Polycythaemia Vera & Myeloproliferative Disorders

The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs) — polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) — are clonal stem-cell disorders unified by overactive JAK-STAT signalling, most often driven by the JAK2 V617F mutation. They sit on a spectrum: too many red cells (PV), too many platelets (ET) or marrow scarring with extramedullary haematopoiesis (PMF), all sharing a tendency to thrombosis and a risk of leukaemic transformation.

Definition & classification

A myeloproliferative neoplasm is a clonal proliferation of one or more myeloid lineages (erythroid, megakaryocytic, granulocytic) with retained maturation, distinguishing it from acute leukaemia (where maturation is blocked). The WHO 2016/2022 framework divides MPNs into BCR-ABL1 positive (chronic myeloid leukaemia, CML) and negative groups.

Disorder	Predominant lineage	Hallmark driver mutation	Signature finding
Chronic myeloid leukaemia (CML)	Granulocytic	BCR-ABL1 (t9;22)	Philadelphia chromosome, basophilia
Polycythaemia vera (PV)	Erythroid (+all)	JAK2 V617F (~95%)	Raised haematocrit, low EPO
Essential thrombocythaemia (ET)	Megakaryocytic	JAK2 (~55%), CALR (~25%), MPL (~3%)	Platelets >450×10⁹/L
Primary myelofibrosis (PMF)	Megakaryocytic + fibrosis	JAK2 (~55%), CALR (~25%), MPL	Tear-drop cells, dry tap

High-yield: JAK2 V617F is a point mutation in exon 14 (valine→phenylalanine at codon 617) causing constitutive, EPO-independent tyrosine-kinase activation. It is present in >95% of PV and roughly half of ET and PMF. The three are sometimes called the "JAK2-driven trio".

CALR (calreticulin) and MPL (thrombopoietin receptor) mutations characterise the JAK2-negative ET/PMF cases. CALR-mutated patients tend to have higher platelet counts but a lower thrombosis risk and better prognosis than JAK2-mutated patients. A patient who is JAK2-, CALR- and MPL-negative is termed "triple negative" — this carries the worst prognosis in PMF.

Etiology & pathophysiology

JAK2 (Janus kinase 2) is a cytoplasmic tyrosine kinase coupling the erythropoietin, thrombopoietin and G-CSF receptors to the STAT5 pathway. The V617F mutation lies in the JH2 pseudokinase (autoinhibitory) domain; losing this brake leaves JAK2 permanently "on," so erythroid progenitors proliferate without needing EPO — the basis of the classic endogenous erythroid colony (EEC) formation in vitro.

Stepwise pathogenesis of PV:

JAK2 V617F clone → EPO-independent erythroid proliferation → raised red cell mass + haematocrit → hyperviscosity & thrombosis → over years "spent phase" / post-PV myelofibrosis → small risk of transformation to AML.

High-yield: Because erythropoiesis is autonomous, the body suppresses EPO. Hence serum EPO is LOW in PV — the single most useful test to separate primary (PV) from secondary polycythaemia, where EPO is normal or high.

Secondary polycythaemia results from appropriate EPO rise (chronic hypoxia — COPD, cyanotic heart disease, high altitude, obstructive sleep apnoea, high-affinity haemoglobin) or inappropriate EPO secretion (renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma, uterine leiomyoma, phaeochromocytoma). Relative (apparent/Gaisböck) polycythaemia is a spurious rise from reduced plasma volume (dehydration, diuretics, smoking).

Clinical features

Polycythaemia vera typically affects patients >60 years and presents with hyperviscosity and a hypermetabolic clone:

• Aquagenic pruritus — intense itching after a warm bath/shower (histamine release from basophils/mast cells). Highly characteristic and frequently tested.
• Plethora (ruddy cyanosis), conjunctival suffusion, headache, dizziness, visual disturbance, tinnitus.
• Erythromelalgia — burning red painful extremities, relieved by aspirin; due to platelet microthrombi.
• Splenomegaly (~70%) and hepatomegaly.
• Thrombosis — arterial and venous; PV is a classic cause of Budd-Chiari syndrome and other splanchnic vein thromboses. Paradoxically, bleeding can also occur (acquired von Willebrand disease at very high platelet counts).
• Gout from high cell turnover (raised uric acid).

High-yield: Any young patient presenting with Budd-Chiari syndrome, portal/splanchnic vein thrombosis or unexplained venous thrombosis at an unusual site should be screened for JAK2 V617F — an occult MPN may underlie it even before blood counts overtly rise.

Essential thrombocythaemia is often asymptomatic (incidental high platelets) or presents with vasomotor symptoms (headache, erythromelalgia, visual aura), thrombosis or — with extreme thrombocytosis — bleeding.

