What are the causes of polycythemia in a patient with no JAK2 (Janus kinase 2) mutation?

Causes of Polycythemia Other Than JAK2

In patients without JAK2 mutations, polycythemia is caused by secondary (hypoxia-driven or hypoxia-independent) or hereditary conditions, with the most common being chronic hypoxia from smoking, lung disease, or sleep apnea. 1, 2

Primary Diagnostic Framework

When JAK2 mutation testing is negative, immediately measure serum erythropoietin (EPO) levels to guide your differential diagnosis 2, 3:

Low or Normal EPO (Suggests Primary Myeloproliferative Disease)

• Consider JAK2 exon 12 mutations - present in approximately 3-5% of polycythemia vera cases that are JAK2 V617F negative 1
• EPO receptor (EPOR) mutations - cause hereditary erythrocytosis with subnormal EPO levels 1, 3, 4
• Proceed with bone marrow biopsy showing panmyelosis with trilineage growth if clinical suspicion for PV remains high 1

Elevated or High-Normal EPO (Suggests Secondary Polycythemia)

Hypoxia-Driven Causes

• Chronic obstructive pulmonary disease (COPD) - the most common pulmonary cause 2, 5
• Smoker's polycythemia - caused by chronic carbon monoxide exposure binding hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia; resolves with smoking cessation 1, 2
• Sleep apnea and hypoventilation syndromes 2
• Cyanotic congenital heart disease with right-to-left shunts 1, 2
• High-altitude habitation 1, 6
• Renal artery stenosis causing peripheral hypoxia 1, 3

Hypoxia-Independent Causes

• EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, parathyroid carcinoma 1, 2, 3
• Post-renal transplant erythrocytosis (PRTE) 1, 2
• Exogenous erythropoietic drugs: testosterone/androgen preparations, recombinant EPO, sodium-glucose cotransporter-2 inhibitors 2, 3

Hereditary/Congenital Causes

• High oxygen-affinity hemoglobinopathies - autosomal dominant, causes low P50 (oxygen pressure at 50% hemoglobin saturation) 1, 6, 3
• 2,3-bisphosphoglycerate (2,3-BPG) mutase deficiency - causes low P50 1, 6, 3
• Oxygen sensing pathway mutations: HIF2A, PHD2, VHL genes (including Chuvash polycythemia) 2, 3, 4
• PIEZO1 mutations 3
• Methemoglobinemia 3

Critical Diagnostic Algorithm

Step 1: Confirm true polycythemia (increased red cell mass) versus relative polycythemia from plasma volume depletion (dehydration, diuretics, burns) 2

Step 2: Obtain detailed smoking history - smoker's polycythemia is the most common secondary cause and resolves with cessation 1, 2

Step 3: Measure serum EPO level 2, 3:

• If low/normal: Test for JAK2 exon 12 mutations, consider EPOR mutations, proceed to bone marrow biopsy 1, 3
• If elevated: Proceed to Step 4

Step 4: Assess for hypoxia 2, 3:

• Arterial blood gas or pulse oximetry
• Carboxyhemoglobin level in smokers
• Sleep study if clinically indicated
• Chest X-ray for chronic lung disease

Step 5: If hypoxia absent, screen for EPO-producing tumors 2:

• Abdominal ultrasound or CT for renal cell carcinoma, hepatocellular carcinoma
• Review medication history for testosterone, EPO, SGLT2 inhibitors

Step 6: If acquired causes excluded and family history positive, consider hereditary erythrocytosis 3, 4:

• Measure P50 (low suggests high oxygen-affinity hemoglobin or 2,3-BPG deficiency)
• Hemoglobin electrophoresis
• Germline mutation screening (HIF2A, PHD2, VHL, EPOR, PIEZO1)

Critical Pitfalls to Avoid

Do not assume COPD explains erythrocytosis without excluding JAK2 mutations - patients can have both conditions simultaneously, and missing polycythemia vera leads to inadequate thrombosis prevention 5

Beware of "normal" EPO levels in chronic hypoxic states - EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 2

Do not overlook smoking as a reversible cause - smoker's polycythemia is a real condition with risk reduction beginning within 1 year of cessation and return to baseline after 5 years 2

Avoid aggressive phlebotomy in secondary polycythemia - this risks iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk, particularly in cyanotic heart disease and high oxygen-affinity hemoglobinopathies 1, 2

Do not miss post-renal transplant erythrocytosis - this condition is distinctly associated with increased thrombosis risk and responds to ACE inhibitors or angiotensin II receptor blockers 1

Consider parathyroid carcinoma when evaluating EPO-producing tumors, especially if hyperparathyroidism is present 2