What is the appropriate management and further workup for a young patient with erythrocytosis, normal ferritin levels, negative JAK (Janus kinase) mutation, and negative thalassemia?

Management and Further Workup of JAK2-Negative Erythrocytosis in Young Patients

In a young patient with JAK2-negative erythrocytosis and normal ferritin, measure serum erythropoietin (EPO) level immediately to distinguish between primary (low EPO) and secondary (normal/high EPO) causes, then proceed with germline mutation testing for hereditary erythrocytosis given the patient's age. 1, 2

Initial Diagnostic Algorithm

Step 1: Confirm True Erythrocytosis

• Review all previous hemoglobin and hematocrit records to determine if this is longstanding (suggesting congenital) versus acquired erythrocytosis 2
• Longstanding erythrocytosis in a young patient, especially with family history, strongly suggests hereditary causes 2
• Document if hemoglobin has been consistently elevated or is a recent finding 3

Step 2: Measure Serum Erythropoietin Level

The EPO level is the critical branching point that directs all subsequent workup 1, 3, 2:

• Low/subnormal EPO: Indicates primary erythrocytosis → Test for EPO receptor (EPOR) mutations 1, 2
• Normal or elevated EPO: Indicates secondary erythrocytosis → Proceed to oxygen-sensing pathway evaluation 1, 3

Workup Based on EPO Level

If EPO is Low (Primary Erythrocytosis)

• Test for EPOR mutations as the primary cause of EPO-independent erythrocytosis 2
• Consider bone marrow biopsy if EPOR testing is negative and acquired clonal process remains a concern 3

If EPO is Normal or High (Secondary Erythrocytosis)

Assess P50 (Oxygen Affinity)

P50 measurement determines whether oxygen delivery to tissues is impaired 2:

Low P50 (High Oxygen Affinity) - suggests:

• High oxygen affinity hemoglobin variants 2
• 2,3-bisphosphoglycerate (2,3-BPG) deficiency 2
• Methemoglobinemia 2
• PIEZO1 mutations 2

Normal P50 - proceed to oxygen-sensing pathway mutations:

• HIF2A (EPAS1) mutations 2
• PHD2 (EGLN1) mutations 2
• VHL (von Hippel-Lindau) mutations 1, 2

Rule Out Acquired Secondary Causes

Even in young patients, consider:

• Cardiopulmonary disease causing central hypoxia 2
• Renal pathology (renal artery stenosis, cystic kidney disease) causing peripheral hypoxia 2
• Medication history: testosterone, erythropoiesis-stimulating agents, SGLT2 inhibitors 2
• Imaging studies: Renal ultrasound or CT to exclude EPO-producing tumors (renal cell carcinoma) or cerebellar hemangioblastoma 2

Genetic Testing Strategy

For young patients with longstanding erythrocytosis, pursue comprehensive germline mutation screening 2:

1. First-tier testing (based on EPO level):

   • Low EPO → EPOR gene sequencing 2
   • Normal/high EPO → Oxygen-sensing pathway panel (VHL, PHD2, HIF2A) 2

2. Second-tier testing (if first-tier negative):

   • Hemoglobin variant analysis for high oxygen affinity variants 2
   • PIEZO1 sequencing 2
   • 2,3-BPG measurement 2

3. Consider next-generation sequencing (NGS) panels for comprehensive evaluation of rare hereditary causes 3

Management Approach

Avoid Aggressive Cytoreduction

Cytoreductive therapy should be avoided in non-clonal erythrocytosis, as there is no evidence supporting its benefit and it may cause harm 2:

• Do not use hydroxyurea or other myelosuppressive agents 2
• Phlebotomy should NOT be performed routinely to arbitrary hematocrit targets 2

Therapeutic Phlebotomy - Use Judiciously

Consider phlebotomy only for documented symptom control (headache, fatigue, poor concentration), not based on hematocrit level alone 4, 2:

• Perform phlebotomy when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% WITH hyperviscosity symptoms 4
• Remove one unit (400-500 mL) per session, replace with equal volume of isotonic saline (750-1000 mL) 4
• Critical warning: Repeated routine phlebotomies risk iron depletion, which paradoxically decreases oxygen-carrying capacity, reduces red blood cell deformability, and increases stroke risk 4
• Monitor iron status (ferritin, transferrin saturation) to avoid iron deficiency 4

Cardiovascular Risk Management

• Low-dose aspirin is reasonable for cardiovascular risk optimization 2
• Address modifiable cardiovascular risk factors (hypertension, hyperlipidemia, smoking) 2
• Avoid dehydration, which increases hyperviscosity risk 4

Critical Pitfalls to Avoid

1. Do not label as "idiopathic erythrocytosis" prematurely: This diagnosis often reflects incomplete evaluation rather than true absence of etiology 5, 2

2. Do not assume thrombotic risk equals polycythemia vera: Evidence for thrombotic complications in non-clonal erythrocytosis is limited and does not justify aggressive cytoreduction 2

3. Do not ignore family history: Even subtle elevations in family members' hemoglobin may indicate hereditary cause 2

4. Do not create iatrogenic iron deficiency: Iron deficiency in erythrocytosis patients is harmful, reducing oxygen delivery and potentially increasing stroke risk 4

5. Do not overlook medication-induced causes: Testosterone, anabolic steroids, and SGLT2 inhibitors are increasingly recognized causes in young patients 2

When to Refer

• Refer to specialized center if germline mutations are identified, as management may require expertise in rare hereditary conditions 3
• Consider hematology referral if diagnostic workup remains unrevealing after comprehensive evaluation 3
• Genetic counseling is appropriate when hereditary erythrocytosis is confirmed, given implications for family members 2