Essential thrombocythaemia
Description
- MPN with sustained clonal thrombocytosis and megakaryocytic proliferation
- The most indolent MPN - near-normal life expectancy in low-risk young patients
- Presentation
- Incidental raised platelet count (~50-60%)
- Microvascular/vasomotor: erythromelalgia, acral paraesthesia, migraine-like headache, transient visual disturbance, atypical chest pain
- Thrombosis - arterial > venous; sometimes at unusual sites (splanchnic, cerebral venous sinus)
- Bleeding at extreme counts - acquired von Willebrand syndrome
- Mild splenomegaly ~20-50%
- *Two mimics must be excluded before the diagnosis stands*
- Prefibrotic primary myelofibrosis - looks identical clinically, worse outcome, distinguished only on trephine
- Masked polycythaemia vera - concurrent iron deficiency suppressing the Hb
Epidemiology
- Incidence ~1-2.5/100,000/yr - the commonest MPN
- Median age ~60, with a distinct second peak in women aged 30-40
- F>M overall (~2:1 in the younger peak)
- Familial clustering - ~5x inc risk in first-degree relatives (germline JAK2 46/1 haplotype)
Aetiopathogenesis
- Clonal haematopoietic stem cell disorder; all drivers converge on constitutive JAK-STAT activation with cytokine-independent megakaryopoiesis
| Driver | Frequency | Phenotype |
|---|---|---|
| JAK2 V617F | ~55-60% | Higher Hb and WCC, older, highest thrombosis risk, more likely to evolve to PV |
| CALR (exon 9: type 1 52bp deletion, type 2 5bp insertion) | ~25% | Younger, male, higher platelet count but lower thrombosis risk, longer survival. Type 1 -> more fibrotic transformation |
| MPL (W515) | ~3-5% | Older, more anaemia, more marrow fibrosis |
| Triple negative | ~10-15% | Indolent; reconsider a reactive cause and prefibrotic PMF |
- CALR mutation -> mutant C-terminus binds and activates MPL (the thrombopoietin receptor) - explains why CALR disease is megakaryocyte-restricted with no erythrocytosis
- Subclonal mutations (ASXL1, SRSF2, TP53, EZH2, IDH1/2, U2AF1) drive transformation, not the phenotype
- Thrombosis mechanism - qualitatively abnormal platelets, leucocyte activation, JAK2-mutant endothelium. Platelet count itself does not predict thrombosis
Diagnosis
WHO criteria - all 4 major, OR major 1-3 + the minor criterion
| Criterion | |
|---|---|
| Major 1 | Platelets >=450 x10^9/L, sustained |
| Major 2 | Marrow: megakaryocyte proliferation with enlarged, mature, hyperlobulated ("staghorn") forms; no granulocytic or erythroid left shift; reticulin no more than grade 1 |
| Major 3 | Does not meet criteria for CML (BCR::ABL1), PV, PMF, MDS or other myeloid neoplasm |
| Major 4 | JAK2, CALR or MPL mutation |
| Minor | Another clonal marker, or absence of evidence of reactive thrombocytosis |
- *Bone marrow trephine is mandatory* - it is the only way to separate ET from prefibrotic PMF, and to grade baseline reticulin
Workup
- Molecular: JAK2 V617F -> if negative, CALR and MPL; BCR::ABL1 in every case
- Ferritin and iron studies - iron deficiency masks PV
- CRP/ESR, autoimmune screen, age-appropriate cancer screening - exclude reactive causes
- LDH, UEC, LFT, urate
- VWF activity/antigen and ristocetin cofactor if platelets >1000-1500 before starting aspirin
- Ultrasound for spleen size and portal vein patency
- NGS myeloid panel where available - prognostic
IPSET-thrombosis - the score that drives treatment
| Category | Definition | Annual thrombosis risk |
|---|---|---|
| Very low | Age <=60, no thrombosis history, JAK2 wild-type | ~0.4-1% |
| Low | Age <=60, no thrombosis history, JAK2 mutated | ~1-2% |
| Intermediate | Age >60, no thrombosis history, JAK2 wild-type | ~1.5-2.5% |
| High | Prior thrombosis, OR age >60 with JAK2 mutation | ~4%+ |
- *The platelet count is deliberately absent from the score*
- IPSET survival: age >=60, WCC >=11, prior thrombosis
Management
Treat to prevent thrombosis and control microvascular symptoms. The count is a means, not the goal.
