What is the management approach for a patient with elevated Red Blood Cells (RBCs) and platelets, but a normal hematocrit?

Management of Elevated RBCs and Platelets with Normal Hematocrit

When RBC count and platelets are elevated but hematocrit remains normal, this represents a diagnostic paradox that requires immediate evaluation for polycythemia vera (PV) or essential thrombocythemia (ET), while simultaneously assessing for relative polycythemia from hemoconcentration. 1

Initial Diagnostic Workup

The first critical step is to determine whether this represents true polycythemia or a measurement artifact:

• Verify hydration status immediately by examining vital signs, mucous membranes, skin turgor, and recent fluid losses, as dehydration commonly causes spurious RBC elevation with disproportionate effects on cell counts versus hematocrit 2
• Review medications that may cause hemoconcentration, including diuretics, testosterone, and erythropoietin-stimulating agents 2
• Obtain serum erythropoietin (EPO) level as the next diagnostic test, since low EPO is highly suggestive (>90% specificity) of PV, while normal or elevated EPO suggests secondary causes 1

Diagnostic Algorithm Based on EPO Results

If EPO is Low or Normal:

Proceed immediately to JAK2 mutation testing, as more than 95% of PV patients harbor JAK2V617F or exon 12 mutations, which distinguishes clonal from secondary erythrocytosis 3, 4

• If JAK2 mutation is positive, obtain bone marrow biopsy with cytogenetic studies to confirm PV diagnosis and assess for prefibrotic myelofibrosis 1
• Bone marrow histology showing hypercellularity with trilineage proliferation confirms PV even when hematocrit appears normal, as iron deficiency or bleeding may lower the measured hematocrit below the pathologic baseline 1

If EPO is Elevated:

• Assess oxygen saturation to identify hypoxia-driven erythrocytosis, as chronic hypoxemia triggers compensatory RBC production 2
• Obtain renal ultrasound and creatinine to evaluate for renal pathology including renal cell carcinoma, polycystic kidney disease, and renal artery stenosis 2

Thrombocytosis Evaluation

The elevated platelet count requires simultaneous evaluation for essential thrombocythemia (ET) versus reactive thrombocytosis:

• Check JAK2, CALR, and MPL mutations, as approximately 55%, 25%, and 3% of ET patients express these driver mutations respectively 5
• Bone marrow examination is mandatory to exclude prefibrotic myelofibrosis, which can present identically to ET but carries different prognosis 5
• Rule out reactive causes including infection, inflammation, iron deficiency, malignancy, and recent hemorrhage 1

Risk Stratification for Thrombosis

Once diagnosis is established, immediate risk stratification determines management intensity:

For PV:

• High risk: Age >60 years OR prior thrombosis history 6, 3
• Low risk: Age ≤60 years AND no thrombosis history 6, 3
• JAK2V617F mutation and cardiovascular risk factors are additional risk factors 5

For ET:

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 6
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 6
• Intermediate risk: Age >60 years, no thrombosis history, JAK2 wild-type 6
• High risk: Thrombosis history present OR age >60 years with JAK2 mutation 6

Immediate Management

All Patients with Confirmed PV:

Initiate therapeutic phlebotomy immediately to maintain hematocrit <45%, as this target reduces thrombotic risk regardless of baseline hematocrit 3, 6

• Start low-dose aspirin 81 mg once daily in the absence of contraindications 6, 3
• Screen for acquired von Willebrand syndrome (AvWS) before administering aspirin if platelet count ≥1000 × 10⁹/L, as extreme thrombocytosis increases bleeding risk 3, 5

High-Risk PV or ET Patients:

Begin cytoreductive therapy with hydroxyurea as first-line treatment 6, 3

• Initial hydroxyurea dose: 15 mg/kg once daily for normal renal function 7
• Reduce dose by 50% if creatinine clearance <60 mL/min 7
• Target: Normalize blood counts while maintaining hematocrit <45% 6, 3
• Monitor complete blood count weekly during initial therapy to detect myelosuppression 7

Low-Risk ET Patients:

• Very low risk: Observation may be appropriate without immediate therapy 6
• Low risk: Aspirin 81 mg daily is advised 6

Intermediate-Risk ET:

Cytoreductive therapy is not mandatory but should be considered based on individual patient factors including symptom burden and cardiovascular risk factors 6

Second-Line Therapies

If hydroxyurea fails or is not tolerated:

• Interferon-α or pegylated interferon is the preferred second-line option, particularly in younger patients and those of childbearing potential 6, 5
• Busulfan is an alternative second-line agent 6
• Ruxolitinib (JAK inhibitor) should be reserved for severe protracted pruritus or marked splenomegaly unresponsive to hydroxyurea, NOT as routine second-line therapy 6

Critical Pitfalls to Avoid

• Do NOT transfuse RBCs in patients with elevated RBC counts, as this worsens hyperviscosity and increases thrombotic risk 2
• Do NOT assume normal hematocrit excludes PV, as iron deficiency, bleeding, or plasma volume expansion can mask true polycythemia 1
• Do NOT delay phlebotomy while awaiting genetic testing results if clinical suspicion for PV is high and hematocrit can be documented 3
• Do NOT use live vaccines during hydroxyurea therapy, as immunosuppression may potentiate viral replication 7
• Avoid azole antifungals during hydroxyurea therapy due to drug interactions 7

Monitoring Parameters

• Recheck hemoglobin and hematocrit weekly during initial phlebotomy until target hematocrit <45% is achieved 2
• Monitor complete blood count weekly during hydroxyurea initiation, then at least monthly once stable 7
• Assess for thrombotic complications including deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, and unusual site thrombosis (splanchnic veins) 3
• Screen for secondary malignancies including skin cancer and acute leukemia during long-term follow-up 7, 3