PV and secondary/relative erythrocytosis can look similar on CBC, but they differ in risk, evaluation, and management:

• Risk and urgency: PV carries a persistent risk of arterial and venous thrombosis, so accurate identification supports timely prevention strategies. [1,5,6]
• Different causes, different fixes: Many secondary causes are reversible (e.g., hypoxia-related conditions, exposures, medication-related erythrocytosis, or EPO-producing tumors) and are managed by correcting the driver. [2]
• Diagnosis guides monitoring: Confirming PV typically triggers structured follow-up and risk-based management, which is not required for many secondary etiologies once corrected. [2]

Polycythemia (umbrella term):

• • Elevated hemoglobin/hematocrit due to relative (hemoconcentration) or absolute (increased red-cell production) mechanisms. [2]

Polycythemia vera (PV):

• • A clonal disorder where the marrow produces excess red cells, most often JAK2-mutated, with characteristic clinical patterns (e.g., aquagenic pruritus, splenomegaly, microvascular symptoms) and elevated lifetime thrombotic risk. [1,3,4]

Practical bottom line: use terminology + stepwise testing to move from “polycythemia” (a finding) to a specific diagnosis (PV vs secondary/relative cause). [2,3,4]

Common contributors include:

• • Relative (hemoconcentration): dehydration/diuretic effect/acute plasma volume loss; repeat CBC after correction may normalize values. [2]

• • Hypoxia-related: chronic lung disease, sleep-disordered breathing, or high altitude (often with low oxygen saturation). [2]
  • Exposures/medications: tobacco/carbon monoxide exposure; androgens or erythropoiesis-stimulating agents. [2]
  • EPO-producing tumors (selected cases): consider when EPO is elevated and clinical suspicion supports imaging evaluation. [2]

  
  

PV remains the key primary (clonal) cause to rule in/out when erythrocytosis is persistent and the pattern suggests marrow-driven disease.[1,2,3,4]

1. Confirm persistence

Repeat CBC to confirm sustained elevation, ideally after addressing potential hemoconcentration. [2]

2. Screen for common secondary drivers

History (altitude, smoking/CO exposure), medication review, and oxygen assessment when indicated. [2]

3. First-line differentiators

Serum EPO: low EPO supports a primary marrow process; normal/high EPO supports secondary causes. [2,3]

JAK2 testing: JAK2 mutation status is central to PV classification frameworks and strongly supports PV in the appropriate clinical/lab context. [1,3,4]

4. Second-line / selected cases

Bone marrow assessment may help resolve borderline/“masked” presentations under ICC/WHO-aligned frameworks. [1,3,4]

PV becomes more likely when erythrocytosis clusters with: [1,2,3,4]

• Aquagenic pruritus
• Splenomegaly
• Microvascular symptoms (e.g., erythromelalgia, transient visual symptoms)
• Unprovoked thrombosis, especially in unusual sites
• Leukocytosis and/or thrombocytosis alongside elevated hemoglobin/hematocrit

1. What is the single most useful test to distinguish PV from secondary polycythemia?

There isn’t one single test that reliably distinguishes all cases. The most informative first-line combination is JAK2 mutation testing plus a serum erythropoietin (EPO) level: a JAK2-positive result with a low EPO strongly supports PV, while a normal/high EPO makes secondary causes more likely and guides the next evaluation steps. [1,2]

2. If blood counts are only mildly high, is immediate hematology referral necessary?

Often the first step is to repeat the CBC to confirm a persistent elevation and to review potentially reversible contributors (e.g., hemoconcentration, hypoxia/exposure history, medication causes). Prompt hematology review is generally appropriate when elevation persists and there are supportive features such as low EPO, JAK2 positivity, splenomegaly, or PV-suggestive symptoms (e.g., aquagenic pruritus). [1,2]

3. Can secondary polycythemia be “cured”?

If the erythrocytosis is secondary to a reversible driver (e.g., hypoxia-related conditions, medication/exposure-related causes, or certain EPO-producing tumors), correcting the cause can lead to normalization of hemoglobin/hematocrit without PV-style long-term hematologic management. [2]

