Polycythemia Vera workup

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Polycythemia Vera (PV) - Diagnostic Workup

PV is a clonal hematopoietic stem cell myeloproliferative neoplasm (MPN) characterized by panmyelosis - excess proliferation of erythroid, granulocytic, and megakaryocytic lines, driven almost universally by a JAK2 mutation. Below is a structured diagnostic workup.

1. When to Suspect PV

Symptoms and signs that should trigger workup:

Elevated Hgb/Hct found on routine CBC (most common presentation - often incidental)
Aquagenic pruritus (itching after warm water contact - occurs in 30-50% and may precede diagnosis by years)
Erythromelalgia (burning pain + redness of hands/feet)
Facial plethora, conjunctival injection, engorged retinal veins
Splenomegaly (2/3 of patients) > hepatomegaly
Thrombotic events: MI, stroke, DVT/PE, splanchnic vein thrombosis (Budd-Chiari)
Headache, tinnitus, visual disturbances, lightheadedness (hyperviscosity symptoms)
Tophaceous gout (from increased nucleic acid turnover)
Hypertension

In a large international study, arterial thrombosis, venous thrombosis, or major hemorrhage were present before or at diagnosis in 16%, 7%, and 4% of patients, respectively.

2. Initial Laboratory Workup

CBC with differential:

RBC >6-12 × 10¹²/L
Hgb >18.5 g/dL in males, >16.5 g/dL in females (or per WHO 2016: Hgb >16.5 g/dL men, >16.0 g/dL women; Hct >49% men, >48% women)
Leukocytosis: moderate neutrophilia (10-30 × 10⁹/L) in most; immature granulocytes in ~50%; absolute basophilia common
Thrombocytosis: elevated in ~2/3 of patients, sometimes >1000 × 10⁹/L
MCV/MCH/MCHC: normal initially; become low (microcytic/hypochromic) if iron depletion occurs from blood loss or phlebotomy
Reduced ESR (high RBC mass)

Peripheral blood smear:

Large/giant platelets
Rarely nucleated RBCs or teardrop cells (more suggestive of myelofibrosis)

Serum erythropoietin (EPO) level:

Subnormal in PV (key minor diagnostic criterion; also key differentiator from secondary erythrocytosis where EPO is normal-to-elevated)

Additional labs to order:

Test	Finding in PV
Uric acid	Often elevated (hyperuricemia from increased cell turnover)
LDH	May be elevated
B12 / B12-binding capacity	Often elevated
Neutrophil alkaline phosphatase (NAP/LAP score)	Markedly elevated in ~80%
Iron studies (serum iron, ferritin, TIBC)	Iron deficiency common (from increased RBC production + phlebotomy)
Arterial O₂ saturation / pulse oximetry	Normal (rules out hypoxic secondary erythrocytosis)
BMP/CMP	Assess renal function, uric acid, LFTs
Coagulation studies	Generally normal; check if thrombosis/bleeding present

3. Molecular Testing (Key Step)

JAK2 V617F mutation (peripheral blood PCR):

Positive in 95-98% of PV patients - establishes the diagnosis when present
Also positive in ~50% of ET and PMF patients (so does not exclude other MPNs)

If JAK2 V617F is negative:

Test for JAK2 exon 12 mutation - found in most remaining PV patients; associated with younger age and isolated erythrocytosis (without leukocytosis/thrombocytosis as prominently)

If both JAK2 mutations negative:

Reconsider the diagnosis; test for CALR and MPL mutations (these favor ET or PMF, not PV - CALR mutations occur in 0% of PV)
Also consider mutations in LNK (a JAK2 inhibitor) as rare PV driver

4. WHO 2016 Diagnostic Criteria

Diagnosis requires all 3 major criteria OR the first 2 major criteria + the minor criterion:

Major Criteria:

Hgb >16.5 g/dL (men) or >16.0 g/dL (women) OR Hct >49% (men) or >48% (women) OR increased red cell mass >25% above mean normal predicted value
Bone marrow biopsy: hypercellularity for age with trilineage growth (panmyelosis) - prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes
Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor Criterion:

Subnormal serum erythropoietin level

Note: Bone marrow biopsy (major criterion 2) may be omitted in patients with very high erythrocytosis (Hgb >18.5 g/dL in men or >16.5 g/dL in women, or Hct >55.5%/49.5%) if major criterion 3 (JAK2 mutation) and the minor criterion (low EPO) are both present. However, BM biopsy is still recommended to detect initial myelofibrosis (present in up to 20% of PV patients at diagnosis), which predicts more rapid progression.

5. Bone Marrow Biopsy Findings

Markedly hypercellular marrow for age
Panmyelosis: erythroid + granulocytic + megakaryocytic hyperplasia
Megakaryocytes: increased number, clustered, variable size (small and large), with nuclear hyperchromasia
Reticulin fibrosis: may be present at diagnosis (grade 1 in up to 20%); higher grades suggest post-PV myelofibrosis
Fat cells markedly decreased

6. Differential Diagnosis of Erythrocytosis (Rule Out Secondary Causes)

Category	Examples	EPO Level
Spurious (relative)	Dehydration, burns, diuretics (Gaisböck syndrome)	Normal
Congenital	High-affinity Hgb, VHL mutations (Chuvash), PHD2/HIF2A mutations, EPO receptor mutations	Variable
Secondary - hypoxia	COPD, R-to-L shunts, high altitude, sleep apnea, carbon monoxide/tobacco	Elevated
Secondary - hypoxia-independent	Androgens/testosterone, exogenous EPO, post-renal transplant, EPO-secreting tumors (RCC, HCC, hemangioblastoma, uterine leiomyoma)	Elevated
PV (primary clonal)	JAK2 mutation, panmyelosis	Subnormal

Key distinguishing point: In secondary erythrocytosis, only RBCs are elevated (no leukocytosis or thrombocytosis), and EPO is normal to elevated. In PV, EPO is low, and the WBC and platelets are often also elevated.

7. Red Cell Mass Measurement (Selective)

Historically important when Hgb/Hct values are borderline. Measured with ⁵¹Cr-labeled RBCs (dilution principle). Absolute erythrocytosis is confirmed if RBC mass is >25% above mean normal predicted value. Now largely replaced by molecular testing in clinical practice.

8. Workup Algorithm Summary

Elevated Hgb / Hct on CBC
        ↓
Rule out spurious (volume depletion) → Rehydrate + repeat CBC
        ↓
Check EPO level
  ↓                         ↓
Low EPO                   Normal/High EPO → Secondary workup
  ↓                           (O₂ sat, sleep study, abdominal imaging for tumor)
JAK2 V617F testing
  ↓              ↓
Positive        Negative → JAK2 exon 12 testing
  ↓                               ↓ (negative)
Diagnosis = PV            CALR/MPL → Consider ET, PMF, other MPN
  ↓
Bone marrow biopsy
(confirm panmyelosis, grade fibrosis, detect initial MF)

9. Risk Stratification After Diagnosis

Risk	Definition
Low	Age <60 AND no prior thrombosis
High	Age ≥60 OR prior thrombosis

High-risk patients require cytoreductive therapy (hydroxyurea or pegylated IFN-α) in addition to phlebotomy + low-dose aspirin.

Sources:

Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill), Chapter on MPNs
Goldman-Cecil Medicine International Edition, Chapter 152
Washington Manual of Medical Therapeutics (WHO 2016 criteria, Table 21-5)
Henry's Clinical Diagnosis and Management by Laboratory Methods

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