What is the management approach for an adult patient with elevated hemoglobin (Hgb), hematocrit (Hct), and red blood cell (RBC) count, and a macrocytic differential, potentially indicating underlying vitamin deficiencies or myeloproliferative disorders?

Differential Diagnosis of Elevated Hemoglobin, Hematocrit, and RBC with Macrocytosis

This presentation is paradoxical and requires systematic evaluation to distinguish true polycythemia with concurrent macrocytosis from artifact or combined pathology. The combination of elevated RBC mass with macrocytosis is unusual because most erythrocytosis causes normocytic or microcytic red cells, while macrocytosis typically occurs with anemia, not erythrocytosis 1.

Initial Diagnostic Approach

Confirm the findings are real, not artifactual, by repeating the complete blood count and reviewing the peripheral blood smear personally 1. Hyperglycemia can falsely elevate MCV and calculated hematocrit without affecting hemoglobin 2, 1. Storage of blood samples can increase hematocrit by 2-4% due to MCV changes 2.

Key Laboratory Evaluation

Obtain the following tests immediately 2, 1:

• Reticulocyte count - This is the critical discriminator. Elevated reticulocytes with macrocytosis suggest active erythropoiesis or hemolysis, while low/normal reticulocytes point to vitamin deficiency or bone marrow disorder 2
• Peripheral blood smear review by a qualified hematologist to assess red cell morphology 1
• Serum ferritin and transferrin saturation - Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia that may be masked by concurrent macrocytosis 2, 1
• Vitamin B12 and folate levels - Macrocytosis classically indicates B12 or folate deficiency 2
• CRP or ESR - Inflammation affects interpretation of ferritin 2

Primary Differential Diagnosis

1. Polycythemia Vera with Reticulocytosis-Induced Macrocytosis

This is the most important diagnosis to exclude due to thrombotic risk. PV causes elevated RBC mass, and the accelerated erythropoiesis shifts immature, larger reticulocytes into circulation, creating macrocytosis 2.

Diagnostic criteria require 1:

• JAK2 mutation testing (positive in 97% of PV cases) 1
• Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women 1
• Bone marrow biopsy showing hypercellularity with trilineage growth if JAK2 positive 1

If PV is confirmed, maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic events (2.7% vs 9.8% event rate, P=0.007) 1. Initiate low-dose aspirin 81-100 mg daily as second cornerstone of therapy 1.

2. Medication-Induced Macrocytosis with Secondary Erythrocytosis

Check medication history meticulously 2:

• Thiopurines (azathioprine, 6-mercaptopurine) cause macrocytosis directly 2
• Testosterone therapy causes erythrocytosis and should be dose-reduced or discontinued if hematocrit >54% 1
• Hydroxyurea causes macrocytosis
• Anticonvulsants (phenytoin, phenobarbital) cause macrocytosis and may impair B12 3

3. Vitamin B12 or Folate Deficiency Masking Underlying Erythrocytosis

This represents combined pathology where vitamin deficiency causes macrocytosis while a separate process (smoking, hypoxia, renal disease) drives erythrocytosis 2, 4.

Diagnostic algorithm for B12 deficiency 3:

• If total B12 <180 pg/mL: confirmed deficiency, treat immediately
• If B12 180-350 pg/mL: measure methylmalonic acid (MMA) to confirm functional deficiency
• MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 3

Critical pitfall: Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage 3.

4. Alcohol-Related Macrocytosis with Smoker's Polycythemia

Alcohol causes direct macrocytosis through membrane lipid changes, while smoking causes polycythemia through chronic carbon monoxide exposure stimulating erythropoietin production 1, 4. This combination is common and resolves with smoking cessation 1.

5. Hypothyroidism

Hypothyroidism causes macrocytosis and can coexist with other causes of erythrocytosis 2. Check TSH, free T4, and thyroid antibodies, particularly in patients with autoimmune conditions 3.

6. Myelodysplastic Syndrome (MDS)

MDS can present with elevated RBC count and macrocytosis in early stages before cytopenias develop 2, 4. This requires bone marrow biopsy with cytogenetic analysis if other causes are excluded 2, 4.

Algorithmic Approach Based on Reticulocyte Count

If Reticulocytes are ELEVATED 2:

This indicates active red cell production and excludes vitamin deficiencies 2.

Evaluate for:

• Hemolysis: Check haptoglobin, LDH, bilirubin 2
• Polycythemia vera: JAK2 mutation testing 1
• Secondary erythrocytosis with stress reticulocytosis: Evaluate hypoxic causes (sleep study, pulmonary function tests, smoking history) 1

If Reticulocytes are LOW or NORMAL 2:

This indicates inappropriate erythropoiesis from deficiencies or bone marrow disease 2.

Evaluate for:

• Vitamin B12 deficiency: Measure B12, MMA if indeterminate 3
• Folate deficiency: Measure serum and RBC folate 2
• Medication effects: Review azathioprine, hydroxyurea, anticonvulsants 2
• Myelodysplastic syndrome: Bone marrow biopsy if other causes excluded 2, 4

Critical Management Principles

Therapeutic phlebotomy is indicated ONLY when 1, 5:

• Hemoglobin >20 g/dL AND hematocrit >65%
• Symptoms of hyperviscosity (headache, fatigue, poor concentration)
• Dehydration has been excluded

Replace removed blood with equal volume of isotonic saline (750-1000 mL) to prevent hemoconcentration 5. Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 1, 5.

Common Pitfalls to Avoid

• Do not assume macrocytosis excludes polycythemia vera - reticulocytosis from accelerated erythropoiesis causes macrocytosis in PV 2
• Do not rely solely on serum B12 to rule out deficiency - up to 50% of functional B12 deficiency occurs with "normal" serum levels 3
• Do not perform phlebotomy without volume replacement - this increases hemoconcentration and stroke risk 1, 5
• Do not overlook coexisting iron deficiency - ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states 2
• Do not use standard PV diagnostic thresholds at high altitude without adjustment for physiologic adaptation 1

When to Refer to Hematology

Immediate referral is indicated if 1:

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup including B12, folate, reticulocyte count, and peripheral smear review