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Summary Table

Feature	Detail
Risk Factors	Age > 60 years, male sex, European descent, JAK2 mutation carrier
Etiology	Clonal myeloproliferative neoplasm driven by a gain-of-function JAK2 mutation (V617F in ~95% of cases; exon 12 mutation in the remainder)
Patient Presentation	Headache, dizziness, blurred vision, facial plethora, aquagenic pruritus (itching after warm bath/shower), early satiety from splenomegaly, fatigue, erythromelalgia (burning pain and redness in hands/feet)
Classic Physical Exam	Plethoric (ruddy) facies, splenomegaly, hepatomegaly, conjunctival injection, hypertension
Key Diagnostic Results	Elevated hemoglobin (>16.5 g/dL in men, >16.0 g/dL in women) or elevated hematocrit (>49% men, >48% women), low serum erythropoietin (EPO), positive JAK2 V617F or JAK2 exon 12 mutation, hypercellular bone marrow with panmyelosis and pleomorphic megakaryocytes
Management	Phlebotomy (target hematocrit < 45%), low-dose aspirin (81 mg daily), cytoreductive therapy with hydroxyurea for high-risk patients
Keywords	"Aquagenic pruritus," "plethoric facies," "low EPO," "JAK2 V617F," "erythromelalgia," "hyperviscosity," "ruddy complexion," "Budd-Chiari syndrome in a young woman"

1. Pathophysiology

Polycythemia vera (PV) is a clonal myeloproliferative neoplasm originating from a mutated hematopoietic stem cell. The central molecular defect is a gain-of-function point mutation in the JAK2 gene located on chromosome 9p. The JAK2 V617F mutation is present in roughly 95% of PV cases. In the remaining approximately 5%, a mutation in JAK2 exon 12 is found. This distinction matters because if V617F is negative, PV is not ruled out until exon 12 testing is performed.

Under normal conditions, the JAK2 tyrosine kinase is activated when erythropoietin binds its receptor on erythroid progenitor cells. In PV, the V617F mutation causes constitutive (ligand-independent) activation of the JAK-STAT signaling pathway, meaning the erythroid progenitors proliferate without requiring EPO stimulation. This is why serum EPO levels are characteristically suppressed in PV, which distinguishes it from secondary causes of erythrocytosis (where EPO is elevated as the driving stimulus).

The unregulated overproduction of red blood cells leads to increased blood viscosity. This hyperviscosity is directly responsible for many of the symptoms: headaches, dizziness, visual disturbances, and tinnitus all result from sluggish blood flow through cerebral and ocular microvasculature. Thrombotic events are the leading cause of morbidity and mortality in PV, driven both by hyperviscosity and by qualitative platelet abnormalities. Patients are at heightened risk for arterial thrombosis (stroke, myocardial infarction), venous thrombosis (deep vein thrombosis, pulmonary embolism), and notably splanchnic vein thrombosis such as Budd-Chiari syndrome (hepatic vein thrombosis) and portal vein thrombosis. A young patient presenting with Budd-Chiari syndrome should immediately prompt evaluation for PV and other myeloproliferative neoplasms.

The single most reliable discriminator on an exam is the EPO level. A low EPO with elevated Hb/Hct points to PV; an elevated EPO with the same lab picture points to a secondary cause. From there, JAK2 testing confirms PV, while history and imaging (chest CT for lung disease, renal imaging for tumors, sleep study for OSA) identify the secondary etiology.

Although PV is primarily an erythroid proliferative disorder, it is actually a panmyelosis: white blood cells and platelets are often elevated as well, reflecting the stem-cell-level nature of the clonal expansion. The splenomegaly seen in PV results from both extramedullary hematopoiesis and sequestration of the excess blood cells by the spleen.

Aquagenic pruritus, a hallmark symptom, occurs in up to 40% of patients and is characterized by intense itching within minutes of contact with warm water. The mechanism is thought to involve mast cell degranulation and histamine release triggered by temperature change, combined with elevated basophil counts seen in myeloproliferative disorders.

Erythromelalgia, another classic finding, presents as episodic burning pain with erythema and warmth in the extremities (particularly the hands and feet), caused by microvascular arteriolar inflammation and platelet-mediated thrombotic occlusion of small vessels. It responds dramatically to aspirin.

