JAK2-mutated myeloproliferative neoplasm with erythrocytosis and increased risk of thrombosis — managed with phlebotomy and cytoreduction.
Also known as: PV, polycythemia vera, polycythaemia rubra vera, primary erythrocytosis
Overview
Chronic myeloproliferative neoplasm characterized by clonal proliferation of erythroid (and often myeloid and megakaryocytic) lineages, leading to absolute erythrocytosis. Driven almost universally by an activating JAK2 mutation — V617F (~95%) or exon 12 mutations (~3-5%). Diagnosis per WHO 2022 requires elevated hemoglobin/hematocrit + JAK2 mutation + characteristic marrow findings.
Epidemiology
Annual US incidence ~1-2 per 100,000. Median age at diagnosis ~60-65 years (rare under 40). Slight male predominance. Median survival historically ~15-20 years; modern outcomes improved with cytoreductive therapy and aspirin.
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JAK2 mutation (V617F or exon 12) — drives nearly all cases; not heritable but acquired in hematopoietic stem cell
Age >60
Family history (modest increased risk in first-degree relatives)
No clear environmental cause
Pathophysiology
Activating JAK2 mutation produces constitutive JAK-STAT signaling that bypasses normal erythropoietin (EPO) regulation, driving autonomous erythropoiesis. Megakaryocyte and granulocyte lineages are often also expanded. Increased red cell mass elevates blood viscosity, promoting thrombosis (arterial and venous). Disease can transform to post-PV myelofibrosis (~15% at 15 years) or acute myeloid leukemia (~5-10% at 20 years).
Clinical presentation
Symptoms
Often asymptomatic — diagnosed on incidental erythrocytosis
Aquagenic pruritus — itching after warm bath/shower (highly characteristic)
Plethora (ruddy facial flushing), facial redness
Erythromelalgia — burning pain and redness of hands and feet (improves with aspirin)
Headache, dizziness, blurred vision, tinnitus, paresthesias from hyperviscosity
Fatigue, night sweats, weight loss, abdominal fullness from splenomegaly
Elderly patient with ruddy complexion, aquagenic pruritus, splenomegaly, elevated hemoglobin/hematocrit, and JAK2 V617F mutation. Budd-Chiari syndrome in a young woman should prompt screening for myeloproliferative neoplasm even if blood counts are normal.
Differential diagnosis
Secondary erythrocytosis (hypoxia-driven) — Chronic lung disease, OSA, smoking, cyanotic heart disease, high altitude — EPO elevated, JAK2 negative
Exogenous androgen / EPO abuse — Athletic doping, supraphysiologic testosterone; history and toxicology
Relative (apparent) erythrocytosis — Plasma volume contraction from dehydration, diuretics, smoking; red cell mass normal
Chuvash polycythemia and other congenital erythrocytoses — VHL, EPOR, HIF mutations; family history; childhood onset
Other MPNs (essential thrombocythemia, primary myelofibrosis) — Distinct presentations; can share JAK2 V617F
Diagnostic workup
Diagnostic criteria
WHO 2022: Major criteria — (1) Hgb >16.5 men / >16.0 women OR Hct >49% men / >48% women OR red cell mass >25% above mean predicted; (2) Bone marrow showing trilineage panmyelosis with pleomorphic megakaryocytes; (3) JAK2 V617F or exon 12 mutation. Minor criterion — subnormal serum EPO. Diagnosis: all 3 major OR first 2 major + minor.
Labs
CBC — elevated hemoglobin (>16.5 in men, >16.0 in women per WHO 2022) or hematocrit (>49% men, >48% women); often elevated WBC and platelets
JAK2 V617F mutation testing (sensitive PCR or NGS) — positive in ~95%; if negative, test JAK2 exon 12 mutations
Serum erythropoietin (EPO) — LOW or subnormal in PV (suppressed by high red cell mass); HIGH in secondary causes
Iron studies (often iron deficiency due to consumption by hyperactive erythropoiesis)
LDH, uric acid
Bone marrow biopsy — hypercellular for age with panmyelosis (erythroid, granulocytic, megakaryocytic hyperplasia); pleomorphic megakaryocytes
Cytogenetics and additional NGS panel (other myeloid mutations) — prognostic information
Oxygen saturation, sleep study if hypoxia suspected (rule out secondary)
Renal/hepatic imaging if secondary EPO source suspected
Carboxyhemoglobin in heavy smokers
Red cell mass and plasma volume studies (rarely needed today; helpful when diagnosis ambiguous)
Imaging
Abdominal ultrasound — splenomegaly assessment; rule out hepatic/portal vein thrombosis
Doppler imaging if Budd-Chiari or thrombosis suspected
Diagnostic algorithm
flowchart TD
A[Elevated Hgb/Hct<br/>Men >16.5 / Women >16.0] --> B[Check JAK2 V617F<br/>+ serum EPO]
B --> C{JAK2 V617F<br/>or exon 12?}
C -->|Positive + low EPO| D[Polycythemia vera]
C -->|Negative + low EPO| E[Investigate exon 12;<br/>consider rare congenital]
C -->|Negative + high EPO| F[Secondary erythrocytosis<br/>Hypoxia, smoking, OSA,<br/>EPO-secreting tumor,<br/>exogenous androgen/EPO]
D --> G[Risk stratify]
G --> H{High risk?<br/>Age >60 or prior thrombosis}
H -->|Yes| I[Phlebotomy + ASA +<br/>hydroxyurea<br/>OR ropeginterferon]
H -->|No| J[Phlebotomy + ASA<br/>Target Hct <45%]
I --> K[Monitor for myelofibrosis<br/>or AML transformation]
J --> K
Polycythemia vera diagnostic and risk-stratified treatment algorithm.
