Polycythemia Vera (PV)

Definition & Classification

• Incidence: 1-3 per 100,000/year in the US, increasing with age to >10/100,000 in older adults
• Familial transmission is uncommon; sporadic cases show female predominance under age 50
• Harrison's Principles of Internal Medicine, 22E, p. 862
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 14

Pathogenesis

The JAK2 Mutation

• JAK2 V617F (valine → phenylalanine at codon 617): found in >95-97% of PV patients. It sits in the autoinhibitory pseudokinase domain, causing constitutive, ligand-independent kinase activation.
• JAK2 normally serves as the cognate kinase for the erythropoietin receptor (EPOR) and thrombopoietin receptor. Constitutive activation bypasses the need for erythropoietin, explaining:
  • Erythropoietin hypersensitivity and EPO-independent erythroid colony formation
  • Increased Bcl-X(L) expression and apoptosis resistance in erythroid progenitors
  • Reduced serum erythropoietin (a key diagnostic clue - opposite of secondary polycythemia)
• Exon 12 JAK2 mutations account for most remaining JAK2 V617F-negative cases - these tend to present with isolated erythrocytosis
• Loss of heterozygosity at 9p (uniparental disomy → JAK2 V617F homozygosity) occurs in ~60% of PV patients and is associated with higher WBC counts, more significant splenomegaly, pruritus, and faster progression to spent phase
• Rare additional driver mutations: LNK (a JAK2 inhibitor), CALR, occasional ASXL1, TET2, DNMT3A (clonal evolution markers)

• Harrison's, p. 862-863
• Robbins & Kumar Basic Pathology, p. 406-407

Morphology

• Robbins, Cotran & Kumar, p. 14-15
• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 14

Clinical Features

Symptoms from Erythrocytosis / Hyperviscosity

• Neurological: Headache, vertigo, tinnitus, visual disturbances, transient ischemic attacks (TIAs), paresthesias
• Systemic hypertension
• Facial plethora, ruddy cyanosis, conjunctival injection, retinal vein engorgement

Thrombosis (most significant complication - ~30% of patients)

• Cerebral, cardiac, mesenteric vessels most common
• Hepatic vein thrombosis (Budd-Chiari syndrome) - especially in young women; PV should be suspected in any woman who develops this
• Portal vein thrombosis more common in males
• Arterial thrombosis in 16%, venous thrombosis in 7% at or before diagnosis

Hemorrhage (5-10% life-threatening)

• Epistaxis, gum bleeding, GI hemorrhage (often peptic ulcer)
• Paradoxically caused by platelet dysfunction and acquired von Willebrand disease (when platelet count >900,000/µL, large platelet mass absorbs high-MW vWF multimers)

Pruritus

• Aquagenic pruritus (itching after warm bath/shower) - affects 30-50% of patients; may precede PV diagnosis by years
• Due to histamine release from basophils

Erythromelalgia

• Erythema, burning, and pain in distal extremities (hands/feet) from platelet-mediated microvascular occlusion

Gout / Hyperuricemia

• Symptomatic gout in 5-10% from high cell turnover and nucleic acid catabolism; uric acid stones

Splenomegaly

• Present in two-thirds of patients at diagnosis
• Harrison's, p. 862-863; Goldman-Cecil Medicine, p. 1750-1751; Henry's, p. 14

Laboratory Findings

WHO Diagnostic Criteria (2016/2022)

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
2. Bone marrow biopsy showing hypercellularity with panmyelosis (trilineage growth: erythroid, granulocytic, megakaryocytic proliferation) with pleomorphic mature megakaryocytes
3. Presence of JAK2 V617F or JAK2 exon 12 mutation

• Subnormal serum EPO level

• Goldman-Cecil Medicine, p. 1750; Henry's, p. 14

Differential Diagnosis

• Relative (spurious) polycythemia (Gaisböck's syndrome): plasma volume contraction from dehydration, diuretics, tobacco, androgens - no absolute increase in red cell mass
• Secondary absolute polycythemia: EPO levels are HIGH (opposite of PV):
  • Hypoxia: COPD, high altitude, sleep apnea, high-affinity hemoglobin, carbon monoxide
  • Ectopic EPO: hypernephroma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine fibroids
• Other MPNs: ET, PMF (can have same JAK2 V617F but different phenotype)
• CML (BCR-ABL1 positive - must be excluded)

Disease Course & Complications

1. Proliferative phase: Controlled erythrocytosis, manageable with phlebotomy
2. Stable phase: Iron deficiency limits red cell expansion; phlebotomy every 3 months
3. Spent (post-PV MF) phase: Marrow fibrosis, cytopenias, massive splenomegaly, extramedullary hematopoiesis - occurs in a subset

• Post-PV myelofibrosis: variable frequency, higher with JAK2 V617F homozygosity
• AML transformation: ~1-2% without myelosuppressive therapy; higher (up to 10-15%) with alkylating agents or ³²P. Alkylating agents and radioactive phosphorus are leukemogenic and should be avoided

• Robbins, Cotran & Kumar, p. 15; Harrison's, p. 864

Management

1. Phlebotomy (first-line for all patients)

• Goal: Hematocrit <45% in men, <42% in women (hematocrit ≥45% significantly increases thrombosis risk)
• Induces iron deficiency that limits re-expansion of red cell mass
• Once iron-deficient, phlebotomy usually needed only every 3 months

2. Low-dose Aspirin

• Reduces risk of thrombotic complications
• Caution: potentially harmful if red cell mass not controlled, and increases bleeding in patients >60 years

3. Cytoreductive Therapy (for high-risk patients)

• Low risk: Age <60, no thrombosis history
• High risk: Age ≥60 OR prior thrombosis

4. Symptom Management

• Pruritus: Antihistamines, antidepressants (doxepin), ruxolitinib, pegIFN-α, hydroxyurea, PUVA
• Hyperuricemia/gout: Allopurinol (especially when starting chemotherapy)
• Erythromelalgia: Low-dose aspirin (usually very effective); platelet count reduction if needed
• Thrombosis: Anticoagulation; newer oral anticoagulants preferred over VKA (no monitoring required)
• Splenomegaly: Ruxolitinib or pegIFN-α; splenectomy rarely needed now with effective JAK2 inhibitors

5. Newer/Emerging Agents

• Ropeginterferon alfa-2b (Besremi): long-acting pegylated interferon; approved specifically for PV. A 2026 systematic review and meta-analysis confirms significant hematologic and molecular response rates.
• A 2024 meta-analysis confirmed ruxolitinib superior to best available therapy for hematocrit control, symptom burden, and spleen volume reduction in hydroxyurea-intolerant/resistant PV.

Key Points Summary