What further tests are indicated for elevated hemoglobin (Hb) and hematocrit (Hct) levels?

Diagnostic Workup for Elevated Hemoglobin and Hematocrit

The initial workup for elevated hemoglobin and hematocrit should include serum erythropoietin (EPO) level, JAK2 mutation testing, and bone marrow biopsy to distinguish between primary polycythemia vera and secondary causes of polycythemia. 1

Step 1: Confirm True Polycythemia

First, determine if the elevated hemoglobin/hematocrit represents true polycythemia or apparent polycythemia:

• Complete Blood Count (CBC) with red cell indices
• Assess for dehydration or plasma volume depletion (common causes of relative polycythemia)
• Rule out obvious causes of plasma volume contraction:
  • Severe dehydration, diarrhea, vomiting
  • Diuretic use
  • Burns, capillary leak syndrome
  • Smoking (carbon monoxide exposure)

Step 2: Measure Serum Erythropoietin (EPO) Level

EPO level is crucial for differentiating between types of polycythemia:

• Low EPO: Suggests polycythemia vera (PV)
• Normal/High EPO: Suggests secondary polycythemia

Note: While low EPO is typical in PV, some PV cases can present with normal or even elevated EPO levels, so further testing is required 2.

Step 3: JAK2 Mutation Testing

• JAK2V617F mutation: Present in >97% of PV cases
• JAK2 exon 12 mutations: Present in some JAK2V617F-negative PV cases

JAK2 mutation testing is now considered a major diagnostic criterion for PV according to WHO guidelines 1.

Step 4: Bone Marrow Examination

If JAK2 testing is positive or clinical suspicion for PV remains high:

• Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation

Step 5: Evaluate for Secondary Causes of Polycythemia

If EPO is normal or elevated, investigate for:

Hypoxia-Driven Secondary Polycythemia:

• Arterial blood gas to assess oxygenation
• Chest X-ray to evaluate for lung disease
• Pulmonary function tests
• Sleep study to rule out sleep apnea
• Echocardiogram to assess for right-to-left cardiac shunts
• Hemoglobin electrophoresis to detect high-oxygen-affinity hemoglobinopathies

Hypoxia-Independent EPO Production:

• Abdominal/pelvic imaging (CT or MRI) to detect:
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Uterine leiomyoma
  • Pheochromocytoma
  • Renal cysts
• Brain imaging for cerebellar hemangioblastoma or meningioma

Diagnostic Algorithm

1. If JAK2 mutation positive AND EPO low: Diagnosis is PV
2. If JAK2 mutation positive BUT EPO normal/high: Still likely PV, but consider concurrent secondary cause
3. If JAK2 mutation negative AND EPO high: Investigate secondary causes thoroughly
4. If JAK2 mutation negative AND EPO low: Consider rare JAK2-negative PV or other myeloproliferative neoplasms

Important Considerations

• According to WHO 2007 criteria, PV diagnosis requires either:

  • Two major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR
  • First major criterion (elevated hemoglobin/hematocrit) plus two minor criteria 1

• Minor criteria include:

  • Bone marrow showing hypercellularity
  • Low serum EPO
  • Endogenous erythroid colony formation

• Latent or masked PV can present with normal hemoglobin/hematocrit but may have higher rates of thrombotic complications 3

• Avoid unnecessary red cell mass measurements in cases where the diagnosis can be established through JAK2 mutation testing and EPO levels 1

Early diagnosis and appropriate management are crucial as untreated polycythemia increases risk of thrombotic events, which significantly impact morbidity and mortality.