Polycythemia Rubra vera

1. Overview & Pathophysiology

Polycythemia Vera (PV) is a chronic, BCR-ABL–negative myeloproliferative neoplasm (MPN) in which a clonal hematopoietic stem cell — driven by an activating JAK2 mutation — overproduces red cells (and often platelets and granulocytes) independent of erythropoietin (EPO). The result is a rising RBC mass → hyperviscosity → a strong tendency to thrombosis. The classic patient is an older adult with a ruddy face, itching after a hot shower, splenomegaly, and an unexpectedly high hemoglobin with a low serum EPO.

• Labs at a glance: ↑ Hb/Hct, often ↑ WBC and platelets (panmyelosis), ↓ serum EPO, positive JAK2.
• Treatment at a glance: phlebotomy + low-dose aspirin for everyone; add hydroxyurea if high risk.
• Long-term risks: thrombosis (leading cause of death), progression to myelofibrosis or AML.

Where PV fits

PV belongs to the BCR-ABL–negative MPNs, together with essential thrombocythemia (ET) and primary myelofibrosis (PMF) — all three share constitutive JAK2 signaling. "Polycythemia" simply means too many red cells; the diagnostic task is to separate true clonal PV from secondary (EPO-driven) and relative (volume-contraction) causes. Refer to the chronic myeloproliferative disorders comparison for the mutations and features that separate CML, ET, PV, and PMF.

Epidemiology

• Age: typically > 60 years (median ~60); rare under 40.
• Sex: slight male predominance.
• Incidence: ~1–2 per 100,000 per year; mostly sporadic.

Pathophysiology — JAK2-driven, EPO-independent erythropoiesis

JAK2 is a non-receptor tyrosine kinase that normally relays the EPO signal into the cell. The acquired JAK2 V617F mutation makes the kinase constitutively active, so STAT5 fires without EPO:

• Normal: EPO binds its receptor → JAK2 phosphorylates STAT5 → controlled RBC production.
• PV: mutant JAK2 signals continuously → uncontrolled erythropoiesis (± megakaryocyte and granulocyte expansion).
• Feedback: the kidney senses the high Hct and suppresses EPO → serum EPO is low — the single best discriminator from secondary polycythemia.

Downstream, the rising RBC mass produces hyperviscosity (headache, dizziness, visual blurring, microvascular ischemia) and thrombosis (viscous blood plus abnormal, sticky platelets); extramedullary hematopoiesis and pooling cause splenomegaly; and increased basophils/mast cells release histamine, driving pruritus and peptic ulcer disease.

2. Clinical Presentation & Diagnosis

Symptoms stem from hyperviscosity, thrombosis, and histamine release; many patients are found incidentally on a routine CBC.

• Constitutional: fatigue, weakness, weight loss, night sweats.
• Hyperviscosity: headache, dizziness, tinnitus, blurred vision, "fullness" in the head.
• Skin (high-yield):
  • Plethora — ruddy/red face, palms, and mucous membranes.
  • Aquagenic pruritus — itching after a hot shower or bath.
  • Erythromelalgia — burning pain + redness of fingers/toes, relieved by aspirin.
• Thrombosis (most dangerous): arterial (stroke, MI, TIA, digital ischemia) and venous (DVT, PE, and classically hepatic vein thrombosis).
• Abdomen: splenomegaly (~75%), hepatomegaly (~30%), peptic ulcer disease (↑ histamine).
• Bleeding paradox: despite high counts, platelet dysfunction → epistaxis and easy bruising.

Suspect PV in any patient with unexplained Budd–Chiari syndrome (hepatic venous outflow obstruction) or other splanchnic-vein thrombosis. See the Budd–Chiari syndrome overview for the etiologies, presentation, and the role of JAK2 testing.

Diagnostic pathway (CBC → EPO/JAK2 → marrow)

• CBC + smear: ↑ Hb/Hct, often ↑ WBC and platelets (panmyelosis); normochromic normocytic RBCs (microcytic if iron-deficient from bleeding/phlebotomy).
• Serum EPO: low in PV — the best discriminator from secondary polycythemia (normal/high EPO).
• JAK2 mutation: V617F (~95%); if negative, test exon 12 (~3%).
• Bone marrow biopsy: hypercellular, panmyelosis, clustered atypical megakaryocytes, absent iron stores.
• Supporting clues: ↑ uric acid (gout), ↑ LDH, ↑ B12, ↑ leukocyte alkaline phosphatase (LAP) — high LAP helps separate PV from CML (low LAP).