Over time, PV may undergo transformation. The two feared long-term complications are evolution into post-PV myelofibrosis (spent phase, occurring in approximately 10-20% over 15-20 years) and transformation into acute myeloid leukemia (occurring in roughly 5-10%, with risk increased by certain cytoreductive agents such as alkylating agents and, historically debated, prolonged hydroxyurea use).

2. Classification and Clinical Manifestation

WHO 2022 Diagnostic Criteria

Criterion	Detail
Major Criterion 1	Hemoglobin > 16.5 g/dL (men) or > 16.0 g/dL (women), OR hematocrit > 49% (men) or > 48% (women), OR increased red cell mass (> 25% above normal predicted value)
Major Criterion 2	Bone marrow biopsy showing hypercellularity with panmyelosis (trilineage growth) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes
Major Criterion 3	Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor Criterion	Subnormal (low) serum erythropoietin level

Diagnosis requires: All 3 major criteria, OR the first 2 major criteria plus the minor criterion.

Risk Stratification

Risk Category	Definition	Thrombosis Risk
Low Risk	Age < 60 years AND no prior thrombotic event	Lower (but not negligible)
High Risk	Age ≥ 60 years OR prior history of thrombosis	Elevated; requires cytoreductive therapy

Additional cardiovascular risk factors (diabetes, hypertension, dyslipidemia, smoking) contribute to the overall thrombotic risk profile but do not independently change the formal risk category in standard classification systems.

Key Clinical Manifestations by System

System	Manifestation
Constitutional	Fatigue, weight loss, night sweats, aquagenic pruritus
Neurological	Headache, dizziness, visual disturbances, tinnitus, transient ischemic attacks
Vascular	Erythromelalgia, thrombosis (arterial and venous), bleeding (paradoxically, with extreme thrombocytosis > 1,000,000/mcL due to acquired von Willebrand disease)
Dermatologic	Plethoric (ruddy) facies, conjunctival injection
Gastrointestinal	Splenomegaly with early satiety, hepatomegaly, peptic ulcer disease (from increased histamine), Budd-Chiari syndrome
Hematologic	Elevated Hb/Hct, leukocytosis, thrombocytosis, elevated LDH, low EPO

3. Diagnostic Workup

Summary Table

Test	Purpose	Expected Finding in PV
CBC with differential	Best initial test	Elevated Hb/Hct; often concurrent leukocytosis and thrombocytosis
Serum EPO	Differentiate primary vs. secondary erythrocytosis	Low (suppressed)
JAK2 V617F mutation	Confirmatory molecular test	Positive in ~95% of PV
JAK2 exon 12 mutation	If V617F is negative	Positive in most V617F-negative PV cases
Bone marrow biopsy	Gold standard for morphologic diagnosis and grading	Hypercellular marrow with panmyelosis, pleomorphic mature megakaryocytes, decreased iron stores
Peripheral blood smear	Supportive evaluation	May show erythrocytosis; basophilia is common
Serum ferritin / iron studies	Assess iron stores (often depleted)	Low ferritin from high iron consumption in erythropoiesis
LDH, uric acid	Reflect high cell turnover	Elevated
Arterial oxygen saturation (SaO2)	Rule out secondary polycythemia from hypoxia	Normal (> 92%) in PV

Diagnostic Approach in Detail

Step 1: Identify the erythrocytosis. The workup typically begins when a routine CBC reveals an elevated hemoglobin or hematocrit. The first clinical question is whether this represents a true (absolute) increase in red cell mass or a relative polycythemia from hemoconcentration (e.g., dehydration). Repeating the CBC after adequate hydration can help clarify this. A persistently elevated Hb > 16.5 g/dL in men or > 16.0 g/dL in women warrants further investigation.

Step 2: Distinguish primary from secondary erythrocytosis. The serum erythropoietin level is the pivotal test here. A low EPO points toward a primary marrow disorder (PV), because the autonomous overproduction of red cells provides negative feedback that suppresses EPO release from the kidneys. A high or inappropriately normal EPO suggests a secondary cause such as chronic hypoxia (COPD, obstructive sleep apnea, high altitude, right-to-left cardiac shunts), EPO-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma), or exogenous EPO use.

