What is the appropriate management for a 66‑year‑old man with hemoglobin 18 g/dL, erythropoietin 44 mIU/mL, and a heterozygous EPOR gain‑of‑function mutation?

Management of Erythrocytosis with Elevated Hemoglobin and Elevated EPO in a 66-Year-Old Male

This patient requires immediate evaluation for secondary causes of erythrocytosis—particularly occult malignancy and hypoxic conditions—because the elevated EPO level (44 mIU/mL, above the normal range of 10-30 mIU/mL) indicates either appropriate physiologic response to hypoxia or autonomous EPO production, not primary polycythemia. 1, 2

Initial Diagnostic Approach

The combination of hemoglobin 18 g/dL with elevated EPO excludes polycythemia vera as the primary diagnosis, since PV characteristically presents with suppressed (subnormal) EPO levels. 3, 4 However, rare cases of PV with elevated EPO have been reported, so JAK2 mutation testing remains mandatory. 5

Mandatory Laboratory Work-Up

• JAK2 V617F and JAK2 exon 12 mutation testing to definitively exclude polycythemia vera, even though elevated EPO makes this unlikely. 3, 4
• Complete blood count with differential and peripheral smear to assess for leukocytosis or thrombocytosis that would suggest myeloproliferative disease. 3
• Arterial blood gas and oxygen saturation to detect occult hypoxemia from cardiopulmonary disease. 2, 3
• Carboxyhemoglobin level if any smoking history or carbon monoxide exposure is possible. 3
• Iron studies, vitamin B12, and folate to exclude nutritional deficiencies masking true hemoglobin concentration. 2, 3

Critical Imaging Studies

Renal and abdominal imaging (CT or ultrasound) is essential to screen for renal cell carcinoma, hepatocellular carcinoma, renal cysts, polycystic kidney disease, or pheochromocytoma—all of which can produce ectopic EPO. 1, 2, 3

Brain MRI should be obtained if clinical suspicion exists for cerebellar hemangioblastoma or meningioma. 2, 3

Echocardiography to evaluate for right-to-left cardiopulmonary shunts. 2, 3

Pulmonary function testing or sleep study if hypoventilation syndrome or obstructive sleep apnea is suspected. 3

Evaluation for Hypoxic Causes

The elevated EPO most commonly reflects appropriate physiologic response to tissue hypoxia. 2

Central Hypoxic Processes to Exclude:

• Right-to-left cardiopulmonary shunts 1, 2
• High-altitude habitation 1, 2
• Carbon monoxide poisoning 1, 2
• Hypoventilation syndromes 1, 2

Peripheral Hypoxic Processes to Exclude:

• Renal artery stenosis 1, 2
• High oxygen-affinity hemoglobinopathies 1, 2
• 2,3-Diphosphoglycerate mutase deficiency 1, 2

Evaluation for Autonomous EPO Production

Malignant Tumors (Priority Evaluation):

• Renal cell carcinoma 1, 2
• Hepatocellular carcinoma 1, 2
• Cerebellar hemangioblastoma 1, 2
• Parathyroid carcinoma 1, 2

Nonmalignant Conditions:

• Renal cysts and polycystic kidney disease 1, 2
• Uterine leiomyomas 1, 2
• Pheochromocytoma 1, 2
• Meningioma 1, 2

Consideration of Congenital Disorders

If the patient has lifelong erythrocytosis (not clearly stated in this case), consider germline mutations:

• EPOR gene mutations (erythropoietin receptor gain-of-function mutations) cause primary familial erythrocytosis with EPO levels that can be normal or elevated, and erythroid progenitors demonstrate hypersensitivity to EPO. 6, 7, 8
• Chuvash polycythemia (VHL gene mutations) presents with abnormally elevated EPO production. 1, 2
• High-oxygen-affinity hemoglobinopathies (HBB and HBA gene mutations) should be sequenced first when erythrocytosis has dominant inheritance with normal or inappropriately high EPO. 6

The heterozygous C282T mutation mentioned in the question likely refers to HFE hemochromatosis (C282Y is the classic mutation), which does not cause erythrocytosis and is irrelevant to this presentation. If "c187 cys 282 T" refers to an EPOR mutation, genetic testing of EPOR, VHL, EGLN1, and EPAS1 genes should be pursued. 6, 4

Monitoring Strategy

• Serial hemoglobin checks every 4-8 weeks initially if no secondary cause is identified, extending intervals if stability persists. 3
• Re-evaluate complete blood count periodically to detect emergence of leukocytosis or thrombocytosis indicating disease progression. 3

Therapeutic Recommendations

Phlebotomy Indications:

If idiopathic erythrocytosis is confirmed and hemoglobin exceeds 18 g/dL, phlebotomy should be employed to maintain hemoglobin below 16 g/dL (target hematocrit <45%) to reduce thrombotic risk. 3

Phlebotomy is contraindicated in patients with high-oxygen-affinity hemoglobinopathies or hemoglobin-M disease, as increased erythrocyte mass compensates for reduced oxygen delivery. 3

Medications:

Low-dose aspirin can be considered for thrombosis prophylaxis, particularly if JAK2 mutation is present. 3

Anticoagulation may be added if thromboembolism occurs. 5

Critical Contraindications:

Exogenous erythropoietin therapy is absolutely contraindicated because endogenous EPO production is already elevated; such therapy increases thromboembolic risk by 67% (RR 1.67,95% CI 1.35-2.06). 2, 3

Never target hemoglobin >12 g/dL with any therapy, as this significantly increases mortality and thrombotic risk. 2, 3

Key Pitfalls to Avoid

• Do not dismiss isolated erythrocytosis as benign variation; elevated EPO with high hemoglobin mandates thorough evaluation for occult malignancy. 3
• A normal EPO level does not exclude secondary polycythemia; cardiopulmonary disease evaluation remains necessary even when EPO is not elevated. 1, 2
• EPO levels >500 mU/mL indicate erythropoietin resistance, making exogenous EPO therapy ineffective—but this patient's EPO of 44 mIU/mL does not reach that threshold. 1, 2
• Do not assume low EPO always indicates PV; rare cases of PV with elevated EPO exist, requiring JAK2 mutation confirmation. 5
• In erythrocytosis with unknown etiology, the majority of cases remain unexplained even after comprehensive genetic testing of all seven known genes. 6