Myeloproliferative Neoplasms (PV, ET, PMF)
A high-yield USMLE lesson on the BCR-ABL1–negative myeloproliferative neoplasms (PV, ET, PMF): JAK2/CALR/MPL driver biology, classic smear and lab buzzwords, EPO-based erythrocytosis triage, and next-best-step diagnosis and management. Structured patho → presentation → diagnosis → treatment with vignettes and a comparison table.</parameter> <parameter name="imageSuggestions">[{"commonsFile":"Polycythemia vera, blood smear.jpg","alt":"Peripheral blood smear from a patient with polycythemia vera showing increased, crowded red blood cells with mild anisopoikilocytosis","caption":"Polycythemia vera: a crowded peripheral smear reflecting increased red cell mass (Wright-Giemsa).","afterBlock":4},{"commonsFile":"Tear Drop Cells in PBS Microscopy.jpg","alt":"Peripheral blood smear showing teardrop-shaped red blood cells (dacrocytes) with elongated tapered ends","caption":"Teardrop cells (dacrocytes): the classic smear finding of primary myelofibrosis and marrow infiltration.","afterBlock":5}]
Overview & Pathophysiology
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders with unregulated proliferation of one or more mature (differentiated) myeloid lineages — in contrast to the maturation block of AML. The classic Philadelphia-chromosome (BCR-ABL1)–negative trio is polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
All three are driven by constitutive JAK2/STAT signaling. Nearly all PV carries JAK2 V617F; ~50–60% of ET and PMF do, with CALR and MPL mutations accounting for most of the rest. Because the driver keeps JAK-STAT "always on," proliferation becomes growth-factor–independent — e.g., erythropoiesis without EPO in PV.
Overlap is the rule: all three can cause splenomegaly, thrombosis, aquagenic pruritus, and gout (high cell turnover → hyperuricemia), and any can evolve to a fibrotic "spent phase" or transform to AML. Distinguish this group from CML, which is BCR-ABL1 positive.
- JAK2 V617F: ~95% of PV; ~50–60% of ET & PMF. Exon 12 mutations cover most V617F-negative PV — so JAK2 is mutated in ~98% of PV overall.
- CALR: ~20–30% of ET/PMF (always JAK2/MPL negative — mutually exclusive); MPL: ~3–5%. "Triple-negative" = none of the three.
- PV hallmark: LOW serum EPO + increased RBC mass — separates true PV from secondary/relative polycythemia.
- Leukocyte alkaline phosphatase (LAP/NAP) is HIGH in MPNs (esp. PV) — the opposite of LOW LAP in CML.
- Thrombosis is the leading cause of morbidity/death in PV and ET, including unusual sites (Budd-Chiari, portal/splanchnic, cerebral vein). Young patient with splanchnic thrombosis → screen JAK2.
- Platelets >1,000–1,500 ×10⁹/L → acquired von Willebrand disease (adsorption of large vWF multimers) → paradoxical bleeding; use caution with aspirin.
- Prognosis: ET best, PMF worst; PMF carries the highest AML transformation risk.
PV vs ET vs PMF — Labs, Smear, Markers, Management
| Feature | Polycythemia Vera (PV) | Essential Thrombocythemia (ET) | Primary Myelofibrosis (PMF) |
|---|---|---|---|
| Dominant lineage | RBCs (trilineage panmyelosis) | Platelets | Marrow fibrosis + extramedullary hematopoiesis |
| Driver mutation | JAK2 ~95% (V617F/exon 12) | JAK2 ~55%, CALR ~25%, MPL ~3% | JAK2 ~55%, CALR ~25%, MPL ~5% |
| Peripheral smear | ↑ RBCs (± ↑ WBC/platelets) | Numerous large/giant platelets | Teardrop cells (dacrocytes) + leukoerythroblastic |
| Serum EPO | Low | Normal | Normal/variable |
| Marrow | Hypercellular panmyelosis | Large hyperlobulated ("staghorn") megakaryocytes | Dry tap; reticulin/collagen fibrosis, clustered atypical megakaryocytes |
| Classic clues | Aquagenic pruritus, plethora, erythromelalgia | Often incidental; vasomotor sx, bleeding if plt very high | Massive splenomegaly, night sweats, cytopenias |
| First-line Rx | Phlebotomy (Hct <45%) + low-dose ASA; hydroxyurea if high-risk | Low-dose ASA; hydroxyurea if high-risk | Ruxolitinib (spleen/sx); allo-HSCT = only cure |
A high Hct is a classic exam branch point, and serum EPO does the triaging:
- Low EPO → Polycythemia vera (autonomous, JAK2+, ↑ RBC mass). The only cause with a low EPO.
