Hematology

Anemia

Evaluate anemia using the hemoglobin trend, clinical stability, MCV, reticulocyte response, peripheral smear, iron studies, hemolysis testing, nutritional testing, kidney function, inflammation, and abnormalities in the other blood-cell lines.

Audience: internal medicine residents Last reviewed: July 2026

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Anemia guide library

Iron Deficiency

Interpret ferritin and TSAT, identify blood loss or malabsorption, select oral or intravenous iron, and monitor response.

Ferritin TSAT Ganzoni
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Microcytic Anemia

Distinguish iron deficiency, thalassemia, inflammatory iron restriction, sideroblastic anemia, and lead exposure.

Low MCV Thalassemia Mentzer index
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Normocytic Anemia

Use the reticulocyte response to separate bleeding and hemolysis from CKD, inflammation, endocrine disease, and marrow disorders.

Reticulocytes RPI CKD
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Macrocytic Anemia

Evaluate vitamin B12, MMA, homocysteine, folate, medications, alcohol, liver disease, reticulocytosis, and MDS.

Vitamin B12 MMA Folate
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Hemolytic Anemia

Confirm red-cell destruction, interpret the DAT and smear, distinguish immune from nonimmune causes, and recognize TMA.

DAT Schistocytes Haptoglobin
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Anemia of CKD and Inflammation

Interpret functional iron restriction, ferritin and TSAT, iron treatment, ESA principles, and transfusion considerations.

Hepcidin ESA Functional iron deficiency
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Hemoglobinopathies

Review sickle cell disease, sickle trait, alpha and beta thalassemia, hemoglobin analysis, transfusion, and iron overload.

Sickle cell Thalassemia Electrophoresis
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Pancytopenia

Evaluate marrow failure, infiltration, nutritional deficiencies, infection, consumption, sequestration, and urgent syndromes.

Marrow failure Copper Blasts
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Core framework

Start with three questions

1. Acute or chronic?

Review prior hemoglobin values, recent fluids, transfusions, bleeding, procedures, medications, and the rate of decline.

2. Is the marrow responding?

Use the absolute reticulocyte count, corrected reticulocyte percentage, or reticulocyte production index.

3. What pattern is present?

Integrate MCV, RDW, RBC count, smear findings, iron studies, hemolysis testing, kidney function, B12, folate, and other cell lines.

Urgent escalation

  • Hemodynamic instability or active major bleeding
  • Chest pain, ischemia, syncope, severe hypoxemia, or shock
  • Rapid unexplained hemoglobin decline
  • Hemolysis with thrombocytopenia or organ injury
  • Schistocytes with suspected thrombotic microangiopathy
  • Severe anemia with profound reticulocytopenia
  • Circulating blasts or suspected acute leukemia
  • Pancytopenia with fever, bleeding, or severe infection

Initial evaluation

History and examination

  • Hemoglobin trend and baseline
  • Bleeding symptoms
  • Diet and malabsorption risk
  • Menstrual and pregnancy history
  • Alcohol and medication exposure
  • Kidney, liver, inflammatory, or malignant disease
  • Neurologic symptoms
  • Family history and ancestry
  • Recent transfusion
  • Lymphadenopathy or splenomegaly

Common initial tests

  • CBC with differential and prior CBC review
  • Absolute reticulocyte count
  • Peripheral smear
  • Ferritin, serum iron, TIBC, and TSAT
  • Creatinine and estimated GFR
  • LDH, bilirubin, and haptoglobin
  • Urinalysis
  • Vitamin B12 and folate when indicated
  • DAT when immune hemolysis is possible
  • TSH or marrow studies when directed by the pattern
The MCV is an average. Combined iron deficiency and vitamin B12 or folate deficiency may produce a normal MCV with an increased RDW or dimorphic peripheral smear.