Step 3: Obtain JAK2 mutation testing. If EPO is low and erythrocytosis is confirmed, JAK2 V617F testing should be ordered. A positive result, in the setting of elevated hemoglobin/hematocrit and low EPO, is often sufficient to confirm the diagnosis. If V617F is negative, proceed to JAK2 exon 12 mutation analysis, as roughly 3-5% of true PV cases carry this alternative mutation.

Step 4: Bone marrow biopsy. A bone marrow biopsy is recommended to fulfill WHO diagnostic criteria and is particularly valuable when there is a need to assess for early/prefibrotic disease, evaluate baseline reticulin fibrosis, and rule out other myeloproliferative neoplasms. The characteristic findings are hypercellularity for age, panmyelosis (trilineage proliferation), and clusters of pleomorphic mature megakaryocytes of varying sizes. Iron stores are frequently absent. Reticulin fibrosis grading at baseline helps track progression to post-PV myelofibrosis over time.

Key point for examinations: A normal SaO2 (> 92%) combined with a low EPO level effectively rules out secondary polycythemia and shifts the differential strongly toward PV.

4. Management and Treatment

Summary Table

Intervention	Indication	Key Details
Phlebotomy	All patients	Target hematocrit < 45%; typically 1 unit (450-500 mL) removed per session every few days initially, then as needed
Low-dose aspirin	All patients (unless contraindicated)	81 mg daily; reduces thrombotic risk and treats erythromelalgia
Hydroxyurea	High-risk patients (age ≥ 60 or prior thrombosis)	First-line cytoreductive agent; starting dose typically 15-20 mg/kg/day; dose adjusted to maintain hematocrit < 45% and platelet count in normal range
Interferon-alpha (pegylated)	High-risk patients intolerant or resistant to hydroxyurea; younger patients; pregnant patients	Pegylated interferon alfa-2a (Ropeginterferon alfa-2b is specifically approved for PV); can induce molecular responses
Ruxolitinib	Patients resistant or intolerant to hydroxyurea	JAK1/JAK2 inhibitor; starting dose 10 mg twice daily; effective for controlling hematocrit, reducing splenomegaly, and alleviating constitutional symptoms including pruritus
Cardiovascular risk management	All patients	Aggressive management of hypertension, diabetes, dyslipidemia; smoking cessation
Allopurinol	Hyperuricemia / gout prophylaxis	Used when uric acid is elevated or symptomatic gout occurs
Antihistamines / SSRIs	Aquagenic pruritus	H1 and H2 blockers; paroxetine or other SSRIs may help refractory pruritus

for all patients

Phlebotomy is the cornerstone of initial treatment. The goal is to achieve and maintain a hematocrit below 45%, which has been shown in the CYTO-PV trial to reduce cardiovascular events and death compared to a more lenient target. Sessions involve removing approximately 450-500 mL of blood, performed every 2-3 days initially if the hematocrit is very elevated, then spaced out to a maintenance schedule (often every 1-3 months) once the target is reached. Iron deficiency resulting from repeated phlebotomy is expected and should generally not be corrected with iron supplementation, as this would counteract the purpose of treatment. However, if the patient develops severely symptomatic iron deficiency (e.g., pica, restless leg syndrome, cognitive symptoms) that outweighs the benefit, cautious low-dose iron replacement with close hematocrit monitoring can be considered.

Low-dose aspirin (81 mg daily) is recommended for virtually all PV patients. The ECLAP trial demonstrated that aspirin reduces the combined risk of nonfatal myocardial infarction, nonfatal stroke, and venous thromboembolism without a meaningful increase in bleeding risk. Aspirin is also remarkably effective for erythromelalgia, often providing relief within hours. Aspirin should be avoided or used with caution in patients with extreme thrombocytosis (platelet count > 1,000,000 to 1,500,000/mcL) because of the risk of acquired von Willebrand disease: the very high platelet count leads to adsorption and proteolysis of von Willebrand factor multimers, creating a bleeding diathesis rather than a thrombotic state. In such cases, ristocetin cofactor activity should be checked before initiating aspirin.

