How should a physician diagnose and treat anemia according to the American Society of Hematology?

Diagnosis and Treatment of Anemia: American Society of Hematology Approach

Initial Diagnostic Workup

Before initiating any anemia therapy, physicians must systematically exclude correctable causes through targeted history, examination, and laboratory testing 1.

Essential History and Physical Examination Elements

• Document all current medications, specifically looking for drugs that cause hemolysis (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, diclofenac) 1
• Assess for occult blood loss through gastrointestinal or genitourinary sources 1
• Evaluate for recent insect, spider, or snake bites that may trigger hemolysis 1
• Screen for renal insufficiency as a contributing factor 1

Core Laboratory Investigations

The diagnostic algorithm begins with three foundational tests 2, 3:

1. Complete blood count (CBC) with red cell indices - provides mean cell volume (MCV), hemoglobin, hematocrit 1, 2
2. Reticulocyte count - distinguishes adequate bone marrow response (hemolysis/blood loss) from inadequate production 1, 2
3. Peripheral blood smear review - identifies characteristic red cell morphology and abnormal cell populations 1, 2

Additional Required Testing Based on Clinical Context

Iron studies are mandatory and should include: iron level, total iron-binding capacity (TIBC), transferrin saturation (TSAT), and ferritin 1, 4

Vitamin deficiencies must be assessed: vitamin B12 and folate levels where indicated by macrocytosis 1

Hemolysis evaluation when reticulocyte count is elevated 1:

• Lactate dehydrogenase (LDH)
• Haptoglobin
• Direct and indirect bilirubin
• Direct antiglobulin test (Coombs test) - particularly for chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history 1
• Free hemoglobin
• Disseminated intravascular coagulation panel (PT/INR)

Specialized testing when initial workup is unrevealing 1:

• Paroxysmal nocturnal hemoglobinuria screening
• Glucose-6-phosphate dehydrogenase level
• Protein electrophoresis and cryoglobulin analysis
• Infectious causes (viral/bacterial including mycoplasma)
• Bone marrow examination with cytogenetic analysis if refractory or myelodysplastic syndrome suspected
• Copper level, parvovirus, thyroid function
• Methemoglobinemia assessment

Classification and Treatment Approach

Microcytic Anemia (MCV < 80 fL)

Iron deficiency anemia is the most common cause worldwide 2, 5.

For absolute iron deficiency (low ferritin, low TSAT):

• Oral iron supplementation is first-line therapy 1
• Recheck iron studies 3-4 weeks after completing oral iron therapy 4
• Monitor hemoglobin and MCV every 3 months for the first year after normalization 4

For functional iron deficiency (TSAT < 20% despite adequate ferritin):

• Intravenous iron is preferred over oral iron 1
• Do not recheck iron parameters within 4 weeks of IV iron administration due to falsely elevated ferritin 4
• Optimal timing for rechecking iron studies is 4-8 weeks after the last IV infusion 4
• Withhold further IV iron when TSAT ≥ 50% or ferritin > 1,000 ng/mL 1, 4

Consider thalassemia screening when iron studies are normal but microcytosis persists 5.

Normocytic Anemia (MCV 80-100 fL)

Anemia of chronic disease/inflammation is a diagnosis of exclusion 5.

Reticulocyte count determines the next step 2:

• Elevated reticulocyte count: pursue hemolysis or acute blood loss workup as detailed above
• Normal/low reticulocyte count: evaluate for bone marrow suppression, chronic kidney disease, or endocrine disorders

Macrocytic Anemia (MCV > 100 fL)

Differentiate based on reticulocyte count 5:

• Elevated reticulocytes: hemolysis or blood loss with compensatory response
• Normal/low reticulocytes: vitamin B12 or folate deficiency, hypothyroidism, liver disease, myelodysplastic syndrome

Treatment of Cancer-Related Anemia

Erythropoiesis-Stimulating Agents (ESAs)

ESAs are recommended only for patients receiving palliative, myelosuppressive chemotherapy with hemoglobin < 10 g/dL and without absolute iron deficiency 1.

ESAs are NOT recommended for 1:

• Patients not receiving myelosuppressive chemotherapy
• Patients with curable disease
• Patients with hemoglobin > 10 g/dL

Before offering ESAs, conduct baseline investigations 1:

• Thorough drug exposure history
• Peripheral blood smear review (and bone marrow in some cases)
• Iron, TIBC, transferrin saturation, ferritin
• Folate, vitamin B12, or hemoglobinopathy screening where indicated
• Reticulocyte count
• Assessment for occult blood loss and renal insufficiency
• Baseline erythropoietin level
• Direct antiglobulin testing for CLL, NHL, or autoimmune disease history

Concurrent IV iron therapy improves ESA response 1:

• Offer IV iron to anemic cancer patients with TSAT < 20% 1
• Mean increase in TSAT ranges between 17-22% with combined ESA and IV iron therapy 1

Transfusion Therapy

Red cell transfusion is appropriate when hemoglobin < 7-8 g/dL in most hospitalized patients 1.

Use restrictive transfusion strategy (hemoglobin threshold 7-8 g/dL) rather than liberal strategy 1:

• Transfusion is generally NOT beneficial when hemoglobin > 10 g/dL 1
• Transfusion may be beneficial when hemoglobin < 6-8 g/dL 1

Administer single-unit RBC transfusions for nonbleeding hospitalized patients, then reassess before giving additional units 1.

One unit of packed red cells increases hemoglobin by approximately 1 g/dL in average-sized adults who are not bleeding 1.

Critical Pitfalls to Avoid

Do not measure ferritin within 4 weeks of IV iron administration - it will be falsely elevated and does not reflect true iron stores 4.

Do not assume transfused red cells correct iron deficiency - the iron from transfused cells takes 100-110 days to become available for erythropoiesis 1.

Do not use ESAs in patients with mild-to-moderate anemia and heart disease - harms outweigh benefits due to increased thrombosis and hypertension risk 1.

Do not rely solely on hemoglobin thresholds for transfusion decisions - consider whether anemia is acute versus chronic, presence of active bleeding, vital sign changes, and patient symptoms 1.

Do not continue iron supplementation indefinitely without monitoring - recheck iron studies and hemoglobin every 3 months during the first year after correction 4.