Reticulocyte-based classification

Response Mechanism Major causes
Inadequate response Impaired or ineffective red-cell production Iron deficiency, B12 or folate deficiency, CKD, inflammation, endocrine disease, marrow failure, marrow infiltration, infection, medications, and ineffective erythropoiesis
Increased response Marrow compensation for red-cell loss or destruction Acute or chronic bleeding, hemolysis, recovery after nutrient replacement, recovery after marrow suppression, or response to erythropoietic treatment
Blunted or mixed response Loss or destruction with limited marrow reserve Hemolysis with iron or folate deficiency, bleeding with CKD, infection with hemolysis, marrow disease, or recent transfusion
A raw reticulocyte percentage may appear elevated because the circulating red-cell denominator is reduced. Use the absolute count or a corrected value when the degree of anemia is clinically important.

MCV-based classification

Use the local laboratory reference range. Common adult categories are microcytic below approximately 80 fL, normocytic approximately 80–100 fL, and macrocytic above approximately 100 fL.

MCV <80 fL

Microcytic

  • Iron deficiency
  • Thalassemia
  • Inflammatory iron restriction
  • Sideroblastic anemia
  • Lead exposure
  • Inherited iron or heme disorders
MCV 80–100 fL

Normocytic

  • Acute blood loss
  • Hemolysis
  • CKD
  • Inflammation
  • Early nutritional deficiency
  • Endocrine disease
  • Marrow disease
MCV >100 fL

Macrocytic

  • Vitamin B12 deficiency
  • Folate deficiency
  • Alcohol
  • Liver disease
  • Reticulocytosis
  • Hypothyroidism
  • Medications
  • MDS or marrow disease

High-yield MCV differential

Pattern Common causes Helpful clues Common next tests
Microcytic Iron deficiency, thalassemia, inflammation, sideroblastic anemia, and lead Ferritin, TSAT, RBC count, RDW, target cells, blood loss, or toxin exposure Iron studies, hemoglobin analysis, blood lead concentration, or marrow evaluation
Normocytic with high retic Bleeding, hemolysis, or marrow recovery Hemoglobin trend, bleeding symptoms, jaundice, dark urine, or abnormal smear LDH, bilirubin, haptoglobin, DAT, urinalysis, and bleeding evaluation
Normocytic with low retic CKD, inflammation, early deficiency, endocrine disease, infection, medications, or marrow disease Reduced GFR, inflammatory disease, other cytopenias, or abnormal smear Iron studies, kidney testing, B12, folate, TSH, inflammatory testing, and marrow evaluation when indicated
Macrocytic B12 or folate deficiency, alcohol, liver disease, hypothyroidism, reticulocytosis, medications, or MDS Macro-ovalocytes, hypersegmented neutrophils, neurologic symptoms, alcohol exposure, or additional cytopenias B12, MMA, homocysteine, folate, TSH, liver tests, reticulocytes, and marrow evaluation when indicated

Peripheral-smear clues

Finding Common associations Clinical response
Schistocytes TMA, DIC, mechanical hemolysis, severe hypertension, or other fragmentation Correlate urgently with platelets, hemolysis testing, coagulation studies, kidney function, and organ injury
Spherocytes Warm autoimmune hemolysis or hereditary spherocytosis Obtain a DAT and assess the clinical and family history
Target cells Thalassemia, hemoglobinopathy, liver disease, or postsplenectomy state Review iron studies, liver disease, and hemoglobin testing
Macro-ovalocytes Megaloblastic anemia Evaluate B12, folate, medications, and marrow disease
Hypersegmented neutrophils B12 or folate deficiency and impaired DNA synthesis Complete nutritional and medication evaluation
Teardrop cells Marrow fibrosis, infiltration, severe dyserythropoiesis, or extramedullary hematopoiesis Look for leukoerythroblastosis, splenomegaly, and additional cytopenias
Bite or blister cells Oxidative hemolysis, including G6PD deficiency Review oxidant exposure and interpret G6PD testing carefully during acute hemolysis
Rouleaux Increased plasma proteins, inflammation, or plasma-cell disorder Consider SPEP, immunofixation, and free light chains when the clinical context supports it