For high-risk patients (age ≥ 60 or history of thrombosis)

Hydroxyurea is the first-line cytoreductive agent. It works by inhibiting ribonucleotide reductase, thereby reducing DNA synthesis in rapidly dividing hematopoietic cells. The typical starting dose is 15-20 mg/kg/day (roughly 500-1000 mg daily for most adults), titrated to achieve a hematocrit < 45%, white blood cell count > 3,000/mcL, and platelet count > 100,000/mcL. Patients on hydroxyurea require regular monitoring with CBC every 2-4 weeks during dose titration, then every 2-3 months once stable. Side effects include cytopenias (dose-dependent), oral ulcers, skin ulcers (particularly leg ulcers), nail changes, and rare mucocutaneous squamous cell changes. Hydroxyurea is absolutely contraindicated in pregnancy (teratogenic).

Pegylated interferon-alpha (notably ropeginterferon alfa-2b, which is FDA-approved for PV) is an alternative first-line cytoreductive agent and is preferred in younger patients, women of childbearing potential, and patients who are intolerant of or resistant to hydroxyurea. Interferon has the advantage of being able to induce molecular responses (reduction in JAK2 V617F allele burden) and is not considered leukemogenic. Ropeginterferon alfa-2b is administered subcutaneously every 2 weeks initially, then every 2-4 weeks during maintenance. Side effects include flu-like symptoms, fatigue, depression, autoimmune phenomena, and hepatotoxicity. Interferon is contraindicated in patients with severe psychiatric disorders (particularly untreated depression) and decompensated liver disease.

Ruxolitinib (a JAK1/JAK2 inhibitor) is indicated for patients who are resistant to or intolerant of hydroxyurea. It is effective at controlling hematocrit, reducing spleen size, alleviating pruritus, and improving constitutional symptoms. The starting dose is typically 10 mg twice daily, adjusted based on response and tolerability. Ruxolitinib carries risks of cytopenias, infections (particularly herpes zoster reactivation), and a withdrawal syndrome with rebound symptoms if discontinued abruptly. Patients should be screened for tuberculosis and hepatitis B before starting ruxolitinib.

Special situations

In pregnancy, hydroxyurea is contraindicated. The preferred management includes phlebotomy, low-dose aspirin, and pegylated interferon-alpha if cytoreduction is necessary. Pregnancy in PV carries elevated risks of thrombosis and pregnancy complications (preeclampsia, placental insufficiency, fetal loss), warranting close multidisciplinary management.

For extreme thrombocytosis (> 1,500,000/mcL), assess for acquired von Willebrand disease by measuring ristocetin cofactor activity. If acquired von Willebrand disease is confirmed, aspirin should be withheld until the platelet count is reduced with cytoreductive therapy.

5. Differential Diagnosis and Distractors

polycythemia vera vs secondary erythrocytosis

Feature	Polycythemia Vera	Secondary Erythrocytosis
Underlying Mechanism	Clonal stem cell disorder with constitutive JAK-STAT activation (JAK2 mutation)	Physiologic or pathologic increase in EPO driving normal marrow to overproduce RBCs
Serum EPO	Low (suppressed by negative feedback from autonomous RBC production)	Elevated or inappropriately normal
JAK2 Mutation	Positive (V617F in ~95%, exon 12 in ~3-5%)	Negative
Common Causes	None (it is the primary disease)	COPD, obstructive sleep apnea, high altitude, cyanotic heart disease, EPO-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma), exogenous EPO/testosterone use
WBC Count	Often elevated (panmyelosis)	Normal
Platelet Count	Often elevated	Normal
Splenomegaly	Present in ~70% of cases	Absent
Aquagenic Pruritus	Present in up to 40%	Absent
Erythromelalgia	Can be present	Absent
Thrombotic Risk	High (arterial, venous, and splanchnic)	Lower (related to hyperviscosity only, not platelet dysfunction)
Bone Marrow Biopsy	Hypercellular with panmyelosis, pleomorphic megakaryocytes, decreased iron stores	Erythroid hyperplasia only, normal megakaryocytes, no panmyelosis
SaO2	Normal (> 92%)	Often low in hypoxia-driven causes; normal in EPO-secreting tumors
Peripheral Smear	May show basophilia, occasional large platelets	Typically unremarkable aside from erythrocytosis
Treatment	Phlebotomy + aspirin + cytoreduction (hydroxyurea) for high-risk	Treat the underlying cause (supplemental O2, CPAP, tumor resection); phlebotomy only if symptomatic hyperviscosity
Hematocrit Target	< 45% (supported by CYTO-PV trial)	No universal target; guided by symptom resolution and treatment of root cause
Risk of Leukemic Transformation	Yes (~5-10% over long term)	No
Risk of Myelofibrosis	Yes (~10-20% over 15-20 years)	No

