What is the initial workup and treatment for a patient presenting with polycythemia?

Initial Workup and Treatment for Polycythemia

The initial workup for polycythemia should begin with serum erythropoietin (EPO) level measurement followed by bone marrow examination with cytogenetic studies to differentiate between polycythemia vera (PV) and secondary polycythemia. 1

Diagnostic Algorithm

Step 1: Determine if polycythemia is suspected

Polycythemia should be suspected when:

• Hemoglobin/hematocrit is higher than the 95th percentile adjusted for sex and race
• Documented increase in hemoglobin/hematocrit above patient's baseline
• PV-related features (thrombocytosis, leukocytosis, microcytosis, splenomegaly, aquagenic pruritus, unusual thrombosis, erythromelalgia) with borderline-high hematocrit 1

Step 2: Serum EPO level measurement

• Low EPO level: Highly suggestive of PV (specificity >90%)
• Normal EPO level: PV still possible (sensitivity of low EPO for PV <70%)
• Elevated EPO level: Suggests secondary polycythemia 1

Step 3: Bone marrow examination with cytogenetic studies

• Look for: Hypercellularity, increased megakaryocytes with cluster formation, giant megakaryocytes, pleomorphic megakaryocyte morphology, mild reticulin fibrosis, decreased iron stores 1
• Test for JAK2V617F mutation (present in >95% of PV cases) 2
• If JAK2V617F negative but PV still suspected, test for calreticulin mutation 1

Step 4: Additional specialized tests (for equivocal cases)

• Endogenous erythroid colony assays
• PRV-1 expression in peripheral blood neutrophils
• Bone marrow c-mpl immunostains 1

Secondary Polycythemia Workup

If EPO is elevated or clinical features suggest secondary causes:

1. Measure arterial hemoglobin-oxygen saturation and carboxyhemoglobin level (especially in smokers)
2. If no central hypoxic state identified, perform renal vascular studies to rule out renal artery stenosis
3. Consider imaging studies of kidney, liver, and central nervous system if above studies are unrevealing
4. Measure P50 (oxygen pressure at 50% hemoglobin-oxygen saturation) if family history suggests congenital cause 1

Treatment Approach

For Polycythemia Vera:

1. All patients require phlebotomy to maintain hematocrit <45% and once-daily low-dose aspirin (81 mg) in the absence of contraindications 2, 3, 4

2. Risk stratification:

   • High risk: Age >60 years or history of thrombosis
   • Low risk: Absence of both risk factors 3, 4

3. Cytoreductive therapy indications:

   • All high-risk patients
   • Symptomatic low-risk patients
   • Patients with difficulty maintaining hematocrit with phlebotomy alone 3

4. Cytoreductive therapy options:

   • First-line: Hydroxyurea
   • Alternative first-line (especially in young women of reproductive age): Pegylated interferon-α
   • Second-line options: Busulfan (preferred in older patients) or ruxolitinib (for symptoms of post-PV myelofibrosis or intractable pruritus) 3

For Secondary Polycythemia:

Treatment depends on the underlying cause:

• Smoking cessation for smoker's polycythemia
• CPAP for sleep apnea
• Treatment of underlying malignancies or benign tumors producing EPO
• Appropriate management of congenital causes 1

Important Caveats and Pitfalls

1. Do not rely solely on red cell mass (RCM) measurement:

   • Normal RCM does not rule out PV (may miss PV at left tail of distribution)
   • RCM measurement with hematocrit >60% is redundant and costly
   • Low likelihood of PV with isolated hematocrit <60% without other PV features 1

2. Avoid overreliance on old diagnostic criteria:

   • The 2016 WHO classification lowered hemoglobin and hematocrit thresholds to improve detection of "masked PV" 5

3. Be aware of complications:

   • Thrombotic events (arterial 16%, venous 7% at diagnosis)
   • Bleeding risk, especially with extreme thrombocytosis
   • Disease transformation (12.7% develop myelofibrosis, 6.8% develop acute myeloid leukemia) 2

4. Consider special situations:

   • In splanchnic vein thrombosis with PV, indefinite anticoagulation is warranted 1
   • Intractable pruritus may respond to selective serotonin reuptake inhibitors or interferon-α 1

By following this systematic approach to diagnosis and treatment, clinicians can effectively manage patients with polycythemia while reducing the risk of complications and improving quality of life.