4. What if JAK2 is negative but erythrocytosis persists?

A negative JAK2 result makes PV less likely and raises the possibility of secondary causes or JAK2-unmutated (non-PV) erythrocytosis (acquired or hereditary). Next steps commonly include reassessing secondary drivers, using serum EPO to guide the pathway, and considering specialist evaluation for additional testing (including selected marrow/genetic workup when indicated). [8,9]

PV — Polycythemia vera

JAK2 — Janus kinase 2

CBC — Complete blood count

EPO — Erythropoietin

BCR-ABL1 — BCR–ABL1 fusion gene

CO — Carbon monoxide

ICC — International Consensus Classification

WHO — World Health Organization

FAQs — Frequently asked questions

1. Tefferi, A., & Barbui, T. (2023). Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. American Journal of Hematology, 98(9), 1465–1487. https://doi.org/10.1002/ajh.27002
2. Mithoowani, S., Laureano, M., Crowther, M. A., & Hillis, C. M. (2020). Investigation and management of erythrocytosis. CMAJ, 192(32), E913–E918. https://doi.org/10.1503/cmaj.191587
3. Arber, D. A., Orazi, A., Hasserjian, R. P., Borowitz, M. J., Calvo, K. R., Kvasnicka, H.-M., Wang, S. A., Bagg, A., … Vardiman, J. W. (2022). International Consensus Classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and genomic data. Blood, 140(11), 1200–1228. https://doi.org/10.1182/blood.2022015850
4. McMullin, M. F., Harrison, C. N., Ali, S., Cargo, C., Chen, F., Ewing, J., Garg, M., Godfrey, A., Knapper, S., McLornan, D., Nangalia, J., Sekhar, M., Wadelin, F., & Mead, A. J. (2019). A guideline for the diagnosis and management of polycythaemia vera. British Journal of Haematology, 184(2), 176–191. https://doi.org/10.1111/bjh.15648
5. Marchioli, R., Finazzi, G., Specchia, G., Cacciola, R., Cavazzina, R., Cilloni, D., De Stefano, V., Elli, E., Iurlo, A., Latagliata, R., Lunghi, M., Lunghi, F., Polverelli, N., Rambaldi, A., Ruggeri, M., Randi, M. L., Santini, V., Vannucchi, A. M., … Barbui, T. (2013). Cardiovascular events and intensity of treatment in polycythemia vera. The New England Journal of Medicine, 368(1), 22–33. https://doi.org/10.1056/NEJMoa1208500
6. Landolfi, R., Marchioli, R., Kutti, J., Gisslinger, H., Tognoni, G., Patrono, C., & Barbui, T. (2004). Efficacy and safety of low-dose aspirin in polycythemia vera. The New England Journal of Medicine, 350(2), 114–124. https://doi.org/10.1056/NEJMoa035572
7. Marchetti, M., Vannucchi, A. M., Griesshammer, M., Harrison, C., Koschmieder, S., Gisslinger, H., Álvarez-Larrán, A., De Stefano, V., Guglielmelli, P., Palandri, F., Passamonti, F., Barosi, G., Silver, R. T., Hehlmann, R., Kiladjian, J.-J., & Barbui, T. (2022). Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. The Lancet Haematology, 9(4), e301–e311. https://doi.org/10.1016/S2352-3026(22)00046-1
8. Gangat, N., Szuber, N., Pardanani, A., & Tefferi, A. (2021). JAK2 unmutated erythrocytosis: Current diagnostic approach and therapeutic views. Leukemia, 35(8), 2166–2181. https://doi.org/10.1038/s41375-021-01290-6
9. Szuber, N., Tefferi, A., & Gangat, N. (2025). JAK2 wild-type erythrocytosis: Concept, differential diagnosis, diagnostic steps, and treatment approaches. Hematology: ASH Education Program, 2025(1), 183–190. https://doi.org/10.1182/hematology.2025000704