What are the next steps in managing a patient with an elevated red blood cell count (erythrocytosis) of 5.91?

Management of Elevated Red Blood Cell Count (5.91)

An RBC count of 5.91 × 10¹²/L represents erythrocytosis requiring immediate diagnostic workup to distinguish primary from secondary causes, with JAK2 mutation testing and peripheral blood smear as first-line investigations. 1, 2

Immediate Diagnostic Workup

Essential Laboratory Testing

• Obtain complete blood count with differential to assess all three cell lines, evaluate for leukocytosis or thrombocytosis suggesting myeloproliferative neoplasm, and examine for left shift or immature cells 1, 2
• Peripheral blood smear is mandatory to evaluate cell morphology, assess for immature myeloid cells, leukoerythroblastosis, and megakaryocyte fragments that suggest primary bone marrow pathology 1, 2
• JAK2 V617F mutation testing on peripheral blood should be performed immediately, as this mutation is present in approximately 95% of polycythemia vera cases 2, 3
• Serum erythropoietin (EPO) levels must be measured: low or inappropriately normal EPO suggests primary erythrocytosis (polycythemia vera), while elevated EPO indicates secondary causes 4, 3

Exclude Secondary Causes

• Rule out hypoxemia through arterial blood gas analysis and pulse oximetry, as chronic hypoxia is a common secondary cause 4, 3
• Assess for renal pathology including renal ultrasound and renal function tests to exclude EPO-secreting renal tumors or cysts 4, 3
• Evaluate for hepatic pathology and other EPO-secreting tumors through appropriate imaging 4, 3
• Measure hemoglobin oxygen affinity (pO₂₅₀) if secondary causes are excluded but EPO is elevated, as high-affinity hemoglobin variants cause familial erythrocytosis 4, 3

Advanced Molecular Testing

• BCR-ABL testing by RT-PCR or FISH is necessary to exclude chronic myelogenous leukemia 2
• VHL gene analysis should be considered if familial erythrocytosis is suspected, as VHL mutations and polymorphisms (particularly rs779805 c.-195G>A) can cause congenital erythrocytosis 3, 5
• Additional genetic testing for EPOR, EGLN1, EPAS1, EPO, HBB, HBA1, HBA2, and BPGM variants may be warranted in JAK2-negative cases with elevated or normal EPO 3

Risk Stratification and Monitoring

Assess Thrombotic Risk

• Age >60 years or prior thrombotic event history automatically classifies as high-risk requiring aggressive cytoreductive therapy 2, 6
• Evaluate cardiovascular risk factors including hypertension, diabetes, smoking, and hyperlipidemia, as these compound thrombotic risk 2, 6
• Obtain abdominal ultrasound to exclude subclinical splanchnic vein thrombosis or spleen infarcts, which may be present at diagnosis 2

Monitor for Complications

• If white blood cell count >100,000/μL, initiate aggressive intravenous hydration at 2.5-3 liters/m²/day to prevent tumor lysis syndrome and leukostasis complications 1
• Monitor for leukostasis symptoms (headache, visual changes, dyspnea, altered mental status), which constitute a medical emergency requiring potential leukapheresis 1
• Serial CBC every 3-7 days is recommended to document persistence and trend of cytopenias 2

Treatment Approach

If Polycythemia Vera is Confirmed

High-Risk Patients (age >60 or prior thrombosis):

• Initiate hydroxyurea 50-60 mg/kg/day to achieve 50% WBC reduction within 1-2 weeks if hyperleukocytosis is present 1, 7
• Standard hydroxyurea dosing is 15 mg/kg once daily for patients with normal renal function, reduced to 7.5 mg/kg once daily if creatinine clearance <60 mL/min 7
• Add low-dose aspirin (81-100 mg daily) for all patients without contraindications to reduce thrombotic risk 8, 6
• Therapeutic phlebotomy should be performed to maintain hematocrit <45% in men and <42% in women, though repeated phlebotomies without iron monitoring increase stroke risk due to iron depletion 1, 6

Low-Risk Patients (age <60 and no prior thrombosis):

• Phlebotomy alone may be sufficient initially, targeting hematocrit <45% in men and <42% in women 6, 9
• Low-dose aspirin should still be initiated unless contraindicated 6, 8
• Hydroxyurea use should be carefully considered in young patients (<40 years old) due to leukemogenic potential with long-term use 6

Monitoring During Treatment

• Monitor blood counts at least once weekly during hydroxyurea therapy to assess for myelosuppression 7
• Evaluate for hemolytic anemia if acute jaundice or hematuria develops with worsening anemia; measure LDH, haptoglobin, reticulocyte count, unconjugated bilirubin, and perform Coombs testing 7
• Discontinue hydroxyurea if confirmed hemolytic anemia occurs in the absence of other causes 7
• Assess for vasculitic toxicities including cutaneous ulcerations and gangrene; discontinue hydroxyurea and institute treatment if these occur 7

Special Considerations

• Avoid live vaccines during hydroxyurea treatment, as normal defense mechanisms are suppressed and severe infection may result 7
• Prophylactic folic acid administration is recommended as hydroxyurea causes macrocytosis that may mask pernicious anemia diagnosis 7
• Monitor for secondary malignancies including skin cancer and acute leukemia, as hydroxyurea is a human carcinogen; advise sun protection 7
• For patients with extreme thrombocytosis (>1,500 × 10⁹/L), platelet-lowering treatment should be considered due to bleeding risk from acquired von Willebrand disease 6, 8

If Secondary Erythrocytosis is Identified

• Treat the underlying cause (e.g., supplemental oxygen for hypoxemia, surgical resection of EPO-secreting tumors) 3, 4
• Phlebotomy may be used for symptomatic relief if hematocrit remains dangerously elevated despite treating the underlying condition 5, 9
• Aspirin is recommended for patients with cardiovascular risk factors 5

Critical Pitfalls to Avoid

• Do not assume polycythemia vera without JAK2 testing, as 70% of erythrocytosis cases remain idiopathic and may represent undiagnosed secondary or familial causes 3
• Do not initiate hydroxyurea if bone marrow function is markedly depressed, as severe myelosuppression may occur 7
• Do not perform repeated phlebotomies without monitoring iron status, as iron depletion decreases oxygen-carrying capacity and paradoxically increases stroke risk 1
• Do not use hydroxyurea in pregnant women or those planning pregnancy, as it causes fetal harm; effective contraception is required for 6 months after therapy in females and 1 year in males 7