Polycythemia Rubra vera

Summary

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm in which a clonal hematopoietic stem cell produces too many red blood cells (and often platelets and granulocytes) independent of erythropoietin (EPO). The driver is an activating mutation in JAK2 (V617F in ~95% of cases).

• Hallmark: ↑↑ RBC mass → hyperviscosity → thrombosis.
• Classic patient: older adult with ruddy face, aquagenic pruritus (itching after a hot shower), splenomegaly, and an unexpectedly high hemoglobin.
• Labs: ↑ Hb/Hct, often ↑ WBC and platelets, ↓ serum EPO, positive JAK2.
• Treatment: phlebotomy + low-dose aspirin for everyone; add hydroxyurea if high risk.
• Long-term risks: thrombosis (most common cause of death), progression to myelofibrosis or AML.

Definition & Classification

Polycythemia Vera is one of the BCR-ABL–negative myeloproliferative neoplasms (MPNs), along with essential thrombocythemia (ET) and primary myelofibrosis (PMF). All three share the JAK2 pathway.

"Polycythemia" simply means too many red cells. It is useful to classify it before discussing PV specifically:

Epidemiology

• Age: Typically > 60 years (median ~60). Rare under 40.
• Sex: Slight male predominance.
• Incidence: ~1–2 per 100,000 per year.
• Family history: Mostly sporadic, but small familial clusters exist.

Pathophysiology

The central event in PV is an acquired JAK2 V617F mutation in a hematopoietic stem cell. JAK2 is a non-receptor tyrosine kinase that normally transmits the EPO signal into the cell.

• Normal: EPO binds its receptor → JAK2 phosphorylates STAT5 → controlled RBC production.
• PV: Mutant JAK2 is constitutively active → STAT5 fires without EPO → uncontrolled erythropoiesis (and often megakaryocyte and granulocyte expansion).
• Negative feedback: The kidney senses the high Hct and suppresses EPO → serum EPO is low (key exam clue).

Downstream consequences:

1. Hyperviscosity from ↑ RBC mass → sluggish flow, microvascular ischemia, headache, dizziness, visual blurring.
2. Thrombosis (arterial > venous) from viscous blood plus abnormal, sticky platelets.
3. Splenomegaly from extramedullary hematopoiesis and pooling.
4. Histamine release from increased basophils/mast cells → pruritus and peptic ulcers.

Clinical Features

Most symptoms come from hyperviscosity, thrombosis, and histamine release. Many patients are diagnosed incidentally on a routine CBC.

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

Diagnosis

Diagnosis follows the 2016 WHO criteria: 3 major criteria, OR the first 2 major + the minor criterion.

Initial workup

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

Differential Diagnosis

The key job is to separate PV (low EPO, JAK2+) from secondary (high EPO) and relative (normal RBC mass) polycythemia.

Also distinguish PV from other MPNs:

• Essential thrombocythemia (ET): isolated ↑↑ platelets, normal Hct.
• Primary myelofibrosis (PMF): cytopenias (anemia), teardrop cells, "dry tap," massive splenomegaly.
• CML: ↑↑ WBC with left shift, Philadelphia chromosome (BCR-ABL), low LAP score (PV has high LAP).

Management

Treatment goals: reduce thrombosis risk, control symptoms, and prevent progression. Risk-stratify first:

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

Treatment for everyone

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. Low-dose aspirin (81 mg/day) — reduces arterial thrombosis and relieves erythromelalgia. Avoid if active bleeding or severe thrombocytosis (> 1,500 × 10⁹/L → risk of acquired vWD).
3. Control cardiovascular risks — stop smoking, treat hypertension, diabetes, hyperlipidemia.

Add for high-risk patients — cytoreductive therapy

• Hydroxyurea — first-line cytoreductive agent (suppresses marrow). Watch for cytopenias and skin ulcers.
• Interferon-α (or pegylated IFN) — preferred in pregnancy and younger patients.
• Ruxolitinib — a JAK1/2 inhibitor, used in hydroxyurea-resistant/intolerant disease. Also helps pruritus and splenomegaly.
• Allopurinol — if hyperuricemia or gout.
• Antihistamines / SSRIs — for refractory pruritus.

Complications & Prognosis

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

Median survival with treatment: > 15–20 years. Untreated PV has a median survival of only ~18 months.

Teardrop cells (dacrocytes) on smear and a "dry tap" bone marrow mark progression to myelofibrosis.

Mnemonics