- High EPO, appropriate (hypoxia-driven): high altitude, COPD, obstructive sleep apnea, cyanotic heart disease, high-affinity hemoglobin, chronic CO exposure/heavy smoking.
- High EPO, inappropriate (EPO-secreting tumor): renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, pheochromocytoma, uterine leiomyoma.
- Relative (spurious) polycythemia — Gaisböck: ↓ plasma volume (dehydration, diuretics); normal RBC mass, normal EPO.
One-liner: high Hct + low EPO + JAK2 = PV; high Hct + high EPO = hunt for hypoxia or tumor.
Stem: A 62-year-old man reports intense itching every time he steps out of a hot shower, plus burning, red hands and headaches. Exam: ruddy facial plethora, palpable spleen. Labs: Hgb 19.5 g/dL, Hct 58%, mildly ↑ WBC and platelets, low serum EPO.
- Diagnosis: Polycythemia vera — aquagenic pruritus + erythromelalgia + high Hct + low EPO.
- Confirm: JAK2 V617F testing (bone marrow biopsy if the picture is unclear).
- Next best step (treatment): Therapeutic phlebotomy to Hct <45% + low-dose aspirin for everyone; add hydroxyurea because he is high-risk (age >60).
- Pitfall: Iron stores are often low from repeated phlebotomy — do NOT give iron; it would fuel erythropoiesis and worsen the disease.
Stem: A 68-year-old woman has fatigue, drenching night sweats, weight loss, and early satiety from a spleen palpable to the pelvis. Labs: anemia; smear shows teardrop-shaped RBCs with nucleated RBCs and immature granulocytes (leukoerythroblastic). Marrow aspiration yields a "dry tap."
- Diagnosis: Primary myelofibrosis — teardrop cells + leukoerythroblastic smear + dry tap + massive splenomegaly.
- Next best step (diagnosis): Bone marrow biopsy (not aspirate) to demonstrate reticulin/collagen fibrosis; test JAK2/CALR/MPL; exclude CML with BCR-ABL1.
- Management: Ruxolitinib (JAK1/2 inhibitor) shrinks the spleen and eases constitutional symptoms; allogeneic HSCT is the only curative option for eligible high-risk patients; otherwise supportive transfusions.
- Why teardrops? RBCs are deformed squeezing out of a fibrotic marrow and from extramedullary sites.
Genuine board classics, not contrived acronyms:
- Itching after a hot shower/bath (aquagenic pruritus) → Polycythemia vera.
- Erythromelalgia (burning, red, warm hands/feet relieved by aspirin) → PV or ET.
- Teardrop cells (dacrocytes) + "dry tap" → Primary myelofibrosis.
- Leukoerythroblastosis (nucleated RBCs + left-shifted myeloids) → marrow infiltration/fibrosis.
- Budd-Chiari / splanchnic vein thrombosis in a young person → occult MPN → check JAK2.
- HIGH LAP → MPN/PV; LOW LAP → CML.
Management Principles & Transformation
Across MPNs, treatment targets thrombosis prevention first, then symptom/count control. Risk stratification drives cytoreduction: patients are high-risk if age >60 or prior thrombosis.
- PV: phlebotomy to Hct <45% + low-dose aspirin for all; add hydroxyurea (or ruxolitinib if resistant/intolerant) when high-risk.
- ET: low-dose aspirin for most; hydroxyurea (alternatives: anagrelide; interferon in pregnancy) for high-risk or platelets >1,500 ×10⁹/L — but withhold aspirin if acquired vWD/bleeding.
- PMF: ruxolitinib for symptomatic splenomegaly/constitutional symptoms; allogeneic stem cell transplant is the only cure; otherwise supportive care.
Watch for transformation: any MPN can evolve to a fibrotic "spent" phase or to AML — new cytopenias, rising blasts, or rapidly worsening splenomegaly should trigger reassessment.
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