On lab reports, essential thrombocythemia (ET) announces itself with persistently high platelets (≥450 × 10⁹/L), while polycythemia vera (PV) is defined by elevated red-cell measures to set cutoffs (Hgb / Hct >16.5 g/dL / 49% in men; >16.0 g/dL / 48% in women). These thresholds are based on contemporary WHO/ICC criteria and patient-facing summaries used in the clinic. [2]

Because counts can be influenced by iron status, hydration, and coexisting conditions, clinicians read results as a pattern over time. For example, iron deficiency can “mask” PV, with a near-normal hematocrit but a high RBC count and a compatible clinical context; therefore, trends and supporting tests (e.g., EPO, marrow) are essential considerations before labeling ET or PV. [3][4]

Both systems diagnose these MPNs using defined major/minor criteria, which are read together rather than in isolation. For PV, the primary criteria are:

1. Elevated hemoglobin/hematocrit to set cutoffs
2. PV-pattern bone marrow (panmyelosis with pleomorphic mature megakaryocytes)
3. A JAK2 mutation; the minor criterion is subnormal EPO

A PV diagnosis is made when all three majors are present, or when the first two majors and the minor are present. [2]

For ET, WHO 2022 lists four primary criteria as follows:

1. Platelets ≥450×10⁹/L
2. Bone marrow with megakaryocytic proliferation of large, mature, hyperlobulated forms and no significant left shift in other lineages
3. Does not meet diagnostic criteria for PV/PMF/CML/MDS
4. Presence of JAK2/CALR/MPL; a minor criterion addresses clonality/reactive causes.

ET is diagnosed by all four majors, or the first three majors + the minor; ICC mirrors this structure. [2]

Why marrow matters: In sustained thrombocytosis, a biopsy helps distinguish ET from prefibrotic myelofibrosis and reactive causes; contemporary criteria and patient guides emphasize this step to improve specificity. [2]

Driver mutations overlap but point in different directions. In polycythemia vera (PV), the disease is almost always driven by a JAK2 mutation, most commonly V617F, with exon 12 variants accounting for many JAK2-V617F–negative cases. That biology aligns with PV’s hallmark: erythrocytosis with panmyelosis on marrow exam. In contrast, essential thrombocythemia (ET) frequently harbors JAK2, CALR, or MPL mutations; when JAK2 is absent, CALR or MPL is more likely. These patterns help steer the differential, but mutation status does not replace the formal diagnostic rule sets. [2]

In PV, activating JAK2 mutations are associated with increased erythrocyte production and often broader panmyelosis, reflected clinically by elevated hemoglobin/hematocrit and sometimes increased white blood cell and platelet counts. In ET, JAK2-, CALR-, and MPL-mutant cases show differing clinical patterns, including variation in platelet production and thrombotic risk. These observations provide clinical context but are interpreted alongside blood counts and marrow morphology rather than as standalone explanatory mechanisms. [2]

In contemporary practice, multitarget next-generation sequencing (NGS) panels are widely available and can assess JAK2 (V617F and exon 12), CALR, MPL, and other myeloid genes simultaneously, rather than strictly following a stepwise single-gene testing algorithm. [2] A positive result supports clonality, but the name (ET vs PV) still comes from meeting WHO/ICC criteria, counts to defined thresholds, the right marrow pattern, and, in PV, a subnormal EPO level. [3][4]

Secondary erythrocytosis is uncommon, but it is more common than primary erythrocytosis, similar to reactive thrombocytosis [5][6], and some MPNs share the same driver mutation (for example, JAK2 appears in both ET and PV). [3] That’s why mutation data are integrated with trends over time, including a complete blood picture (CBC), iron status, EPO, and marrow morphology before a label is applied; this avoids misclassifying masked PV as ET (or vice versa) and prevents overcalling disease in reactive states. [3]

Core patterns differ at first glance. In polycythemia vera (PV), the primary signal is erythrocytosis, characterized by elevated hemoglobin/hematocrit levels above defined cutoffs, often accompanied by low erythropoietin (EPO) levels and, in the marrow, trilineage overgrowth (panmyelosis). In essential thrombocythemia (ET), the defining feature is persistent thrombocytosis (platelet count≥450 × 10^9/L), with the marrow showing enlarged, mature megakaryocytes; other counts may be near baseline. These findings are best understood when read in conjunction over time, rather than in isolation. [3]

Iron deficiency can suppress hemoglobin and hematocrit values, making the diagnosis of polycythemia vera more challenging despite an underlying increase in red cell mass; in this setting (“masked PV”), the red blood cell count and other clinical features may provide important diagnostic clues. [3][7] Pairing the CBC with EPO and iron studies helps avoid a miss; in contemporary practice, red-cell mass testing is rarely required. Leukocytosis and thrombocytosis can accompany PV, but the primary driver of the disease is the red blood cell line. [3][4]

Platelets are persistently high; WBC and RBC may be less disturbed. When platelets are highly elevated, acquired von Willebrand disease can emerge (loss of high–molecular–weight multimers), presenting with mucocutaneous bleeding despite high counts, an essential counterpoint to the thrombotic risk that often requires immediate evaluation. It’s important to distinguish reactive (secondary) thrombocytosis (from infection/inflammation, iron deficiency, or postsplenectomy) before establishing the ET diagnosis. [5]

