Definition: hemoglobin <13.5 or hematocrit <41 in men, or 12 and 36 in women. MCV must be between 80 and 100.

Differential Diagnosis

Stratified by reticulocyte count: decreased (underproduction) or increased (destruction).

• Decreased reticulocyte count
  • Primary bone marrow failure:
    • Aplastic anemia/red cell aplasia: diagnosed by bone marrow biopsy.
    • Myelophthisis (replacement of the bone marrow with tumor, granulomas, fibrosis, etc.): tear drops, nucleated red cells, immature granulocytes on smear (i.e. leukoerythroblastic smear).
    • Clonal marrow disorders: leukemia, myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH)
  • Secondary bone marrow failure:        
    • Anemia of chronic disease (most common cause in adults).
    • Acute or critical illness.
    • Chronic kidney disease: consider erythropoietin when the creatinine clearance drops below 30 ml/min.
    • Hypersplenism: usually anemia is concomitant with mild pancytopenia.
    • Endocrine disorders (hypothyroidism, adrenal insufficiency, hypogonadism).
    • Multiple myeloma.
    • Infection: HIV/AIDS, parvovirus B19.
    • Drugs: commonly chemotherapy.
    • Mixed: e.g., megaloblastic anemia from folate deficiency and iron deficiency from GI bleeding. The MCV is normal, but the RDW is increased reflecting anisocytosis (cells of varying sizes).
• Increased reticulocyte count
  • Acute blood loss: if you can’t find a source, don’t forget to rule out occult retroperitoneal bleed.
  • Correction of a production deficit. Peak MCV/reticulocyte count at 7-10 days.
  • Hemolysis: see below.

Evaluation

• Decreased reticulocyte count:
  • Peripheral smear, iron, ferritin, transferrin and transferrin saturation, TSH, as well as B12 levels.
  • If these are not revealing, check SPEP/serum free light chains to assess for myeloma. Consider checking testosterone level in men.
  • If diagnosis is not made with these tests, strong consideration of bone marrow biopsy is indicated.
• Increased/normal reticulocyte count:
  • Consider acute blood loss, with evaluation possibly including rectal exam for occult blood loss and CT for retroperitoneal hematoma.
  • Otherwise, peripheral smear should be obtained, with the following workup for hemolysis:
    • LDH, total and direct bilirubin, haptoglobin, direct Coomb’s and review of the peripheral smear. 
    • Autoimmune hemolytic anemia (AIHA): smear typically reveals spherocytes. Direct Coomb’s is diagnostic. Drug-induced immune hemolysis is common as well.
    • Microangiopathic hemolytic anemia (MAHA): TTP, HUS, DIC, mechanical heart valves, hemodialysis, malignant HTN, vasculitis, HELLP, cardiopulmonary bypass, trauma/red cell fragmentation should be considered: look for schistocytes and helmet cells (even 1-2 per HPF). See section Thrombotic Microangiopthies for further details.
    • Enzyme deficiencies (e.g. G6PD deficiency): smear may show bite cells, blister cells, Heinz body prep will show Heinz bodies (unstable Hgb aggregates), but normal smear also possible. Coomb’s normal. Check G6PD levels, which may be normal after an acute hemolytic episode or post transfusion. Consider this in all HIV patients, particularly African Americans, taking PCP prophylaxis. Dapsone is a common culprit so check G6PD levels prior to or soon after initiating medication.
    • Hemoglobinopathy: sickle cell disease, thalassemias, Hgb C, Hgb E.
    • PNH: complement-mediated lysis. Consider with pancytopenia, unexplained thrombosis (especially intra-abdominal) or unexplained hemolysis. Flow cytometry using antibodies against GPI-anchored proteins (CD55, CD59) on RBCs and WBCs is the most sensitive assay for this rare disorder.
    • Other hemolytic anemias include: hereditary spherocytosis, hereditary elliptocytosis, parasitic infection (e.g. malaria), bacterial infections (e.g. clostridial sepsis), pyruvate kinase deficiency, cold agglutinins (a form of AIHA, may be associated with mycoplasma, EBV infection), paroxysmal cold hemoglobinuria. Hereditary spherocytosis and elliptocytosis, as well as malaria, may all be diagnosed by peripheral smear.

Management

Acute management for symptomatic anemia is always transfusion except in cases complicated by hyperviscosity or hyperleukocytosis. Otherwise, management should be directed at the cause.

• Erythropoietin and related agents are commonly used in cancer patients receiving chemotherapy (as well as in patients with renal disease). However, these agents are associated with increased mortality from a number of causes, as well as stroke, DVT and tumor progression. The 2010 ASCO guidelines limit their use to patients with low risk myelodysplastic syndromes and to patients actively or recently (within 8 weeks) receiving chemotherapy, only after discussion of the risks and benefits. They should be used only when the hemoglobin falls below 10 grams/dl. There is controversy about the goal hemoglobin for patients with end stage renal disease, but it is generally agreed that erythropoietin should be discontinued when hemoglobin >12 grams/dl.

Key Points

• Key differentiation points are based on reticulocyte counts, and much of the analysis can be done based on a peripheral smear.
• Always consider what is most likely for your patient before sending a huge number of tests.
• Remember that transfusion can obscure analysis, so be sure to get a few tubes of blood for analysis while preparing to transfuse.

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Dhaliwal G, Cornett PA, Tierney LM, Jr. Hemolytic anemia. Am Fam Physician 2004;69:2599-2606.

Garratty G. Immune hemolytic anemia-a primer. Semin Hematol 2005;42:119-121.

Hayden SJ, Albert TJ, Watkins TR, Sweson ER. Anemia in Critical Illness. Am J Respir Crit Care Med 2012; 185(10): 1049-1057.

Rizzo JD, Brouwers M, Hurley P et al. American society of clinical oncology / American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol 2010; 28(33) 4996-5010.

Weiss G, Goodnough LT, Anemia of chronic disease, New Eng J Med 2005; 352(10):1011-23.