other differential diagnoses

Differential Diagnosis	Why It Is Similar	Key Discriminator
Relative Polycythemia (Gaisbock syndrome / dehydration)	Elevated hematocrit on labs	Red cell mass is normal; Hct normalizes with hydration; no splenomegaly or JAK2 mutation
Essential Thrombocythemia (ET)	Myeloproliferative neoplasm with JAK2 V617F positivity (in ~60%); can have thrombotic events	Hemoglobin/hematocrit is normal in ET; the dominant abnormality is isolated thrombocytosis (> 450,000/mcL); bone marrow shows large, hyperlobulated megakaryocytes (not panmyelosis)
Primary Myelofibrosis (PMF)	Myeloproliferative neoplasm; splenomegaly; can have JAK2 mutation (~50-60%)	Leukoerythroblastic blood smear (tear-drop cells, nucleated RBCs, immature granulocytes); bone marrow fibrosis; patients are often anemic, not polycythemic; dry tap on marrow aspiration
Chronic Myeloid Leukemia (CML)	Leukocytosis, splenomegaly, myeloproliferative neoplasm	Defined by BCR-ABL1 fusion gene (Philadelphia chromosome); basophilia is prominent; CML does not typically cause true erythrocytosis; JAK2 is negative
Obstructive Sleep Apnea (OSA)	Can cause secondary polycythemia; patient may be obese and plethoric	EPO is elevated or normal; SaO2 desaturations during sleep; no JAK2 mutation; no splenomegaly
EPO-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)	Erythrocytosis, elevated Hb	EPO is elevated (the tumor is producing it); JAK2 negative; imaging reveals the tumor; usually no leukocytosis or thrombocytosis

6. Traps and High-Yield Pearls

The most common pitfall with PV questions is confusing primary and secondary erythrocytosis. Many students see an elevated hemoglobin or hematocrit and immediately reach for the right diagnosis, but then select the wrong EPO level. The rule is straightforward: in PV, the marrow is autonomously producing red cells independent of EPO, so EPO is suppressed. In secondary causes, EPO is the driver of the erythrocytosis, so it is elevated. If you remember only one lab value for PV, make it low EPO.

A second common trap involves the Budd-Chiari syndrome presentation. When a young patient (often a young woman on oral contraceptives) presents with hepatomegaly, ascites, and abdominal pain from hepatic vein thrombosis, students may focus on the thrombotic event itself and forget to evaluate the underlying cause. PV and other myeloproliferative neoplasms are among the most common causes of Budd-Chiari syndrome, and JAK2 testing should be ordered even when the CBC is not obviously abnormal (because the expanded plasma volume from liver disease can mask the elevated red cell mass).

Another frequently tested concept is the hematocrit target of < 45%. This number is firmly supported by trial data (CYTO-PV) and appears repeatedly. Students sometimes confuse this with a less strict target or forget that it applies to both men and women.

Do not forget the association between extreme thrombocytosis and paradoxical bleeding. When platelet counts exceed approximately 1,000,000-1,500,000/mcL, acquired von Willebrand disease can develop. In this setting, aspirin is potentially harmful because it worsens bleeding. The test to confirm this is ristocetin cofactor activity.

Finally, be aware that aquagenic pruritus can precede the diagnosis by years and may be the presenting complaint. A patient who describes intense itching after a hot shower, without a rash, should prompt a CBC and consideration of PV even if other symptoms are minimal.

The core competency being tested in PV questions is the ability to integrate a clinical presentation (plethora, hyperviscosity symptoms, unusual-site thrombosis, pruritus) with the correct laboratory profile (elevated Hb/Hct, low EPO, positive JAK2), differentiate primary from secondary erythrocytosis, and sequence the management correctly (phlebotomy and aspirin for all, add hydroxyurea for high-risk).

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