What is the workup for a patient with elevated hemoglobin (Hgb), hematocrit (Hct), and red blood cell (RBC) count?

Workup for Elevated Hemoglobin, Hematocrit, and RBC Count

Initial Confirmation and Laboratory Evaluation

Begin by confirming true erythrocytosis with repeat measurements, as a single elevated value is unreliable, then immediately order a comprehensive laboratory panel including CBC with differential, reticulocyte count, serum ferritin, transferrin saturation, and JAK2 mutation testing. 1

Diagnostic Thresholds for True Erythrocytosis

• Men: Hemoglobin >18.5 g/dL or hematocrit >55% warrants full evaluation 1, 2
• Women: Hemoglobin >16.5 g/dL or hematocrit >48-49% warrants full evaluation 1, 2
• Any patient: A sustained increase of ≥2 g/dL from baseline, even below absolute thresholds, requires investigation 2

Essential First-Line Laboratory Tests

• Complete blood count with differential to assess for associated thrombocytosis or leukocytosis, which suggests myeloproliferative disease 1, 2
• Reticulocyte count to evaluate bone marrow erythropoietic activity and distinguish production versus destruction 1
• Serum ferritin and transferrin saturation to identify coexisting iron deficiency, which can mask the true severity of erythrocytosis 1, 2
• C-reactive protein (CRP) to assess for inflammatory conditions 1
• JAK2V617F mutation testing (including exon 12 and 14) as the primary test to identify polycythemia vera, which accounts for >95% of clonal erythrocytosis 1, 2

Distinguishing Primary from Secondary Erythrocytosis

JAK2 Mutation Testing: The Critical Branch Point

If JAK2 mutation is positive, proceed immediately to hematology referral and bone marrow biopsy to confirm polycythemia vera. 1, 2

• JAK2 mutations are present in up to 97% of polycythemia vera cases 1
• Diagnosis requires both major criteria (elevated Hgb/Hct AND JAK2 mutation) plus ≥1 minor criterion, OR first major criterion plus ≥2 minor criteria 1, 2
• Minor criteria include bone marrow panmyelosis, subnormal serum erythropoietin level, and endogenous erythroid colony formation 1, 2

If JAK2 Mutation is Negative: Evaluate Secondary Causes

Systematically evaluate for hypoxic and non-hypoxic secondary causes before considering rare genetic disorders. 1

Hypoxic Causes (Normal-to-Elevated Erythropoietin)

• Obstructive sleep apnea: Consider sleep study if nocturnal hypoxemia suspected 1
• Chronic obstructive pulmonary disease (COPD): Assess pulmonary function and arterial blood gases 1
• Smoking/carbon monoxide exposure: "Smoker's polycythemia" from chronic tissue hypoxia; resolves with cessation 1
• Cyanotic congenital heart disease: Right-to-left shunting causes compensatory erythrocytosis 1
• High altitude residence: Physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 1

Non-Hypoxic Causes (Inappropriate Erythropoietin Production)

• Testosterone therapy: Common cause in young adults; requires dose adjustment or discontinuation 1
• Erythropoietin-producing tumors: Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 1
• Renal dysfunction: Abnormal glomerular function may stimulate erythropoietin production 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration, diuretic use, burns, stress polycythemia (Gaisböck syndrome): Assess hydration status and volume status 1

Serum Erythropoietin Level: Adjunctive Test

• Low or subnormal EPO suggests polycythemia vera (<70% sensitivity, >90% specificity) 2
• Normal-to-elevated EPO suggests secondary erythrocytosis 2
• Important caveat: EPO has limited sensitivity and should not be used alone to exclude polycythemia vera 1

Bone Marrow Biopsy Indications

Perform bone marrow biopsy if JAK2 mutation is positive OR if diagnosis remains unclear after initial workup. 1, 2

• Confirms polycythemia vera by demonstrating hypercellularity with trilineage growth (panmyelosis) and characteristic megakaryocyte clustering 1, 2
• Excludes other myeloid neoplasms 1
• Cytogenetic studies may reveal abnormalities (trisomy 8 or 9, deletions of 13q or 20q) in 13-18% of cases 2

Critical Pitfalls to Avoid

Iron Deficiency Can Mask Polycythemia Vera

• Microcytosis with thrombocytosis or leukocytosis strongly suggests iron-deficient polycythemia vera 2
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; use serum ferritin and transferrin saturation 1
• Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk 1

Hemoglobin is More Reliable Than Hematocrit

• Hemoglobin remains stable during sample storage, while hematocrit can falsely increase by 2-4% 1
• Hyperglycemia falsely elevates MCV and calculated hematocrit but does not affect hemoglobin 1
• Use hemoglobin as the primary measurement for monitoring 1

Don't Perform Aggressive Phlebotomy Without Clear Indication

• Therapeutic phlebotomy is indicated ONLY when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity, after excluding dehydration 1
• Repeated routine phlebotomies risk iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk 1
• For confirmed polycythemia vera, maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic risk 1

Borderline Values Require Clinical Context

• The new WHO thresholds have substantial overlap with normal reference ranges 3
• In patients with borderline hemoglobin levels, only pursue diagnostic workup if clinical features suggest myeloproliferative neoplasm (splenomegaly, thrombocytosis, leukocytosis, aquagenic pruritus, unusual thrombosis) 1, 3

Immediate Hematology Referral Indications

Refer immediately to hematology if: 1

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup
• Associated thrombocytosis or leukocytosis suggesting myeloproliferative disorder

Management Principles Based on Etiology

For Secondary Erythrocytosis

• Treat the underlying condition: smoking cessation, CPAP for sleep apnea, management of COPD 1
• Testosterone dose adjustment or discontinuation if causative 1
• Target hematocrit of 55-60% may be appropriate, as elevated hematocrit serves compensatory physiological role 1

For Confirmed Polycythemia Vera

• Maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic events (2.7% vs 9.8% event rate, P=0.007) 1
• Initiate low-dose aspirin (81-100 mg daily) as second cornerstone of therapy for thrombosis prevention 1
• Consider cytoreductive therapy (hydroxyurea) for high-risk patients 1