Polycythemia vera (PV) is a chronic myeloproliferative neoplasm, diagnosed by a pattern of findings rather than a single test. Current frameworks (WHO, 2022; ICC) define PV using clear laboratory and pathological features considered together, rather than in isolation [1][3]

In practice, the “major” pieces are: raised red blood cell measures, bone-marrow features consistent with PV, and a JAK2 mutation; a low erythropoietin (EPO) level serves as the “minor” piece. A diagnosis is made when these criteria align per the rule set (all three majors, or the first two majors plus the minor). [1]

Both frameworks diagnose PV by major criteria (raised red blood cell measures, PV-pattern bone marrow, and a JAK2 mutation) plus a minor criterion (low EPO). A diagnosis is made when all three majors are present, or when the first two majors and the minor are present. Commonly used hemoglobin or hematocrit cutoffs are more than 16.5 g/dL or 49% in men and greater than16 g/dL or 48% in women. [1][3]

When is bone marrow aspiration recommended?

Bone marrow morphology improves diagnostic certainty and provides prognostic information. While biopsy may be omitted in patients with sustained absolute erythrocytosis and a JAK2 mutation who meet hemoglobin or hematocrit thresholds, bone marrow evaluation remains important to detect early myelofibrosis, which may predict progression to post-PV myelofibrosis. [1][3][4]

Most evaluations begin with a complete blood count (CBC) to assess hemoglobin hematocrit, and red blood cell count, as well as platelets and white blood cells. [5] Iron studies (including ferritin and transferrin saturation) are commonly included early in the evaluation, because iron status can influence how red blood cell measures appear on the report. These routine labs establish the pattern that prompts targeted testing for PV. [6][7]

Targeted tests typically include JAK2 V617F; if negative and suspicion remains, testing for JAK2 exon 12 follows. At the same time, a serum erythropoietin (EPO) level is checked because it helps distinguish PV from secondary causes of erythrocytosis. [6][7]

Interpreting EPO

A subnormal EPO level supports primary erythrocytosis. In contrast, a normal or elevated EPO level points toward secondary causes (e.g., hypoxia, exogenous EPO, or androgens), always interpreted in conjunction with the CBC and clinical context. Occasional exceptions occur, so EPO serves as a supporting piece rather than a stand-alone decision-maker. [6][7]

Laboratory findings typically show elevated hemoglobin or hematocrit, often with an increased red blood cell count. Some patients also have leukocytosis or thrombocytosis. A subnormal serum erythropoietin (EPO) level supports polycythemia vera. [6][7]

A key pitfall is iron deficiency, which can lower the mean cell volume (MCV) and mask true erythrocytosis; hematocrit may appear “normal” while the RBC count is high (so-called masked polycythemia). Clues include microcytosis with discordantly high RBCs and a low EPO in the proper clinical context. [7][8]

Not all elevated hemoglobin or hematocrit is PV. Common secondary causes include hypoxic lung disease, obstructive sleep apnea, smoking or carbon monoxide poisoning, high altitude, cyanotic congenital heart disease, renal disease or EPO-secreting tumors, and medications such as androgens or exogenous EPO; relative erythrocytosis from dehydration can also mimic PV. [6]

A practical screen pairs history and exam with targeted tests: pulse oximetry (± sleep study), smoking/CO exposure review, medication inventory, EPO level (often high in secondary causes), iron studies, and selective imaging when EPO is inappropriately elevated without hypoxia, before concluding a polycythemia vera diagnosis. [5][6]

Suppose JAK2 V617F is not detected, but PV is still suspected. In that case, most clinicians test for JAK2 exon 12 variants and interpret the results in conjunction with hemoglobin and hematocrit thresholds, bone marrow morphology, and a subnormal erythropoietin (EPO) level; this combination can still meet diagnostic criteria. [1][3]

When JAK2 testing is negative and the criteria are not met, the differential shifts toward secondary erythrocytosis or a different myeloproliferative neoplasm (MPN), using each condition’s criteria to avoid misclassification. [1]

At diagnosis, clinicians typically document: CBC (Hgb, Hct, RBC, platelets, WBC), EPO, iron studies (ferritin, transferrin saturation), and context labs (e.g., uric acid, LDH), plus exam/imaging notes, such as spleen size. Red blood cell mass testing is rarely necessary

At diagnosis, clinicians document baseline laboratory studies including a complete blood count (hemoglobin, hematocrit, RBC count, platelets, WBC) and serum erythropoietin; additional investigations such as LDH and uric acid are also commonly included, with assessment for iron deficiency often part of extended evaluation. Red blood cell mass testing is rarely necessary. [5][11][12][13]

A polycythemia vera diagnosis is based on how laboratory results and bone marrow features align with JAK2 testing and EPO, rather than relying on any single result; reading them together helps avoid both over- and under-diagnosis. When the pattern fits, naming PV helps you and your team set monitoring plans and next steps.