Differential diagnosis

The core task is separating clonal PV (low EPO, JAK2⁺) from secondary (high EPO) and relative (normal RBC mass) polycythemia. See the primary vs secondary polycythemia differential for the full EPO-based work-up.

Among the other MPNs: ET = isolated ↑↑ platelets with normal Hct; PMF = cytopenias, teardrop cells, "dry tap," massive splenomegaly; CML = ↑↑ WBC with left shift, Philadelphia chromosome (BCR-ABL), and low LAP. The chronic myeloproliferative disorders comparison lays out the defining mutation for each.

3. Management

Treatment goals: reduce thrombosis risk, control symptoms, and prevent progression. Risk-stratify first, because the universal therapy is the same for everyone and only cytoreduction is added for high-risk disease:

• Low risk: age < 60 AND no prior thrombosis.
• High risk: age ≥ 60 OR prior thrombosis.

Universal therapy — all patients

1. Step 1: Therapeutic phlebotomy — remove 250–500 mL of blood as needed to keep Hct < 45% (both sexes). This is the single most important intervention.
2. Step 2: Low-dose aspirin 81 mg PO daily — reduces arterial thrombosis and relieves erythromelalgia. Hold if active bleeding or extreme thrombocytosis (> 1,500 × 10⁹/L → acquired von Willebrand disease).
3. Step 3: Aggressive cardiovascular risk control — smoking cessation; treat hypertension, diabetes, and hyperlipidemia.

Add for high-risk patients — cytoreduction

• Hydroxyurea — first-line cytoreductive agent (suppresses marrow); watch for cytopenias and skin ulcers.
• Interferon-α / pegylated IFN — preferred in pregnancy and younger patients.
• Ruxolitinib — a JAK1/2 inhibitor for hydroxyurea-resistant or -intolerant disease; also controls pruritus and splenomegaly.
• Supportive: allopurinol for hyperuricemia/gout; antihistamines or SSRIs for refractory pruritus.

4. Complications &amp; Prognosis

• Thrombosis — arterial (stroke, MI) and venous (DVT, PE, Budd–Chiari). Leading cause of death.
• Hemorrhage — GI bleeding, epistaxis (platelet dysfunction; acquired von Willebrand disease at very high platelet counts).
• Hyperuricemia → gout and uric acid stones (high cell turnover).
• Peptic ulcer disease — from increased histamine release.
• Transformation — post-PV myelofibrosis ("spent phase," ~10–20% over years) — marrow fibrosis, falling Hb, worsening splenomegaly, teardrop cells (dacrocytes) on smear.
• Transformation to AML (~5–10%) — higher with alkylating-agent therapy.

Two smear/marrow clues mark progression to the spent phase: teardrop cells appear in the blood and the marrow shows reticulin fibrosis with a "dry tap." See the primary myelofibrosis overview for the pathogenesis and how post-PV fibrosis behaves.

Prognosis: with treatment, median survival exceeds 15–20 years. Untreated PV has a median survival of only ~18 months — driven largely by thrombotic events.

5. High-Yield Exam Pearls

The most testable points in one place:

• Mechanism: clonal JAK2 V617F → EPO-independent erythropoiesis → low serum EPO.
• Best discriminator: low EPO + JAK2⁺ = PV; high EPO = secondary; normal RBC mass with ↓ plasma volume = relative.
• Classic clues: aquagenic pruritus, facial plethora, erythromelalgia (aspirin-relieved), splenomegaly.
• Budd–Chiari in an otherwise unexplained patient = PV until proven otherwise.
• Treatment: phlebotomy to Hct < 45% + low-dose aspirin 81 mg for everyone; add hydroxyurea if age ≥ 60 or prior thrombosis.
• Phlebotomy-induced iron deficiency is intended — do NOT supplement iron.
• Thrombosis is the leading cause of death; long-term, watch for post-PV myelofibrosis and AML. Avoid alkylating agents.

For a single-screen revision sheet, see the polycythemia vera summary covering manifestations, examination, labs, complications, and treatment.