Family Medicine Board Review · Hematology / Oncology · Source: AAFP 2021
Polycythemia Vera: High-Yield Board Summary
WHO diagnostic criteria, the primary-vs-secondary erythropoietin trick, presenting symptom frequencies, treatment triad, pregnancy management, and prognosis — all board-trap annotated.
Definition
- A form of myeloproliferative neoplasm
- Often concurrent stimulation of myeloid and megakaryocytic lineages → increased WBC and platelet production alongside erythrocytosis
- Median age at diagnosis: 64 years
- No treatments have been shown to reduce the risk of transformation to leukemia or myelofibrosis
Board trap: PV is not "just" an RBC disease — the concurrent WBC and platelet elevation is a key feature distinguishing it from isolated secondary erythrocytosis.
Risk Factors
Non-modifiable
Older age, male sex, White race, European descent
Modifiable
Smoking, obesity, hypertension, diabetes mellitus, hyperlipidemia
2016 Revised WHO Diagnostic Criteria
Must meet all 3 major criteria, OR the first 2 major criteria + the minor criterion.
Major Criteria
1) Hemoglobin >165 g/L (16.5 g/dL) in men or >160 g/L (16.0 g/dL) in women, OR hematocrit >49% in men or >48% in women
2) Increased red cell mass (>25% above normal)
3) Bone marrow showing hypercellularity with tri-lineage proliferation and pleomorphic mature megakaryocytes
Minor Criterion
Subnormal erythropoietin level
4) Presence of JAK2 mutation (listed as major criterion #3 in some formats —
JAK2 mutation presence is essentially mandatory in nearly all PV cases)
Board trap: bone marrow biopsy is not always needed — it may be skipped in the presence of a hemoglobin/hematocrit persistently above specific higher thresholds (>185 g/L [18.5 g/dL] men or >165 g/L [16.5 g/dL] women, hematocrit >55.5% men or >49.5% women) plus the other qualifying criteria — otherwise it's typically pursued to confirm diagnosis and help stratify risk.
Primary vs. Secondary Erythrocytosis
Primary Erythrocytosis
2,3-Biphosphoglycerate deficiency; high oxygen-affinity hemoglobin variants; Lindau-Von Hippel disease; other myeloproliferative neoplasms (essential thrombocytosis, primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome); familial/congenital polycythemia (
EPOR mutation)
Secondary Erythrocytosis
Cardiopulmonary disease (chronic hypoxia, left-to-right shunt); erythropoietin-producing tumors (hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine leiomyoma); high-altitude habitat; iatrogenic (testosterone, anabolic steroids, erythropoietin, blood doping); renal disease (renal artery stenosis, hydronephrosis, transplant); sleep apnea, obesity-hypoventilation syndrome, Pickwickian syndrome; smoking, chronic carbon monoxide poisoning
Pearl — the single most important discriminator: in secondary causes, erythropoietin will be HIGH; in PV, erythropoietin will be LOW. Memorize this before anything else in this section.
Clinical Features — Presenting Symptom Frequencies
Pruritus on contact with water36–68%
Concentration problems61%
*Erythromelalgia = excessive dilation of superficial blood vessels with hyperemia, warmth, and burning pain.
Board trap: fatigue (91%) — not pruritus or thrombosis — is actually the most common presenting symptom. Aquagenic pruritus (water-triggered itching) is the classic "textbook" symptom, but it's less common than fatigue, insomnia, and concentration problems.