Common pitfalls that blur the distinction between ET and PV are:

• Relative erythrocytosis (dehydration/hemoconcentration) can transiently raise hematocrit without an increase in red-cell mass; repeat after rehydration. [3]
• Secondary erythrocytosis (hypoxia from lung disease/OSA/high altitude; smoking/CO exposure; exogenous androgens or EPO; renal lesions) can mimic PV, screen with history, pulse oximetry, medication review, and targeted imaging when EPO is inappropriately high. [3]
• Iron deficiency can mask PV (microcytosis, “normal” Hct but high RBC count); correct iron deficiency before final classification. [4]

You can first look at the trends in Hgb/Hct, RBC, and platelets, and add EPO and iron studies early on. Then, once you’ve ruled out confounders like iron deficiency, dehydration, and inflammation, you can go back and reconsider the label. This approach helps lower the risk of misdiagnosis or a delayed diagnosis. If things still don’t quite fit, bone marrow morphology can help you distinguish PV from ET and from reactive conditions. [3][5]

Symptoms in essential thrombocythemia (ET) and polycythemia vera (PV) reflect different biological mechanisms, including platelet-mediated microvascular effects (and bleeding at very high platelet counts) in ET, versus increased red blood cell mass and hyperviscosity in PV. Because these MPNs can share drivers (e.g., JAK2) and overlap clinically, symptom clusters are interpreted alongside trends in counts and marrow context. [1][2]

Polycythemia vera (PV)

PV symptoms often stem from hyperviscosity: headache, dizziness, visual disturbances, fatigue, facial plethora, and aquagenic pruritus (itching after warm showers). Microvascular complaints (e.g., light-headedness, transient visual changes) can occur, and splenomegaly is not uncommon. The primary clinical concern is thrombosis, encompassing both arterial and venous events, which is associated with higher hematocrit levels and other risk factors. In contrast, bleeding is less typical, occurring only when platelets are extremely high due to acquired von Willebrand syndrome. [1][5]

Essential thrombocythemia (ET)

ET frequently presents with microvascular symptoms, including headache, visual changes, acral burning pain (erythromelalgia), or paresthesias, which are thought to arise from platelet-mediated small-vessel disturbances. Thrombotic events can occur, particularly in JAK2-positive ET, while bleeding risk rises at very high platelet counts due to acquired von Willebrand disease (loss of high–molecular–weight multimers). Splenomegaly may be present, but erythrocytosis is not a defining feature. [1][5]

Why symptoms overlap, and why the pattern still matters?

Both PV and ET are BCR::ABL1–negative MPNs that can share driver mutations (e.g., JAK2), so headaches, dizziness, and microvascular symptoms may be present in either condition. The differentiator is the dominant cell line and the associated lab pattern over time, specifically erythrocytosis in PV versus thrombocytosis in ET, supported by marrow morphology and mutation profile. Reading symptoms with counts prevents misclassification (e.g., “masked PV” when iron deficiency depresses MCV and blunts hematocrit despite increased RBC mass). [1][3][4]

Before confirming essential thrombocythemia (ET) or polycythemia vera (PV), clinicians first exclude reactive thrombocytosis and secondary erythrocytosis, which are common look-alikes that can temporarily elevate counts. This step keeps labels accurate and ensures marrow and mutation testing are used where they add the most value. [3]

When platelets are high (ET look-alikes)

Before diagnosing essential thrombocythemia, clinicians exclude common causes of reactive (secondary) thrombocytosis, including infection or inflammation (such as postsurgical states), iron deficiency, active malignancy, and postsplenectomy, as well as early myelofibrosis. Iron studies, inflammatory markers (as appropriate), review of recent surgery or blood loss, and peripheral smear are routine; persistent thrombocytosis after correction of reversible factors strengthens the case for ET. [5]

When red cells are high (PV look-alikes)

Not all erythrocytosis is PV. Secondary causes include chronic hypoxia (COPD, interstitial lung disease), obstructive sleep apnea, smoking/carboxyhemoglobin exposure, high altitude, exogenous androgens or EPO, and renal disease or EPO-secreting lesions. A practical screen pairs history and exam with pulse oximetry (± sleep study), medication review, erythropoietin (EPO) level (often normal/high in secondary erythrocytosis), and targeted imaging when EPO is inappropriately elevated without hypoxia. Relative erythrocytosis from dehydration/hemoconcentration can transiently raise hematocrit and should normalize with rehydration. [3][5]

Why this step matters

ET and PV are diagnoses of inclusion under WHO/ICC rules, made when sustained count patterns, marrow morphology, and mutation status align and common reactive or secondary explanations have been addressed. This prevents misclassification (e.g., labeling iron-deficiency thrombocytosis as “ET” or hypoxia-driven erythrocytosis as “PV”) and focuses subsequent decisions on the correct disease biology. [2][3][5]

Start with the dominant cell line on repeat labs, then confirm with marrow and mutations.