Treatment
First-line
Phlebotomy — first-line for all patients; target hematocrit <45% (CYTO-PV trial); typically 250-500 mL removed weekly initially, then as needed
Low-dose aspirin 81 mg daily — reduces thrombotic events in all patients without contraindications (ECLAP trial); avoid in active bleeding or extreme thrombocytosis (>1000-1500K, acquired vWD risk)
Risk stratification: HIGH RISK = age >60 OR prior thrombosis → cytoreduction in addition to phlebotomy/aspirin; LOW RISK = age ≤60 AND no prior thrombosis → phlebotomy + aspirin alone
Hydroxyurea — first-line cytoreductive agent for high-risk PV; titrate to control counts and spleen
Pegylated interferon alfa (ropeginterferon alfa-2b — FDA approved 2021; pegasys also used) — preferred in younger patients, pregnancy, and those preferring molecular response; can induce molecular remission with deep JAK2 reduction (PROUD-PV/CONTINUATION-PV trials)
Management of pruritus: antihistamines, SSRIs (paroxetine), phototherapy, JAK2 inhibitor if refractory
Second-line / adjunct
Ruxolitinib (JAK1/2 inhibitor) — for hydroxyurea-resistant or intolerant disease (RESPONSE trial); also effective for refractory pruritus, splenomegaly
Busulfan (alkylator) — older agent, less commonly used due to leukemogenic risk
Anagrelide — primarily for thrombocytosis if not controlled with first-line agents
Allogeneic HSCT — reserved for transformation to myelofibrosis or AML in younger fit patients
Pregnancy: aspirin throughout, phlebotomy to maintain hematocrit <45% (lower target in pregnancy), interferon if cytoreduction needed (avoid hydroxyurea — teratogenic), LMWH postpartum
JAK2 V617F mutation is the single most useful test for PV diagnosis — positive in ~95%; exon 12 mutations cover most of the remainder.
Suppressed (subnormal) erythropoietin distinguishes PV from secondary causes — secondary erythrocytosis has elevated EPO.
Aquagenic pruritus (itching after warm bath/shower) is highly characteristic of PV and frequently the presenting complaint.
Budd-Chiari syndrome, portal vein thrombosis, or other unusual-site thrombosis in a young patient should prompt JAK2 testing even if CBC normal.
Target hematocrit <45% (men and women) — CYTO-PV trial showed lower cardiovascular events at this threshold compared to <50%.
Iron deficiency from repeated phlebotomy is therapeutic — do NOT supplement iron in PV patients.
Erythromelalgia (burning, red distal extremities) is highly responsive to low-dose aspirin.
Hydroxyurea is first-line cytoreductive therapy; ropeginterferon alfa-2b is preferred for younger patients, pregnancy, and those seeking molecular response.
Transformation to myelofibrosis (post-PV MF) or AML is the major cause of disease-related mortality; cytoreductive agents may modestly increase AML risk (especially alkylators like busulfan and chlorambucil) — favor non-leukemogenic agents (hydroxyurea, interferon).
References
WHO 5th edition 2022 — WHO Classification of Haematolymphoid Tumours, 5th edition (2022)
NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms
CYTO-PV — Cardiovascular Events and Intensity of Treatment in Polycythemia Vera (Marchioli et al., NEJM 2013)
ECLAP — Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera (Landolfi et al., NEJM 2004)
PROUD-PV / RESPONSE — Ropeginterferon alfa-2b in polycythemia vera (Gisslinger et al., Lancet Haematol 2020); Ruxolitinib vs Standard Therapy for PV (Vannucchi et al., NEJM 2015)
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