Primary myelofibrosis presents with massive splenomegaly, constitutional symptoms (weight loss, night sweats, fever), progressive anaemia and bone marrow failure. Extramedullary haematopoiesis explains the huge spleen/liver.

Diagnosis & investigation of choice

Polycythaemia vera — WHO 2016 criteria

Diagnosis needs all 3 major, OR first 2 major + the minor criterion.

	Criterion
Major 1	Hb >16.5 g/dL (men) / >16.0 g/dL (women) OR Hct >49% (men) / >48% (women) OR raised red cell mass
Major 2	Bone marrow trilineage hypercellularity (panmyelosis) with pleomorphic mature megakaryocytes
Major 3	Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor	Subnormal serum erythropoietin level

High-yield cut-offs: Hb >16.5 (M) / 16.0 (F) g/dL or Hct >49% (M) / 48% (F). Memorise these — examiners love the haematocrit threshold.

Practical work-up flow when polycythaemia is found:

1. Confirm true erythrocytosis (repeat FBC; exclude dehydration).
2. Check JAK2 V617F — if positive with raised Hct, PV is essentially confirmed.
3. Serum EPO — low → supports PV; normal/high → look for secondary cause.
4. If JAK2-negative but EPO low → test JAK2 exon 12.
5. Bone marrow biopsy for trilineage hyperplasia (and baseline reticulin fibrosis).
6. Adjuncts: low or normal serum EPO, often raised WCC, platelets, uric acid, raised LAP/NAP score (contrasts with the low NAP score of CML), low ferritin (iron utilised).

High-yield: The investigation of choice to differentiate primary from secondary polycythaemia is serum erythropoietin (low in PV). JAK2 mutation testing is the key confirmatory molecular test.

Essential thrombocythaemia — WHO criteria (all 4 major, or first 3 major + minor)

• Major 1: Platelets ≥450×10⁹/L (sustained).
• Major 2: Marrow shows proliferation of large mature megakaryocytes with hyperlobulated nuclei; no significant granulocytic/erythroid increase, no relevant fibrosis.
• Major 3: Does not meet WHO criteria for CML, PV, PMF, MDS.
• Major 4: JAK2, CALR or MPL mutation present.
• Minor: A clonal marker, or absence of a cause of reactive thrombocytosis.

Always exclude reactive (secondary) thrombocytosis: iron deficiency, infection/inflammation, post-splenectomy, malignancy, haemorrhage.

Primary myelofibrosis

Peripheral smear shows a leukoerythroblastic picture (immature myeloid cells + nucleated red cells) and tear-drop poikilocytes (dacrocytes). Marrow aspirate gives a "dry tap"; trephine biopsy shows reticulin/collagen fibrosis and atypical clustered megakaryocytes.

High-yield triad of PMF: tear-drop RBCs + leukoerythroblastic blood film + massive splenomegaly. The dry tap on aspiration is classic.

Management & drug of choice

Polycythaemia vera

The cornerstone is to lower haematocrit and reduce thrombosis.

• Venesection (therapeutic phlebotomy) is the first-line / primary treatment — target haematocrit <45% (CYTO-PV trial showed fewer cardiovascular deaths/thromboses at <45% vs 45–50%).
• Low-dose aspirin (75–100 mg) for all patients (unless contraindicated) — reduces thrombotic events (ECLAP trial).
• Cytoreduction for high-risk patients (age >60 or prior thrombosis):
  • Hydroxyurea (hydroxycarbamide) — drug of choice for cytoreduction.
  • Interferon-α / pegylated IFN-α — preferred in young patients and pregnancy (does not cross placenta significantly, non-teratogenic).
  • Ruxolitinib (JAK1/2 inhibitor) — for hydroxyurea-resistant/intolerant PV.
• Manage pruritus: antihistamines, SSRIs, IFN-α; control hyperuricaemia with allopurinol.

High-yield: Venesection to keep haematocrit <45% + low-dose aspirin is the backbone for all PV patients; add hydroxyurea if high-risk. Interferon-α is the cytoreductive agent of choice in pregnancy.

Essential thrombocythaemia

Risk-stratified (IPSET-thrombosis: age >60, prior thrombosis, JAK2 mutation, cardiovascular risk):

• Low risk: low-dose aspirin ± observation.
• High risk: hydroxyurea + aspirin. Anagrelide (reduces platelet production) is an alternative. IFN-α in young/pregnant patients.