High-yield laboratory patterns

Condition Reticulocytes Typical pattern Important caution
Iron deficiency Usually inadequate Low ferritin, low serum iron, low TSAT, and often increased TIBC Ferritin may be less clearly reduced when inflammation coexists
Anemia of inflammation Usually inadequate Low serum iron and TSAT with normal or elevated ferritin and low-normal TIBC Absolute iron deficiency may coexist
Hemolysis Usually increased Increased LDH and indirect bilirubin, reduced haptoglobin, and possible hemoglobinuria The reticulocyte response may be blunted by marrow or nutritional disease
Vitamin B12 deficiency Often inadequate Low or borderline B12 with increased MMA; homocysteine may also be increased MMA may rise with impaired kidney function
Folate deficiency Often inadequate Low folate with increased homocysteine and normal MMA Exclude B12 deficiency before relying on folate treatment alone
CKD Inadequate Usually normocytic anemia with reduced kidney function Exclude iron deficiency, bleeding, inflammation, hemolysis, and nutritional deficiency
Marrow failure Markedly inadequate Additional cytopenias, abnormal smear, or profound reticulocytopenia Consider aplasia, MDS, leukemia, fibrosis, infiltration, or infection

Diagnostic pathway

Compact anemia algorithm

Step 1: Confirm the anemia and assess urgency Review the hemoglobin trend, symptoms, vital signs, bleeding, ischemia, hypoxemia, fluids, and recent transfusion.
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Step 2: Review the full CBC and smear Note MCV, RDW, RBC count, leukocytes, platelets, differential, and abnormal morphology.
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Step 3: Determine the reticulocyte response An inadequate response suggests impaired production. An increased response suggests bleeding, hemolysis, or recovery.
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Step 4A: Inadequate response Use MCV, iron studies, B12, folate, kidney function, inflammation, endocrine testing, medications, infection, and the other cell lines to identify underproduction.
Step 4B: Increased response Evaluate bleeding and hemolysis using the history, examination, LDH, bilirubin, haptoglobin, urinalysis, DAT, coagulation studies, and smear findings.
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Step 5: Escalate unexplained or complex cases Consider hematology consultation and marrow evaluation for persistent unexplained anemia, additional cytopenias, dysplasia, blasts, leukoerythroblastosis, monoclonal protein, or profound reticulocytopenia.

When to suspect marrow disease

  • Persistent unexplained anemia
  • Progressive decline despite correction of reversible causes
  • Leukopenia, neutropenia, or thrombocytopenia
  • Circulating blasts or immature myeloid cells
  • Dysplastic neutrophils or platelets
  • Teardrop cells or a leukoerythroblastic smear
  • Profound reticulocytopenia
  • Constitutional symptoms, lymphadenopathy, or splenomegaly
  • Monoclonal protein with concerning clinical features
  • Unexplained macrocytosis or iron overload
Bone-marrow biopsy is not required for every anemia. It becomes more useful when anemia remains unexplained, the smear is abnormal, the reticulocyte response is markedly reduced, or additional cell lines are affected.

Resident summary

  1. Confirm the anemia and determine whether it is acute or chronic.
  2. Assess stability before completing a detailed classification.
  3. Review the entire CBC, reticulocyte response, and smear.
  4. Use MCV to organize the differential, not establish the diagnosis.
  5. Low reticulocytes suggest impaired production.
  6. High reticulocytes suggest bleeding, hemolysis, or recovery.
  7. Normal MCV does not exclude iron, B12, or folate deficiency.
  8. Normal or elevated ferritin does not exclude iron deficiency during inflammation.
  9. Additional cytopenias or abnormal smear findings increase concern for marrow disease.
  10. Open the matching detailed guide near the top of this page.

References

  1. Oyedeji CI, Artz AS, Cohen HJ. How I treat anemia in older adults. Blood. 2024;143:205–215. Open article
  2. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133:40–50. Open article
  3. Kidney Disease: Improving Global Outcomes. KDIGO 2026 Clinical Practice Guideline for Anemia in Chronic Kidney Disease. KDIGO guideline
  4. Carson JL, et al. Red blood cell transfusion: 2023 AABB international guidelines. JAMA. 2023. AABB resource
  5. American Society of Hematology. Clinical Practice Guidelines on Sickle Cell Disease. ASH guidelines

Educational disclaimer

This guide is intended for clinician education and does not replace local laboratory reference ranges, institutional protocols, transfusion-service guidance, hematology consultation, or individualized clinical judgment. Active bleeding, severe symptomatic anemia, suspected TMA, acute hemolysis, and marrow-failure syndromes require urgent local evaluation.