Overview of anemia

Classify anemia and conduct workup based on peripheral smear appearance and MCV...
Abdelwahab Ward, BS Pharm, PharmD

Screening ― Do not perform routine screening for anemia in nonpregnant, asymptomatic patients. Although determination of hemoglobin concentration or hematocrit is important to evaluating a variety of complaints (e.g., fatigue, weight loss, abdominal pain, GI bleeding) and may provide clues in asymptomatic patients to presence of treatable disease (e.g., GI malignancy), these determinations are less sensitive and less specific than well-recognized screening methods identified for such conditions (e.g., stool guaiac testing, sigmoidoscopy, colonoscopy).

Obtain screening hematocrit or hemoglobin concentration at time of first prenatal visit in pregnant women, because iron deficiency anemia is common in this setting and associated with poorer pregnancy outcomes. Do not screen for anemia in menstruating nonpregnant women because there is no clear relationship between mild to moderate degrees of anemia and symptoms and no clearly measurable benefits from treating iron deficiency anemia.

Prevention

For iron deficiency, advise adequate iron intake to prevent iron deficiency in those with increased needs (e.g., pregnant women and young children) and recommend iron-rich foods to avoid need for iron supplements (e.g., liver, oysters, moderately to heavily iron-enriched cereals, lean beef, veal, and beans). Green vegetables are rich in iron, but iron absorption is poor because of binding to plant phytates and phosphates.

  • When diet alone seems inadequate and needs are very high (e.g., pregnancy), prescribe 150–300 mg/day ferrous sulfate.
  • Counsel against iron supplement use in most other instances; supplementation is unnecessary, expensive, and associated with increased risks for malignancy and atherosclerotic disease.
  • For B12 deficiency, prevent vitamin B12 deficiency in the elderly by recommending frequent feedings and total intake of ≥ 25 g/day cyanocobalamin orally.

Diagnosis

GENERAL STRATEGY ― Classify anemia and conduct workup based on peripheral smear appearance and MCV:

  1. Microcytic if MCV < 80 fL and RBCs are small.
  2. Macrocytic if MCV > 100 fL and RBCs are large
  3. Normocytic if MCV is 80–100 fL and RBCs are normal size. See figure 2, "Algorithm for the assessment of anemia".

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Image source: https://healthjade.net/anemia
Figure 1; Differential diagnosis of anemia.

LAB TESTS ― For microcytic anemia, test first for iron deficiency by obtaining serum ferritin (test of choice for iron deficiency). No need to order serum iron or TIBC for diagnosis of iron deficiency unless there is concurrent inflammation (ferritin is an acute-phase reactant and its level may be elevated in the setting of inflammatory disease). If iron deficiency identified, but cause is not evident, begin search of GI tract for source of occult blood loss. If iron deficiency ruled out, assess for thalassemia. Check for Mediterranean extraction and family history of anemia or thalassemia. Examine peripheral smear and RBC indices for characteristic manifestations (e.g. target cells, teardrops, increased RBC count, reduced MCHC), and consider testing for hemoglobin A2 level. If iron deficiency and thalassemia have been ruled out, review ferritin level and obtain transferrin saturation (iron/TIBC) to help differentiate anemia of chronic disease (ferritin normal, transferrin saturation low to normal) from sideroblastic anemia (ferritin high, transferrin saturation high). If sideroblastic anemia suspected, obtain hematologic consultation for consideration of bone marrow aspirate to check for ringed sideroblasts.

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Figure 2
Algorithm for the assessment of anemia.

For macrocytic anemia, examine peripheral smear for hypersegmented polymorphonuclear leukocytes and oval macrocytes. If present, obtain serum vitamin B12 and folate levels. If serum vitamin levels are not diagnostic, obtain serum homocysteine and methylmalonate levels to enhance diagnostic sensitivity, or perform diagnostic trial with small dose of vitamin B12 or folate, monitoring reticulocyte count. If you detect vitamin B12 deficiency, consider Schilling test to differentiate lack of intrinsic factor from malabsorption. If macrocytic anemia is nonmegaloblastic, obtain reticulocyte count and examine peripheral smear to determine if marrow activity is increased, normal, or decreased. If reticulocyte count is high in absence of hemorrhage, check for hemolysis (haptoglobin, bilirubin, LDH); if normal or slightly reduced, consider hepatic and thyroid dysfunction; if markedly reduced, review peripheral smear for teardrops and ringed sideroblasts, and consider bone marrow biopsy.

For normocytic anemia, determine whether reticulocyte count is elevated, inappropriately normal, or low. If count is elevated, evaluate for evidence of recent hemorrhage; if none, confirm hemolysis with haptoglobin, bilirubin, and lactate dehydrogenase determinations. If hemolysis confirmed, check for drug-induced cause (direct Coombs' test), autoimmune mechanism (IgG or cold agglutinins), or hemoglobinopathy (sickle cell disease, G-6-PD deficiency). If reticulocyte count is not elevated, search for underlying hepatocellular, endocrine, and renal causes and for early iron deficiency anemia and anemia of chronic disease (see above). If reticulocyte count is nil, if peripheral blood count and smear show pancytopenia, teardrop forms, and fragmented cells, and if halting all potentially offending medications does not promptly restore marrow function, obtain hematology consultation for bone marrow biopsy.