Primary myelofibrosis

• Ruxolitinib (JAK1/2 inhibitor) — drug of choice for symptomatic splenomegaly and constitutional symptoms; improves quality of life and survival (COMFORT trials).
• Allogeneic stem-cell transplant — the only curative option, reserved for high-risk younger patients.
• Supportive: transfusions, erythropoiesis-stimulating agents, danazol for anaemia; splenectomy/splenic irradiation in selected cases.

Complications

• Thrombosis — the leading cause of morbidity/mortality (stroke, MI, DVT/PE, Budd-Chiari, portal vein thrombosis).
• Haemorrhage — acquired von Willebrand disease with extreme thrombocytosis (>1000–1500×10⁹/L); paradoxically aspirin can worsen bleeding here, so check vWF before starting it at very high counts.
• Transformation to myelofibrosis ("spent phase" / post-PV or post-ET MF).
• Transformation to acute myeloid leukaemia (AML) — risk increased by alkylating agents and radioactive phosphorus (³²P); low but serious.
• Gout / urate nephropathy from high cell turnover.
• Portal hypertension in PMF from massive extramedullary haematopoiesis.

High-yield: Risk of leukaemic transformation rises with older cytotoxic therapy (alkylators, ³²P) — a reason hydroxyurea/interferon are preferred. PV → post-PV myelofibrosis → AML is the natural late progression.

Key differentials

Polycythaemia (raised Hb/Hct):

Feature	PV (primary)	Secondary polycythaemia	Relative/apparent
Serum EPO	Low	Normal/high	Normal
JAK2 V617F	Positive (>95%)	Negative	Negative
Red cell mass	True ↑	True ↑	Normal (plasma ↓)
Splenomegaly	Common	Absent	Absent
Pruritus/plethora	Yes (aquagenic)	No	No
Cause	Clonal MPN	Hypoxia / EPO tumour	Dehydration, smoking

Thrombocytosis: ET vs reactive thrombocytosis (iron deficiency, infection, malignancy, post-splenectomy) — reactive has a clear trigger, normal ferritin once treated, no clonal marker.

Leukoerythroblastic film / marrow fibrosis: PMF vs marrow infiltration (metastatic carcinoma, lymphoma, granulomatous disease), and post-PV/post-ET myelofibrosis.

CML vs other MPNs: CML has basophilia, very high WCC, low NAP/LAP score and the Philadelphia chromosome (BCR-ABL) — distinct from the JAK2-driven trio (which classically has a high NAP score).

Recently asked / exam angle

• JAK2 V617F location and effect (exon 14, codon 617, pseudokinase domain, EPO-independent signalling) — recurring molecular MCQ.
• WHO Hct/Hb cut-offs for PV (Hct >49% men / >48% women).
• Low serum EPO as the discriminating investigation between primary and secondary polycythaemia — a perennial favourite.
• Aquagenic pruritus linked to PV.
• Venesection to keep Hct <45% as first-line PV therapy (CYTO-PV).
• JAK2 screening in Budd-Chiari / splanchnic vein thrombosis — image/clinical vignette stems.
• Tear-drop cells + leukoerythroblastic picture + dry tap = primary myelofibrosis.
• CALR mutation — better prognosis, JAK2-negative ET/PMF; triple-negative = worst prognosis.
• Ruxolitinib as JAK1/2 inhibitor for myelofibrosis; interferon-α preferred in pregnancy.
• High NAP/LAP score in PV vs low NAP score in CML — classic contrast.

Rapid revision

1. PV, ET and PMF are BCR-ABL-negative MPNs unified by JAK2-STAT overactivation.
2. JAK2 V617F = exon 14, codon 617 (Val→Phe); present in >95% PV, ~50% ET & PMF.
3. Serum EPO is LOW in PV — best test to separate primary from secondary polycythaemia.
4. WHO PV cut-offs: Hb >16.5 (M)/16.0 (F) g/dL or Hct >49% (M)/48% (F).
5. Aquagenic pruritus (itch after warm bath) is the signature symptom of PV.
6. PV is a classic cause of Budd-Chiari syndrome — screen JAK2 in unusual-site thrombosis.
7. PV treatment: venesection to Hct <45% + low-dose aspirin; add hydroxyurea if high-risk.
8. Interferon-α is the cytoreductive agent of choice in pregnancy.
9. ET = platelets ≥450×10⁹/L; CALR mutation = better prognosis, triple-negative = worst.
10. PMF film: tear-drop cells + leukoerythroblastic picture + dry tap + massive splenomegaly.
11. Ruxolitinib (JAK1/2 inhibitor) is the drug of choice for symptomatic myelofibrosis; allo-SCT is the only cure.
12. High NAP/LAP score favours PV; low NAP + Philadelphia chromosome favours CML.