• Suspect PV when hemoglobin/hematocrit exceeds set cutoffs (>16.5 g/dL / 49% in men; >16.0 g/dL / 48% in women) or RBC count trends high, especially with low EPO; confirm with PV-pattern marrow (panmyelosis) and JAK2 positivity per WHO/ICC. [1][2]
• Suspect ET when platelets ≥450 × 10⁹/L are persistent, marrow shows megakaryocytic proliferation of large mature forms, criteria for PV/PMF/CML/MDS are not met, and a clonal driver (JAK2/CALR/MPL) is present. [1][2][8]

Use a stepwise re-check before final diagnosis:

• Correct iron deficiency or dehydration and repeat the CBC; iron deficiency can mask PV (microcytosis with a “normal” Hct but high RBC count), and hemoconcentration can falsely elevate Hct. [3][4]
• Review for secondary erythrocytosis (hypoxia from lung disease/OSA/high altitude, smoking/CO exposure, exogenous androgens/EPO, renal lesions) when EPO is normal/high; investigate reactive thrombocytosis (infection/inflammation, postsplenectomy, iron deficiency) before calling ET. [3][5]

Molecular testing may be performed sequentially, beginning with JAK2 V617F and, if negative, followed by JAK2 exon 12 testing in PV phenotypes or CALR/MPL testing in ET phenotypes, or by multitarget next-generation sequencing panels that assess these driver mutations simultaneously. A positive result supports clonality; however, the classification (ET vs PV) ultimately follows the WHO/ICC criteria, not the genotype alone. [1][2][3][8]

Bone marrow examination is particularly useful when blood counts and clinical features are discordant, for example, persistent thrombocytosis with only borderline elevation in hemoglobin/hematocrit (to distinguish essential thrombocythemia from masked polycythemia vera), or unexplained cytoses with concern for prefibrotic primary myelofibrosis, because marrow morphology (panmyelosis versus isolated megakaryocytic proliferation or prefibrotic changes) improves diagnostic specificity and reduces misclassification. [2]

1. What single lab trend most strongly separates ET from PV?

Start with the cell line that is consistently highest on repeat CBCs. Persistent platelets ≥450 × 10⁹/L points toward ET, while erythrocytosis meeting the hemoglobin/hematocrit cutoffs points toward PV. The final diagnosis still depends on bone marrow and mutation findings. [1]

2. Can iron deficiency make PV hard to recognize?

Yes, iron deficiency can lower MCV and mask PV; hematocrit may look “normal” while RBC count runs high. Replete iron and reassess before final classification. [4]

3. Do ET and PV share the same mutations?

Both ET and PV can be JAK2-positive, but the patterns differ. Most PV is JAK2-driven (V617F or exon 12), whereas ET more often shows mutations in JAK2, CALR, or MPL. Mutation status informs the picture but does not replace the WHO/ICC criteria. [1][2]

4. When is a bone-marrow biopsy recommended?

Bone marrow examination makes the diagnosis more specific: it can confirm panmyelosis in PV, help separate ET from prefibrotic myelofibrosis, and rule out reactive causes when the blood counts don’t match the picture. Many experts recommend confirming the diagnosis with a bone marrow biopsy before assigning an MPN label. [2][9][10]

5. Which symptoms warrant urgent attention regardless of ET or PV?

New neurologic deficits, chest pain, shortness of breath, unilateral leg swelling, or severe, atypical headache are red-flag symptoms for potential thrombotic events and need urgent evaluation; bleeding with very high platelets also warrants prompt care. [3][9]

6. Can blood counts (platelets or hemoglobin/hematocrit) normalize on their own if the cause is not a myeloproliferative neoplasm?

Reactive thrombocytosis (infection/inflammation, postsplenectomy) and secondary erythrocytosis (hypoxia, smoking/CO, exogenous androgens/EPO) often resolve when the underlying cause is addressed. This is one reason clinicians confirm persistence over time before diagnosing ET or PV. [3][5]

• AJH – American Journal of Hematology
• aVWD – Acquired von Willebrand disease
• BCR::ABL1 – BCR-ABL1 fusion gene
• CBC – Complete blood count
• CMAJ – Canadian Medical Association Journal
• CML – Chronic myeloid leukemia
• CO – Carbon monoxide
• COPD – Chronic obstructive pulmonary disease
• DVT – Deep vein thrombosis
• EPO – Erythropoietin
• ET – Essential thrombocythemia
• Hct – Hematocrit
• Hgb – Hemoglobin
• ICC – International Consensus Classification
• ID – Iron deficiency
• JAK2 – Janus kinase 2
• MCV – Mean corpuscular volume
• MF – Myelofibrosis
• MPN – Myeloproliferative neoplasm
• MDS – Myelodysplastic syndrome
• NGS – Next-generation sequencing
• OSA – Obstructive sleep apnea
• PE – Pulmonary embolism
• PMF – Primary myelofibrosis
• PV – Polycythemia vera
• RBC – Red blood cell
• STAT – Signal transducer and activator of transcription
• TIA – Transient ischemic attack
• WHO – World Health Organization
• WBC – White blood cell

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