1. Do all patients with PV require a bone marrow biopsy?

Bone marrow examination improves diagnostic certainty and provides important morphologic and prognostic information, and both the WHO and ICC classifications include marrow morphology as a major diagnostic criterion. However, a bone marrow biopsy may not be required in selected patients with sustained absolute erythrocytosis who have hemoglobin or hematocrit values above diagnostic thresholds together with a JAK2 mutation, in whom a working diagnosis of PV can be made. [1][3][4]

2. Is red blood cell mass testing still used?

Red blood cell mass (RCM) testing is now rarely performed. WHO 2022 no longer requires RCM for PV diagnosis, whereas ICC 2022 retains increased RCM (>25% above predicted) as a criterion, mainly for selected cases with inconclusive hemoglobin or hematocrit results. [3][4]

3. Which hemoglobin and hematocrit cutoffs are used today?

WHO 2022 and ICC diagnostic frameworks typically use thresholds of hemoglobin >16.5 g/dL or hematocrit >49% (men) and hemoglobin >16.0 g/dL or hematocrit >48% (women) when evaluating PV. [1][3][4]

4. Can dehydration mimic PV?

Yes. Dehydration can cause relative erythrocytosis, in which plasma volume is reduced, but red blood cell mass remains normal. Clinical context and volume assessment help differentiate this from true PV. [4][6][9]

5. What if iron deficiency hides a high hematocrit?

Iron deficiency can lower MCV and mask erythrocytosis, leading to “masked PV.” Reported clues include microcytosis with iron deficiency and a red blood cell count that is higher than expected for the hemoglobin level, prompting further evaluation once iron deficiency is recognized or corrected. Case reports and cohort studies document this presentation. [7][8]

6. Do all patients with suspected PV need JAK2 exon 12 testing?

Most patients first undergo JAK2 V617F testing. If negative and suspicion remains high, clinicians test for JAK2 exon 12 mutations, which can meet diagnostic criteria when paired with compatible labs and marrow morphology. [1][3][4]

7. What does a low EPO level mean?

Once true erythrocytosis has been confirmed and relative causes such as dehydration have been excluded, a subnormal erythropoietin (EPO) level supports a primary erythrocytosis such as polycythemia vera. In contrast, a normal or elevated EPO level suggests secondary causes, including hypoxia, medications, tumors, or carbon monoxide exposure. EPO results should always be interpreted alongside the complete blood count and the clinical context. [5][6][7]

8. How do doctors rule out secondary erythrocytosis?

Evaluation includes but not limited to pulse oximetry, sleep-apnea assessment, smoking/CO review, medication history, iron studies, and imaging when EPO is elevated without hypoxia. These steps help separate PV from lung disease, OSA, renal causes, and hormone-related erythrocytosis. [5][6][9][10]

9. Is PV ever diagnosed without a bone marrow biopsy?

In some clinical settings, a provisional diagnosis can be made based on the presence of JAK2 mutation and sustained elevated hemoglobin or hematocrit. However, bone marrow confirmation is still important for diagnostic certainty. [1][3][4]

ABG – Arterial blood gas

CBC – Complete blood count

CNS – Central nervous system

CO – Carbon monoxide

CO-Hb – Carboxyhemoglobin

COPD – Chronic obstructive pulmonary disease

CT – Computed tomography

EPO – Erythropoietin

ET – Essential thrombocythemia

Hct – Hematocrit

Hgb – Hemoglobin

ICC – International Consensus Classification

JAK2 – Janus kinase 2

LDH – Lactate dehydrogenase

LLS – Leukemia & Lymphoma Society

MCV – Mean cell volume

MPN – Myeloproliferative neoplasm

MRI – Magnetic resonance imaging

OSA – Obstructive sleep apnea

PFTs – Pulmonary function tests

PV – Polycythemia vera

RCM – Red cell mass

RCC – Renal cell carcinoma

RBC – Red blood cell

SGLT2 – Sodium–glucose cotransporter-2

TSAT – Transferrin saturation

WBC – White blood cell

WHO – World Health Organization

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