What is the most likely diagnosis and recommended evaluation and treatment for a 28‑year‑old woman with erythrocytosis, hyperhemoglobinemia, polycythemia, normal neutrophil count, hypophosphatemia, and vitamin D deficiency?

Polycythemia Vera: Most Likely Diagnosis

This 28-year-old woman with marked erythrocytosis (hemoglobin 19.7 g/dL, hematocrit 57%, RBC 6.17) most likely has polycythemia vera (PV), and immediate JAK2 mutation testing (both V617F and exon 12) is mandatory to confirm the diagnosis. 1, 2

Diagnostic Evaluation

Immediate Laboratory Testing Required

Order JAK2 V617F mutation testing immediately as the first-line molecular assay, which detects >90–95% of PV cases. 2, 3 If negative, proceed directly to JAK2 exon 12 mutation analysis, which identifies an additional 2–3% of cases. 2, 3

Obtain the following baseline studies now:

• Complete blood count with differential to assess for thrombocytosis (platelets) and leukocytosis (WBC >10 × 10⁹/L), both of which support PV diagnosis 2
• Serum erythropoietin level—a value below the laboratory reference range is a WHO minor criterion and has >90% specificity for PV 1, 2, 3
• Peripheral blood smear to evaluate red cell morphology and identify any dysplastic features 4
• Serum ferritin and transferrin saturation—iron deficiency frequently coexists with PV and can mask the true hemoglobin elevation 1, 4
• Serum creatinine and BUN to assess renal function 2
• Lactate dehydrogenase (LDH) as a marker of cell turnover 2

WHO Diagnostic Criteria Application

This patient meets the first WHO major criterion (hemoglobin >16.5 g/dL in women; her value is 19.7 g/dL). 1, 2, 3 To confirm PV, she needs either:

1. Both major criteria (elevated Hb/Hct AND JAK2 mutation) plus ≥1 minor criterion, OR
2. First major criterion (elevated Hb/Hct) plus ≥2 minor criteria 1, 2, 3

Minor criteria include:

• Bone marrow biopsy showing hypercellularity with trilineage (panmyelosis) growth and pleomorphic megakaryocytes 1, 2, 3
• Subnormal serum erythropoietin level 1, 2, 3
• Endogenous erythroid colony formation in vitro (limited availability) 2, 3

Bone Marrow Biopsy Indications

Perform bone marrow biopsy with cytogenetics if:

• JAK2 V617F is positive (to confirm diagnosis and assess trilineage proliferation) 2
• JAK2 testing is negative (to evaluate for characteristic PV histology as a minor criterion) 2, 3
• Diagnosis remains unclear after initial molecular testing 2

Expected findings in PV include: hypercellularity, panmyelosis with prominent erythroid and megakaryocytic proliferation, pleomorphic megakaryocytes forming loose clusters, and absent or markedly reduced iron stores. 1, 2

Concurrent Laboratory Abnormalities

Hypophosphatemia (Phosphorus 2.9 mg/dL)

The low phosphorus is likely secondary to increased red cell mass and enhanced cellular phosphate uptake during accelerated erythropoiesis in PV. This finding does not alter the diagnostic approach but should be monitored. (General medical knowledge)

Vitamin D Deficiency (18 ng/mL)

The vitamin D level of 18 ng/mL represents insufficiency (<20 ng/mL) but is unrelated to the erythrocytosis. 1 Treat with vitamin D supplementation per standard protocols, but this does not impact PV diagnosis or management. (General medical knowledge)

Normal Neutrophil Count (7.3 × 10⁹/L)

The neutrophil count is within normal range, which does not exclude PV. 1 However, leukocytosis (WBC >10 × 10⁹/L) when present supports the diagnosis. 2

Management Pending Diagnosis

Phlebotomy Decision

Do NOT perform therapeutic phlebotomy at this time. 1, 4 Phlebotomy is indicated only when hemoglobin >20 g/dL AND hematocrit >65% AND the patient has documented hyperviscosity symptoms (headache, visual changes, confusion) AND dehydration has been excluded. 1, 4 This patient's hemoglobin is 19.7 g/dL and hematocrit is 57%—below these thresholds. 1, 4

Repeated routine phlebotomies are explicitly contraindicated because they cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk. 1, 4

Iron Status Assessment

Evaluate iron stores immediately with serum ferritin and transferrin saturation. 4, 2 Iron deficiency frequently coexists with erythrocytosis, particularly in PV, causing microcytic polycythemia. 1, 4

If transferrin saturation <20%, initiate cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1, 4 Iron deficiency reduces oxygen-carrying capacity and increases stroke risk even in the presence of elevated hemoglobin. 1, 4

Secondary Causes to Exclude

Before confirming PV, systematically exclude secondary erythrocytosis:

Hypoxic Causes

• Sleep study if nocturnal hypoxemia or obstructive sleep apnea is suspected (snoring, daytime somnolence, witnessed apneas) 4
• Pulmonary function tests and chest imaging to evaluate for chronic obstructive pulmonary disease or restrictive lung disease 4
• Arterial oxygen saturation—values <92% indicate hypoxia-driven secondary polycythemia 2
• Smoking history—chronic carbon monoxide exposure causes "smoker's polycythemia" 4

Non-Hypoxic Causes

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease that can produce erythropoietin 4
• Medication review—testosterone use (prescribed or unprescribed) causes erythrocytosis in young adults 4
• Hepatic imaging if clinically indicated to exclude hepatocellular carcinoma 4

Congenital Causes

In a young patient (age 28), consider congenital causes if JAK2 is negative and family history is present:

• High-oxygen-affinity hemoglobin variants 4
• Erythropoietin receptor mutations 4
• Chuvash polycythemia (VHL gene mutation) 4
• PHD2 or HIF2A mutations 4

Hematology Referral

Refer immediately to hematology if:

• JAK2 mutation is positive 4
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 4
• Unexplained splenomegaly on examination or imaging 2
• Diagnosis remains unclear after initial workup 4

Management After PV Confirmation

Hematocrit Target

If PV is confirmed, maintain hematocrit strictly <45% through therapeutic phlebotomy to reduce thrombotic risk. 4, 2 The CYTO-PV trial demonstrated that hematocrit <45% reduced cardiovascular death or major thrombosis to 2.7% versus 9.8% with hematocrit 45–50% (HR 3.91, P=0.007). 4

A slightly lower target of ≈42% is reasonable for women. 4

Aspirin Therapy

Initiate low-dose aspirin (81–100 mg daily) as the second cornerstone of therapy for thrombosis prevention in confirmed PV. 4

Cytoreductive Therapy

Consider cytoreductive agents (hydroxyurea, interferon-α-2a, or ruxolitinib) when:

• Phlebotomy requirements become excessive 4
• Thrombocytosis (platelets >400 × 10⁹/L) or leukocytosis (WBC >10 × 10⁹/L) persists after 3 months of hydroxyurea 2

Critical Pitfalls to Avoid

Never perform aggressive phlebotomy without equal-volume fluid replacement (normal saline or dextrose), as this increases hemoconcentration and stroke risk. 1, 4

Do not overlook coexisting iron deficiency—it mimics hyperviscosity symptoms but requires iron supplementation, not phlebotomy. 1, 4

Do not diagnose PV based solely on low erythropoietin; this is only a minor criterion and requires JAK2 mutation testing plus additional criteria. 3

Do not use standard PV hemoglobin thresholds without considering iron deficiency—iron depletion can mask true erythrocytosis by lowering hemoglobin while red cell mass remains elevated. 3