What are the differential diagnoses for a patient with low hemoglobin (Hb) and high hematocrit (Hct)?

Differential Diagnoses for Low Hemoglobin with High Hematocrit

Understanding This Paradoxical Laboratory Pattern

This combination of low hemoglobin with elevated hematocrit is physiologically unusual and typically represents either a laboratory artifact, measurement error, or a specific pathological condition affecting red blood cell characteristics.

The most important consideration is that hemoglobin is a more accurate and reliable measure than hematocrit because hematocrit can falsely increase by 2-4% with prolonged sample storage due to MCV changes, while hemoglobin remains stable 1. Additionally, hyperglycemia can falsely elevate MCV and calculated hematocrit without affecting hemoglobin measurement 1.

Primary Differential Diagnoses

1. Laboratory Error or Artifact (Most Common)

• Repeat the measurements immediately using fresh samples, as a single measurement is not reliable for establishing any diagnosis 1
• Hematocrit measurement is less reproducible across laboratories and more prone to pre-analytical errors than hemoglobin 1
• Ensure samples are processed promptly, as prolonged storage artificially elevates hematocrit 1

2. Masked Polycythemia Vera with Concurrent Iron Deficiency

• Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count and hematocrit but paradoxically reduced hemoglobin 1
• This occurs because iron-deficient red cells have reduced hemoglobin content per cell (low MCH) but increased cell numbers 1
• Order serum ferritin, transferrin saturation, and complete iron studies immediately, as MCV is unreliable for screening iron deficiency in erythrocytosis 1
• Consider JAK2 mutation testing if iron deficiency is confirmed alongside elevated hematocrit, as up to 97% of polycythemia vera cases carry this mutation 1, 2

3. Hemoglobin Variants (Methemoglobinemia or Hemoglobin M Disease)

• Methemoglobinemia causes functional anemia where measured hemoglobin may appear reduced while hematocrit reflects the actual red cell volume 3, 4
• Hemoglobin M disease, caused by autosomal dominant variants in globin genes, leads to MetHb levels typically 12.5%-25% 4
• Obtain methemoglobin level measurement using spectrophotometric method (Evelyn-Malloy technique measuring absorbance at 630 nm) 3
• Evaluate for cyanosis, family history of "dusky skin" or "blue sclera," and drug/toxin exposure history 3
• Consider hemoglobin electrophoresis at pH 7.1 or direct sequencing of α- and β-globin genes if HbM variant suspected 3

4. Unstable Hemoglobin Variants

• Some unstable hemoglobin variants develop elevated methemoglobin and can present with discordant hemoglobin/hematocrit values 3
• These patients may have chronic hemolytic anemia with compensatory erythrocytosis 3
• Obtain peripheral blood smear review by a qualified hematologist to identify abnormal red cell morphology 1

5. Hyperglycemia-Related Artifact

• Severe hyperglycemia falsely elevates MCV and calculated hematocrit but does not affect direct hemoglobin measurement 1
• Check blood glucose level and repeat hematocrit after glucose correction if diabetic ketoacidosis or hyperosmolar state present 1

Diagnostic Algorithm

Step 1: Confirm the Discrepancy

• Repeat CBC with fresh sample processed immediately 1
• Verify hemoglobin measurement directly (not calculated) 1
• Check for hyperglycemia that could falsely elevate hematocrit 1

Step 2: Initial Laboratory Workup

• Complete blood count with red cell indices (MCV, MCH, MCHC) 1
• Reticulocyte count to assess bone marrow response 1
• Peripheral blood smear review for red cell morphology 1
• Serum ferritin, transferrin saturation, and iron studies 1
• Methemoglobin level if cyanosis present or family history suggestive 3, 4

Step 3: Targeted Testing Based on Initial Results

• If iron deficiency confirmed with elevated hematocrit: JAK2 mutation testing for masked polycythemia vera 1, 2
• If methemoglobin elevated: CYB5R3 enzyme activity measurement and genetic testing 3, 4
• If abnormal red cell morphology: Hemoglobin electrophoresis or globin gene sequencing 3

Critical Management Considerations

Avoid Common Pitfalls

• Never rely on hematocrit alone for clinical decisions in this scenario—hemoglobin is the more reliable parameter 1
• Do not perform therapeutic phlebotomy based solely on elevated hematocrit without confirming true erythrocytosis 1
• Screen for iron deficiency even with elevated hematocrit, as iron-deficient red cells have reduced oxygen-carrying capacity and increased stroke risk 1

When to Refer to Hematology

• JAK2 mutation positive with any degree of erythrocytosis 1
• Confirmed methemoglobin level >25% 4
• Unexplained discordance persisting after repeat testing 1
• Abnormal peripheral smear suggesting hemoglobinopathy 3