Essential Thrombocythaemia
Myeloproliferative neoplasm characterised by sustained thrombocytosis with risk of thrombotic and haemorrhagic complications, driven by JAK2, CALR, or MPL mutations.
Key Facts
Essential thrombocythaemia (ET) is a chronic MPN defined by sustained platelet count ≥450 × 10⁹/L with clonal mutation Driver mutations: JAK2 V617F (~60%), CALR (~25%), MPL (~5%); ~10% are triple-negative CALR-mutated ET has the best prognosis and lowest thrombotic risk; JAK2-mutated has highest thrombotic risk Risk of thrombosis: 10-25% at 10 years; risk of major haemorrhage: 5-10% First-line cytoreduction for high-risk patients: hydroxycarbamide 500mg-1g OD (PT-1 trial) Anagrelide 0.5mg BD is second-line (lowers platelets via megakaryocyte inhibition) Median survival exceeds 20 years; risk of transformation to myelofibrosis or AML is relatively low
Overview
Key Facts
Essential thrombocythaemia is a myeloproliferative neoplasm characterised by megakaryocyte proliferation leading to persistent thrombocytosis. The main clinical consequences are thrombosis and haemorrhage.
Epidemiology
- Incidence: 1-2.5 per 100,000/year in the UK
- Median age at diagnosis: 55-60 years (bimodal: peak at 30 and 55)
- Slight female predominance
- Most common MPN at presentation
Aetiology
- JAK2 V617F: ~60% (shared with PV and PMF)
- CALR mutations (calreticulin): ~25% (type 1 and type 2)
- MPL mutations (thrombopoietin receptor): ~5%
- Triple-negative: ~10% (no known driver mutation)
Pathophysiology
- Driver mutations cause cytokine-independent megakaryocyte proliferation
- Increased platelet production → sustained thrombocytosis
- Abnormal platelet function → paradoxical thrombosis AND bleeding
- Extreme thrombocytosis (>1500 × 10⁹/L) → acquired von Willebrand disease (consumption of large vWF multimers) → bleeding risk
- Leukoerythroblastic change and fibrosis suggest transformation to myelofibrosis
Clinical Presentation
Common Presentations
- Incidental finding of raised platelet count on FBC (~50%)
- Microvascular symptoms: erythromelalgia, headache, dizziness, visual disturbance, acral paraesthesiae
- Thrombotic events: stroke, TIA, MI, DVT/PE, splanchnic vein thrombosis
- Haemorrhagic events: mucosal bleeding, bruising (especially with very high platelets)
- Splenomegaly (mild, in ~40%)
Red Flags
- Splanchnic vein thrombosis in a young patient → screen for MPNs
- Platelets >1500 × 10⁹/L with bleeding → acquired von Willebrand disease
- Rapidly rising platelets with constitutional symptoms → consider transformation
- Leukoerythroblastic blood film → myelofibrotic transformation
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Reactive thrombocytosis | Infection, iron deficiency, post-splenectomy, malignancy | CRP, ferritin, clinical context |
| Polycythaemia vera | Predominant erythrocytosis, JAK2+ | Hb/Hct, EPO, bone marrow |
| Primary myelofibrosis (prefibrotic) | Anaemia, splenomegaly, leukoerythroblastic film | Bone marrow (fibrosis) |
| CML | Leucocytosis, basophilia, BCR-ABL positive | BCR-ABL (Philadelphia chromosome) |
| MDS with ring sideroblasts and thrombocytosis | Anaemia, ring sideroblasts, SF3B1 mutation | Bone marrow |
| Iron deficiency | Microcytosis, low ferritin, reactive platelets | Ferritin, iron studies |
Diagnosis / Investigation
Bedside
- Examination for splenomegaly, evidence of thrombosis or bleeding
Bloods
- FBC: sustained platelets ≥450 × 10⁹/L on two occasions at least 1 month apart
- Blood film: large platelets, platelet clumps; exclude leukoerythroblastic features
- JAK2 V617F: first-line molecular test
- CALR mutation: if JAK2 negative
- MPL mutation: if JAK2 and CALR negative
- BCR-ABL: to exclude CML (mandatory)
- Iron studies, CRP, ESR: exclude reactive causes
- LDH: raised in MPNs
- vWF activity/antigen and ristocetin cofactor: if platelets >1000 and bleeding
Imaging
- Abdominal ultrasound: splenomegaly assessment
Special Tests
- Bone marrow biopsy: proliferation of large mature megakaryocytes with hyperlobulated nuclei; no significant fibrosis (reticulin grade 0-1); mandatory for diagnosis
- Cytogenetics: exclude MDS, CML
Management
Non-pharmacological
- Cardiovascular risk factor modification: smoking cessation, weight management
- Low-risk patients may require observation only
Pharmacological
Low-risk (age <60, no prior thrombosis):
- Aspirin 75mg OD (if microvascular symptoms or cardiovascular risk factors)
- Some very low-risk patients (CALR-mutated, young) may not need aspirin
High-risk (age ≥60 OR prior thrombosis):
- Hydroxycarbamide 500mg-1g OD – first-line cytoreductive therapy (PT-1 trial)
- Target platelet count <400 × 10⁹/L
- Plus aspirin 75mg OD
Hydroxycarbamide-intolerant/resistant:
- Anagrelide 0.5mg BD (titrate to response, max 10mg/day) – PT-1 trial showed non-inferiority but more arterial thrombosis and fibrosis
- Interferon alfa (pegylated): preferred in younger patients and pregnancy
- Busulfan: elderly patients, short course
Very high platelets (>1500 × 10⁹/L):
- Withhold aspirin (acquired vWD risk → bleeding)
- Check vWF activity: restore aspirin when platelets reduced and vWF normalised
Referral Criteria
- All patients with sustained thrombocytosis >450 → haematology
- Thrombotic or haemorrhagic events → urgent haematology
Prognosis
- Median survival: >20 years (near-normal life expectancy for low-risk)
- Thrombosis risk: 10-25% at 10 years (higher in JAK2-positive)
- Transformation to myelofibrosis: 3-10% at 10 years
- Transformation to AML: 1-3% at 10 years
- CALR-mutated ET has best prognosis and lowest thrombotic risk
- IPSET-thrombosis score guides risk stratification: age, JAK2 status, prior thrombosis, cardiovascular risk factors
Other Relevant Information
IPSET-Thrombosis Risk Stratification
| Risk | Criteria | Management |
|---|---|---|
| Very low | Age <60, no thrombosis, CALR+/JAK2- | Observation or aspirin |
| Low | Age <60, no thrombosis, JAK2+ | Aspirin 75mg OD |
| Intermediate | Age ≥60, no thrombosis, CALR+/JAK2- | Aspirin or cytoreduction |
| High | Age ≥60 with JAK2+ OR prior thrombosis | Cytoreduction + aspirin |
Driver Mutation Comparison
| Mutation | Frequency | Thrombosis Risk | Survival |
|---|---|---|---|
| JAK2 V617F | ~60% | Highest | Intermediate |
| CALR | ~25% | Lowest | Best |
| MPL | ~5% | Intermediate | Intermediate |
| Triple-negative | ~10% | Variable | Variable |