What is the diagnosis if reticulocyte (retic) count is elevated, red blood cell (RBC) count is elevated, hematocrit (Hct) is elevated, and mean corpuscular hemoglobin concentration (MCHC) is elevated?

Polycythemia Vera (Masked by Iron Deficiency or Concurrent Conditions)

The combination of elevated reticulocyte count, elevated RBC count, elevated hematocrit, and elevated MCHC most strongly suggests polycythemia vera (PV), particularly when iron deficiency has been corrected or is absent. 1

Primary Diagnostic Consideration

• Polycythemia vera is the leading diagnosis when all three red cell parameters (RBC count, hematocrit, reticulocytes) are elevated together, especially with elevated or high-normal MCHC 1
• The WHO diagnostic criteria for PV require hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), OR evidence of increased red cell volume, PLUS presence of JAK2V617F or JAK2 exon 12 mutation 1
• Elevated RBC count (>73.9% of cases) combined with positive JAK2V617F mutation (100% when tested) strongly indicates PV, even when hematocrit may be initially masked by concurrent conditions 2

Why MCHC Elevation is Critical

• Elevated MCHC is unusual and highly specific - it typically indicates either hereditary spherocytosis, cold agglutinins causing laboratory artifact, or polycythemia vera after iron repletion 3
• In the context of elevated RBC count and hematocrit, elevated MCHC suggests robust erythropoiesis with adequate iron availability, which is characteristic of treated or iron-replete PV 2, 4
• Low MCHC would suggest iron deficiency masking PV, but elevated MCHC indicates this is not the case 5, 2

Diagnostic Algorithm

Step 1: Confirm True Polycythemia

• Verify hydration status - dehydration causes relative polycythemia with elevated hematocrit but typically normal reticulocytes 5, 6
• Repeat CBC after ensuring adequate hydration to confirm persistent elevation 5, 6
• If values persist, this represents true (absolute) polycythemia, not relative polycythemia 6

Step 2: Test for JAK2 Mutations

• Order JAK2V617F mutation testing (exon 14) as first-line, followed by JAK2 exon 12 mutation if negative 1, 6
• JAK2V617F is positive in essentially 100% of unclassifiable myeloproliferative disease cases with these laboratory features 2
• Positive JAK2 mutation with elevated hemoglobin/hematocrit fulfills major criteria for PV diagnosis 1, 6

Step 3: Assess Bone Marrow and Minor Criteria

• Bone marrow biopsy showing trilineage myeloproliferation supports PV diagnosis (present in 83.3% of cases with this presentation) 1, 2
• Measure serum erythropoietin level - subnormal EPO supports PV diagnosis as a minor criterion 1
• Check for endogenous erythroid colony growth if available 1

Step 4: Rule Out Secondary Causes

• Measure arterial oxygen saturation to exclude hypoxia-driven erythrocytosis 6
• Evaluate for sleep apnea, COPD, smoking history, or high-altitude residence 6
• Screen for erythropoietin-secreting tumors (renal cell carcinoma, hepatocellular carcinoma) if JAK2 negative 6
• Check testosterone use history, as exogenous testosterone causes secondary erythrocytosis 6

Critical Pitfalls to Avoid

• Do not dismiss the diagnosis if hematocrit is only mildly elevated - iron deficiency commonly masks PV by reducing MCV, which artificially lowers hematocrit (since Hct = RBC × MCV) 2, 4
• RBC count may be more reliable than hematocrit in detecting PV when microcytosis is present, with specificity of 98% when combined with ESR <2 mm 4
• Do not perform aggressive phlebotomy if iron deficiency coexists, as this worsens iron depletion and paradoxically increases stroke risk 6
• Elevated MCHC can be artifactual due to cold agglutinins or RBC agglutination - verify with blood smear and consider using optical RBC parameters (RBC-O, HGB-O) to confirm 3

Management Implications

• Phlebotomy is indicated only when hematocrit >65% with hyperviscosity symptoms in confirmed PV 1, 6
• Target hematocrit should be maintained strictly below 45% to reduce thrombotic risk 1
• Low-dose aspirin is cornerstone therapy to prevent cardiovascular events 1
• Cytoreductive therapy (hydroxyurea or interferon-alpha) is recommended for high-risk patients (age >60 or prior thrombosis) 1

Alternative Diagnoses (Less Likely)

• Hemolytic anemia with compensatory reticulocytosis would show elevated reticulocytes but typically normal or low hematocrit, not elevated 1
• Hemoglobinopathies (thalassemia) show elevated reticulocytes with microcytosis, but hematocrit is typically normal or low, not elevated 1
• Hereditary spherocytosis can cause elevated MCHC with reticulocytosis, but RBC count and hematocrit are usually normal or decreased due to hemolysis 3