What is the initial workup and management plan for a patient presenting with anemia?

Initial Workup for Anemia

Begin with a complete blood count (CBC) with red cell indices, reticulocyte count, iron studies panel (serum ferritin, transferrin saturation, total iron-binding capacity), and C-reactive protein—these tests should be ordered simultaneously at initial presentation to establish the diagnosis and guide treatment. 1, 2, 3

Diagnostic Thresholds

Anemia is defined as:

• Hemoglobin < 13 g/dL in men 1, 2, 3
• Hemoglobin < 12 g/dL in non-pregnant women 1, 2, 3
• Hemoglobin < 11 g/dL in pregnant women 1, 2

Essential First-Line Laboratory Tests

Order these tests together at the initial visit:

• Complete blood count with differential including hemoglobin, hematocrit, MCV, MCH, MCHC, RBC count, and RDW 1, 2, 3
• Reticulocyte count (absolute, not just percentage) to assess bone marrow response 1, 2, 3
• Iron studies panel: serum ferritin, transferrin saturation (TSAT), and total iron-binding capacity 1, 2, 3
• C-reactive protein to identify inflammation that may affect ferritin interpretation 2, 3

Morphologic Classification and Next Steps

Microcytic Anemia (MCV < 80 fL)

Most commonly indicates iron deficiency anemia, but also consider thalassemia trait, anemia of chronic disease, or sideroblastic anemia. 1, 2, 3

Confirm iron deficiency with:

• Serum ferritin < 30 μg/L (in absence of inflammation) 1, 2
• Transferrin saturation < 15-16% 2

Critical caveat: Ferritin is an acute phase reactant and can be falsely elevated in inflammation, chronic disease, malignancy, or liver disease—interpret in clinical context. 2, 3

If iron studies are normal, obtain hemoglobin electrophoresis to evaluate for thalassemia trait, particularly in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent. 2

Normocytic Anemia (MCV 80-100 fL)

May indicate acute blood loss, hemolysis, anemia of chronic disease, early iron deficiency, or chronic kidney disease. 2, 3

Additional workup includes:

• Assess for blood loss: detailed history for gastrointestinal bleeding, menstrual losses, or occult bleeding 2
• Evaluate for hemolysis: measure haptoglobin, LDH, indirect bilirubin, and examine peripheral smear for schistocytes 4, 2
• Screen for chronic kidney disease: measure serum creatinine and calculate GFR 3
• Consider anemia of chronic disease: assess for underlying inflammatory conditions using CRP and clinical history 2, 3

Macrocytic Anemia (MCV > 100 fL)

Most commonly indicates vitamin B12 or folate deficiency, but also consider medications (methotrexate, hydroxyurea), alcohol use, hypothyroidism, or myelodysplastic syndrome. 2, 3

Measure vitamin B12 and folate levels in all patients with macrocytic anemia. 2, 3

Important pitfall: High-dose folic acid supplementation can mask vitamin B12 deficiency and allow irreversible neurologic damage to progress—always check B12 before treating with folate. 5

Reticulocyte Count Interpretation

• Low or normal reticulocyte count indicates impaired erythropoiesis (production problem) 2
• Elevated reticulocyte count suggests increased red cell production in response to blood loss or hemolysis (destruction or loss problem) 2

Additional Testing Based on Clinical Suspicion

If Hemolysis is Suspected:

• Haptoglobin (decreased) 4, 2
• LDH (elevated) 4, 2
• Indirect bilirubin (elevated) 4, 2
• Peripheral blood smear for schistocytes 4
• Direct antiglobulin test (Coombs test) 4
• Glucose-6-phosphate dehydrogenase level if drug-induced hemolysis suspected 4

If Bone Marrow Failure is Suspected:

• Vitamin B12 and folate levels 4, 2
• Copper level 4
• Thyroid function tests 4
• Parvovirus B19 testing 4

If Chronic Kidney Disease is Present:

• Monitor hemoglobin at least every 3 months in patients with GFR < 30 mL/min/1.73 m² 1, 3
• Initiate full workup if hemoglobin drops below diagnostic thresholds 1, 3
• Do not routinely measure serum erythropoietin levels—this is not indicated in CKD patients with normochromic, normocytic anemia 1

Investigation for Underlying Cause

In Adult Men and Postmenopausal Women with Iron Deficiency:

Gastrointestinal evaluation with endoscopy is required to exclude malignancy, regardless of anemia severity. 2

In Premenopausal Women:

Assess menstrual blood loss history, but still consider GI evaluation if iron deficiency is severe or refractory to treatment. 2

Critical Pitfalls to Avoid

• Never assume anemia is "normal aging" in elderly patients—always investigate the underlying cause 1, 3
• Watch for combined deficiencies (iron plus B12, or iron plus folate), especially in elderly patients and those with inflammatory bowel disease 1, 3
• Do not treat with folic acid before excluding B12 deficiency—doses of folic acid > 0.1 mg daily may produce hematologic remission while allowing irreversible neurologic damage to progress 5
• Recognize that low MCH with elevated RDW can indicate early iron deficiency even when MCV and hemoglobin appear normal—this pattern has 72% sensitivity for detecting iron deficiency 2
• In cancer patients, folate and B12 deficiency are rare (0% and 3.9% respectively)—reserve testing for patients with high clinical suspicion such as elevated MCV or neurologic symptoms 4

Special Populations

Cancer-Related Anemia:

The etiology can be traced to production (bone marrow infiltration, chemotherapy), destruction (hemolysis, hypersplenism), or loss (bleeding, surgery) of red blood cells. 4

Chronic Kidney Disease:

Treat identified iron deficiency first (target TSAT > 30% and ferritin > 500 ng/mL), and if anemia persists despite iron repletion, consider erythropoietin therapy. 1, 3