism (eg, methotrexate).

• Anemia of inflammation (AI) is a newer term used to describe both anemia of chronic disease and anemia of critical illness. AI is a hypoproliferative anemia that traditionally has been associated with infectious or inflammatory processes, tissue injury, and conditions associated with release of proinflammatory cytokines.

• Age-related reductions in bone marrow reserve can render elderly patients more susceptible to anemia caused by multiple minor and often unrecognized diseases (eg, nutritional deficiencies) that negatively affect erythropoiesis.

• Pediatric anemias are often due to a primary hematologic abnormality. The risk of IDA is increased by rapid growth spurts and dietary deficiency.

CLINICAL PRESENTATION

• Signs and symptoms depend on rate of development and age and cardiovascular status of the patient. Acute-onset anemia is characterized by cardiorespiratory symptoms such as tachycardia, light-headedness, and breathlessness. Chronic anemia is characterized by weakness, fatigue, headache, symptoms of heart failure, vertigo, faintness, cold sensitivity, pallor, and loss of skin tone.

• IDA is characterized by glossal pain, smooth tongue, reduced salivary flow, pica (compulsive eating of nonfood items), and pagophagia (compulsive eating of ice) seen when Hb concentration is less than 9 g/dL (<90 g/L; <5.59 mmol/L).

• Neurologic effects (eg, numbness and ataxia) of vitamin B12 deficiency may occur in absence of anemia. Psychiatric findings, including irritability, depression, and memory impairment, may also occur with vitamin B12 deficiency. Anemia with folate deficiency is not associated with neurologic or psychiatric symptoms.

DIAGNOSIS

• Rapid diagnosis is essential because anemia is often a sign of underlying pathology.

• Initial evaluation of anemia involves a complete blood cell count (CBC), reticulocyte index, and examination of the stool for occult blood. Figure 33–2 shows a broad, general algorithm for the diagnosis of anemia based on laboratory data.

• The earliest and most sensitive laboratory change for IDA is decreased serum ferritin (storage iron), which should be interpreted in conjunction with decreased transferrin saturation and increased total iron-binding capacity (TIBC). Hb, hematocrit (Hct), and RBC indices usually remain normal until later stages of IDA.

• In macrocytic anemias, mean corpuscular volume is usually elevated to greater than 100 fL. Vitamin B12 and folate concentrations can be measured to differentiate between the two deficiency anemias. A vitamin B12 value less than 150 pg/mL (<111 pmol/L), together with appropriate peripheral smear and clinical symptoms, is diagnostic of vitamin B12–deficiency anemia. A decreased RBC folate concentration (<150 ng/mL [<340 nmol/L]) appears to be a better indicator of folate-deficiency anemia than a decreased serum folate concentration (<3 ng/mL [<7 nmol/L]).

• The diagnosis of AI is usually one of exclusion, with consideration of coexisting iron and folate deficiencies. Serum iron is usually decreased, but, unlike IDA, serum ferritin is normal or increased, and TIBC is decreased. The bone marrow reveals an abundance of iron; the peripheral smear reveals normocytic anemia.

• Elderly patients with symptoms of anemia should undergo a CBC with peripheral smear and reticulocyte count and other laboratory studies as needed to determine the etiology of anemia.

• The diagnosis of anemia in pediatric populations requires use of age- and gender adjusted norms for laboratory values.

TREATMENT

• Goals of Treatment: The goals are to alleviate signs and symptoms, correct the underlying etiology (eg, restore substrates needed for RBC production), replace body stores, and prevent recurrence of anemia.

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

• Iron is poorly absorbed from vegetables, grain products, dairy products, and eggs, and best absorbed from meat, fish, and poultry. Administer iron at least 1 hour before meals because food interferes with absorption, but administration with food may be needed to improve tolerability.