A. All patients
- Cardiovascular risk factor modification - smoking cessation, BP, lipids, glycaemic control, weight
- Thromboprophylaxis for surgery, immobility, long-haul travel
B. Antiplatelet - by risk
| Risk | Antiplatelet |
|---|---|
| Very low | Observation. Aspirin only if cardiovascular risk factors or microvascular symptoms |
| Low | Aspirin 100 mg daily |
| Intermediate | Aspirin daily |
| High | Aspirin + cytoreduction |
- Twice-daily aspirin for persistent erythromelalgia or vasomotor symptoms - platelet turnover outstrips once-daily COX inhibition
- *Withhold aspirin if platelets >1000-1500 until acquired von Willebrand syndrome is excluded and the count is reduced* - bleeding risk
C. Cytoreduction
Indications: high-risk category; prior thrombosis; progressive or symptomatic disease; extreme thrombocytosis with bleeding
| Agent | Position | Key toxicity |
|---|---|---|
| Hydroxyurea | First line in patients >40-60 | Cytopenias, oral and leg ulcers, macrocytosis, nail/skin pigmentation, non-melanoma skin cancer (sun protection + annual skin check). Teratogenic |
| Interferon (peg-IFN alfa-2a, ropeginterferon alfa-2b) | Preferred in younger patients and in pregnancy; molecular responses | Flu-like symptoms, fatigue, depression, autoimmune thyroiditis/hepatitis, cytopenias. Avoid in significant psychiatric or autoimmune disease |
| Anagrelide | Second line | Headache, palpitations, diarrhoea (early, often dose-limiting); fluid retention, tachyarrhythmia, cardiomyopathy - baseline echo; increases bleeding risk; *accelerates marrow fibrosis with long-term use*. Reduces platelets only, no effect on WCC or Hb |
| Busulfan | Elderly / refractory only | Leukaemogenic - avoid where life expectancy is long |
- Target platelets <400 x10^9/L in patients receiving cytoreduction
- PT-1 trial: hydroxyurea + aspirin beat anagrelide + aspirin for arterial thrombosis, but anagrelide was better for venous events - hence hydroxyurea first
D. Pregnancy
- Aspirin throughout (unless bleeding phenotype)
- Interferon is the only cytoreductive agent to use - hydroxyurea and anagrelide are contraindicated
- LMWH prophylaxis for 6 weeks postpartum
- Risks: first-trimester loss (~25-40%), placental infarction, IUGR, pre-eclampsia
E. Thrombosis when it happens
- Treat the acute event conventionally, then anticoagulate long term and add cytoreduction
- Splanchnic vein thrombosis -> indefinite anticoagulation
- DOACs are increasingly used but the trial evidence in MPN is limited - warfarin remains standard for splanchnic events with varices
Associations
- Other MPNs - PV, prefibrotic and overt primary myelofibrosis
- Acquired von Willebrand syndrome at extreme platelet counts
- Splanchnic vein thrombosis - Budd-Chiari, portal, mesenteric; test JAK2 V617F even with normal counts
- Cerebral venous sinus thrombosis
- Erythromelalgia
- Recurrent pregnancy loss and placental insufficiency
- Familial MPN; germline JAK2 46/1 haplotype
- Rarely germline THPO or MPL (hereditary thrombocythaemia - not clonal, no transformation risk)
Natural history & complications
- The best survival of any MPN - median >20 years; near-normal in low-risk patients under 60
- Most morbidity is thrombotic, not from marrow failure
Transformation
- Post-ET myelofibrosis: ~4-10% at 15 years (higher with CALR type 1, MPL, high baseline reticulin, anaemia)
- AML/MDS: ~1-2% at 10 years, ~5% at 15 years - risk substantially increased by prior alkylator or P-32, and by sequential cytoreductive agents
- Evolution to polycythaemia vera in JAK2-mutated disease
Adverse markers
- Age >60, prior thrombosis, leucocytosis >=11 x10^9/L, anaemia
- JAK2 V617F (thrombosis), CALR type 1 / MPL (fibrosis)
- Adverse mutations - TP53, SRSF2, SF3B1, U2AF1, EZH2, IDH1/2
Monitoring
- FBE 3-monthly once stable; symptom review (MPN-SAF); spleen size; cardiovascular risk
- New anaemia, rising LDH, progressive splenomegaly, leucoerythroblastic film -> repeat marrow for fibrotic transformation
- Annual skin check on hydroxyurea
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