Evaluation of Erythrocytosis — Algorithm
Start: Elevated hemoglobin (>165 g/L men / >160 g/L women) or hematocrit (>49% men / >48% women)
↓
Order peripheral blood testing for JAK2 V617F and serum erythropoietin level
↓
JAK2 V617F (+), EPO low
→ PV probable; bone marrow biopsy encouraged
JAK2 V617F (+), EPO normal/high
→ Both tests should be repeated; bone marrow exam necessary if results remain unchanged
JAK2 V617F (−), EPO low
→ PV possible; consider JAK2 exon 12 mutation testing and bone marrow examination
JAK2 V617F (−), EPO normal/high
→ PV unlikely; consider secondary polycythemia
Exam pearl: a negative JAK2 V617F does not fully exclude PV — a rarer JAK2 exon 12 mutation can still be responsible, particularly when erythropoietin is low. Don't stop the workup after one negative JAK2 test if EPO is low.
Treatment
Phlebotomy
All patients should receive phlebotomy with a goal
hematocrit <45%.
Each unit phlebotomized (500 mL) drops hematocrit by
~3% in an average-sized adult.
Thromboprophylaxis
All patients should receive daily
low-dose aspirin (40–100 mg) absent contraindications.
Reduces vasomotor symptoms (headache, erythromelalgia, pruritus) alongside phlebotomy.
Avoid aspirin if platelets >1,000 × 10⁹/L (risk of bleeding from acquired von Willebrand disease).
Cytoreductive Therapy
Hydroxyurea is first-line.
In patients
<40 years old, use with caution due to
leukemogenic concerns with long-term use.
Board trap: know the exact numbers — hematocrit goal <45%, each unit drops Hct by ~3%, aspirin dose 40–100 mg, avoid aspirin if platelets >1,000 × 10⁹/L. These precise figures are prime single-fact test material.
Risk-Based Survival & Management Chart
| Risk Factor | Points |
|---|
| Age ≥67 years at diagnosis | 5 |
| Age 57–66 years at diagnosis | 2 |
| Leukocyte count ≥15 × 10⁹/L | 1 |
| History of venous thromboembolism | 1 |
| Risk Group (Points) | Median Survival (years) |
|---|
| Low (0) | 28 |
| Intermediate (1–2) | 19 |
| High (3+) | 11 |
- Low-risk: phlebotomy to Hct <45% + low-dose aspirin (40–100 mg)
- High-risk (history of thrombosis or age ≥60): add hydroxyurea; consider twice-daily aspirin if persistent symptoms/cardiovascular risk factors/leukocytosis; add anticoagulation for venous thrombosis; consider pegylated interferon-alfa (younger patients) or busulfan/ruxolitinib (older patients with symptomatic splenomegaly) for resistance/intolerance to hydroxyurea
Management of Pruritus
First-line therapy: aspirin, antihistamines, and paroxetine (Paxil).
Exam pearl: paroxetine (an SSRI) as a specific pruritus treatment in PV is a somewhat unexpected but testable fact — don't overlook it in favor of antihistamines alone.
Treatment in Pregnancy
- Hydroxyurea (potentially teratogenic) should be stopped in men and women at least 3 months before conception
- All pregnant patients with PV should receive low-dose aspirin
- Avoid iron supplementation in the absence of actual iron depletion
- Maintain gestational age-appropriate hematocrit levels
- Treat with enoxaparin (Lovenox) for 6 weeks postpartum if no contraindications
- Interferon-alfa is the drug of choice for cytoreductive therapy if needed during pregnancy
Board trap: the hydroxyurea preconception stop rule applies to both partners, mirroring the same rule tested in sickle cell disease — and interferon-alfa, not hydroxyurea, is the pregnancy-safe cytoreductive choice.
Prognosis
- Poor prognostic features: age >60 years, history of thrombosis, leukocytosis, high JAK2 burden, abnormal karyotype, established cardiovascular risk factors (smoking, hypertension, diabetes, obesity, hyperlipidemia)
- Without treatment: death typically occurs within 2 years, mostly from thrombotic events
- With standard-of-care treatment (aspirin + hydroxyurea): median survival 13.5 years
Exam pearl: the dominant cause of death in untreated PV is thrombosis, not bleeding or leukemic transformation — this reinforces why phlebotomy and aspirin (thrombosis prevention) are the treatment backbone.