• Consider parenteral iron for patients with iron malabsorption, intolerance of oral iron therapy, or noncompliance. Parenteral administration, however, does not hasten the onset of hematologic response. The replacement dose depends on the etiology of anemia and Hb concentration.

• Iron dextran, sodium ferric gluconate, ferumoxytol, and iron sucrose are available parenteral iron preparations with similar efficacy but different molecular size, pharmacokinetics, bioavailability, and adverse effect profiles.

VITAMIN B12–DEFICIENCY ANEMIA

• Oral vitamin B12 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of intrinsic factor. Initiate oral cobalamin at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily.

• Parenteral therapy acts more rapidly than oral therapy and is recommended if neurologic symptoms are present. A popular regimen is IM cyanocobalamin, 1000 mcg daily for 1 week, then weekly for 1 month, and then monthly. Initiate daily oral administration after symptoms resolve.

FOLATE-DEFICIENCY ANEMIA

• Oral folate, 1 mg daily for 4 months, is usually sufficient for treatment of folic acid–deficiency anemia, unless the etiology cannot be corrected. If malabsorption is present, a dose of 1 to 5 mg daily may be necessary.

ANEMIA OF INFLAMMATION

• Treatment of anemia of inflammation (AI) is less specific than that of other anemias and should focus on correcting reversible causes. Reserve iron therapy for an established IDA; iron 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 (80–100 g/L; 4.97–6.21 mmol/L).

• Erythropoiesis-stimulating agents (ESAs) can be considered, but response can be impaired in patients with AI (off-label use). The initial dosage for epoetin alfa is 50 to 100 units/kg three times weekly and darbepoetin alfa 0.45 mcg/kg once weekly. ESA use may result in iron deficiency. Many practitioners routinely supplement ESA therapy with oral iron therapy.

• Potential toxicities of exogenous ESA administration include increases in blood pressure, nausea, headache, fever, bone pain, and fatigue. Hb must be monitored during ESA therapy. An increase in Hb greater than 12 g/dL (>120 g/L; >7.45 mmol/L) with treatment or a rise of greater than 1 g/dL (>10 g/L; >0.62 mmol/L) every 2 weeks has been associated with increased mortality and cardiovascular events.

• In patients with anemia of critical illness, parenteral iron is often used but is associated with a theoretical risk of infection. Routine use of ESAs or RBC transfusions is not supported by clinical studies.

ANEMIA IN PEDIATRIC POPULATIONS

• Anemia of prematurity is usually treated with RBC transfusions. ESA use is controversial because it has not been shown to clearly reduce transfusion requirements.

• Infants aged 9 to 12 months: administer iron sulfate 3 mg/kg (elemental iron) once or twice daily between meals for 4 weeks. Continue for 2 additional months in responders to replace storage iron pools. The dose and schedule of vitamin B12 should be titrated according to the clinical and laboratory response. The daily dose of folate is 1 to 3 mg.

EVALUATION OF THERAPEUTIC OUTCOMES

• IDA: Positive response to oral iron therapy characterized by modest reticulocytosis in a few days with an increase in Hb seen at 2 weeks. Reevaluate the patient if reticulocytosis does not occur. Hb should return to normal after 2 months; continue iron therapy until iron stores are replenished and serum ferritin normalized (up to 12 months).

• 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 should not progress during therapy. Reticulocytosis should occur within 3 to 5 days. Hb begins to rise a week after starting vitamin B12 therapy and should normalize in 1 to 2 months. Hct should rise within 2 weeks after starting folate therapy and should normalize within 2 months.

• ESAs: Reticulocytosis should occur within a few days. Monitor iron, TIBC, transferrin saturation, and ferritin levels at baseline and periodically during therapy. The optimal form and schedule of iron supplementation are unknown. Discontinue ESAs if a clinical response does not occur after 8 weeks.

• Pediatrics: Monitor Hb, Hct, and RBC indices 6 to 8 weeks after initiation of iron therapy. Monitor Hb or Hct weekly in premature infants.