Treatment

Management of IDA

For iron deficiency anemia (IDA), never treat empirically until underlying etiology identified. Correcting iron deficiency without attending to underlying cause can mask important clues to treatable disease and compromise timely treatment. Begin replacement therapy when symptomatic, underlying cardiac or pulmonary disease, anemia moderately severe (hemoglobin level 8–9 g/dL), pregnant, subtotal gastrectomy and gastrojejunostomy, continued heavy blood loss anticipated and recovering from megaloblastic anemia.

For maximum cost-effectiveness, prescribe generic ferrous sulfate tablets. Maximize compliance by starting with small dose of ferrous sulfate (e.g. 300 mg/day) and building to 900 mg/day to minimize GI upset. Minimize upper GI side effects by taking iron with meals and using lowest effective dose; reducing frequency of dosing is less effective than reducing dose itself. Avoid use of slow-release and enteric-coated preparations because they dissolve slowly and can bypass proximal small bowel (in which most absorption takes place). Limit use of parenteral iron to patients who have had adequate trial of oral iron and have shown genuine intolerance to all available preparations (e.g. patients with inflammatory bowel disease). If parenteral iron required, administer using IV route, first by very small test dose and then by slow drip; draw up syringe with epinephrine at same time and keep it on hand. Avoid IM administration of iron (sarcomas at injection sites). Consider effect of iron on absorption of other drugs when taken simultaneously (e.g., levodopa, methyldopa, tetracycline, and fluoroquinolone antibiotics). Delay iron intake for several hrs after intake of these other medications.

Take iron with orange juice (rich in ascorbic acid) or use ascorbic acid–containing preparation when gastric acid suppression is necessary. Watch for reticulocytosis at 10 days into therapy followed by daily rise in hemoglobin concentration of 0.1–0.2 g/dL. Continue therapy at maximum tolerated doses for several weeks until hemoglobin level is normal; fully replenishing iron stores may take several months: educate patient to maximize compliance. If speed of replacement is an issue, consider blood transfusion rather than iron therapy (response to parenteral iron therapy is no more rapid with oral preparations).

Management of folate deficiency

Treat with pharmacologic doses of folic acid (1–2 mg/day orally). Continue for 4–5 weeks. When underlying cause persists (e.g. malabsorption, malignancy, psoriasis, hemodialysis), continue treatment indefinitely. Prescribe folinic acid for patients taking methotrexate. Avoid nonspecific folic acid monotherapy to treat megaloblastic anemia. If alcoholism is basis of folate deficiency, address drinking problem. Provide dietary counseling and perhaps referral to nutritionist. Avoid large empiric doses of PO folate monotherapy (5 mg) for megaloblastic anemia because of risk of partial and nonspecific correction of anemia while masking underlying vitamin B12 deficiency.

Management of vit. B12 deficiency

For patients with vitamin B12 deficiency caused by bacterial overgrowth or terminal ileum disease, treat underlying bowel problem (e.g., oral tetracycline or amoxicillin for bacterial overgrowth; steroids and sulfa drugs for inflammatory bowel disease). Promptly recognize and treat vitamin B12 deficiency to minimize risk of permanent neurologic damage. Prescribe parenteral therapy (except in rare patient with poor intake) because most vitamin B12 deficiency is secondary to impaired absorption. In some cases, use of large oral doses (> 100 g/day) may result in sufficient absorption of vitamin B12. Consider use of parenteral cyanocobalamin or hydroxocobalamin (better bound to serum proteins and less rapidly excreted, requiring less frequent administration). Choose from host of initial replacement regimens; all are adequate.

For pernicious anemia, begin with 100–1,000 mcg/day IM cyanocobalamin or hydroxocobalamin for 1–2 weeks, repeated 2 × week for 1 month, then monthly for remainder of patient's life. Alternatively, consider follow-up injection every 3–4 months, which suffices for many patients; if neurologic symptoms are present, administer twice/month follow-up dose for 6 months. More important than interval of therapy is its indefinite continuation; ensure long-term administration; have visiting nurse or family member give injection. Avoid empiric use of parenteral vitamin B12 as nonspecific treatment for fatigue. During treatment, monitor serum potassium and replace if low because serious hypokalemia can develop in patients who have had severe B12 depletion. For further information, see note on, "Management of vitamin B12 deficiency".

Erythropoietin deficiency states

Consider erythropoietin in dialysis patients with regular transfusion requirements (IV injections of recombinant erythropoietin, 150 U/kg, 3 × week). Concurrent iron supplementation is often necessary. Also consider in situations associated with severe anemia and reduced serum erythropoietin levels (e.g. HIV infection, malignancy, cancer chemotherapy).

Preoperative anemia

Consider allogeneic transfusion for patients undergoing elective surgery if there is anemia before surgery and expected operative blood loss. Alternatively, consider preoperative erythropoietin therapy (erythropoietin, 300–600 U/kg SQ, 2–4 × week) if you want to limit allogeneic transfusion requirements and facilitate donation of autologous blood. Best candidates have preoperative hematocrit of 33–39% and expected blood loss of 1–3 L.

References

Abdelwahab Ward, BS Pharm, PharmD