Essential thrombocythaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

ET is diagnosed by integration, not by a high platelet count. Reactive thrombocytosis is much more common, and iron deficiency, infection, inflammation, malignancy, tissue injury and hyposplenism must be sought. JAK2, CALR or MPL supports clonality, but marrow trephine defines the megakaryocyte pattern and excludes prefibrotic myelofibrosis and masked PV. Triple-negative cases require especially careful expert review and sometimes broader myeloid sequencing.

The main treatment goal is thrombosis prevention without causing bleeding. Prior thrombosis is the strongest adverse factor; age over 60, JAK2 mutation and cardiovascular risks add risk. Platelet count does not correlate linearly with thrombosis and becomes most relevant at extreme levels because acquired VWD increases bleeding. Low-risk CALR-mutated younger adults may be observed, while JAK2-positive or symptomatic adults often receive aspirin when haemostasis permits. High-risk disease adds cytoreduction.

Hydroxycarbamide is first-line cytoreduction for many older or high-risk adults and is titrated to safe counts and symptoms rather than normalising every result at the cost of cytopenia. Pegylated interferon is suitable for younger people, pregnancy and those avoiding a potentially genotoxic oral agent. Anagrelide is a specialist later option but can cause palpitations, heart failure, headache and fibrotic concerns. Plateletpheresis lowers counts rapidly but briefly and is reserved for a life-threatening event while cytoreduction begins.

Pregnancy needs preconception review. Hydroxycarbamide and anagrelide are stopped; low-dose aspirin is usual when safe, interferon is used if cytoreduction is needed and LMWH is added according to previous thrombosis and obstetric risk, especially postpartum. At all ages, new anaemia, leucoerythroblastosis, splenic growth, systemic symptoms or blasts should prompt marrow reassessment for progression rather than automatic dose escalation.

Acute vascular events are treated through the relevant stroke, coronary or venous thrombosis pathway while haematology controls the clone. Cytoreduction does not replace reperfusion, anticoagulation or antiplatelet care, and antithrombotic treatment does not replace cytoreduction in high-risk ET. Before surgery, document thrombosis history, platelet count, VWF function when counts are extreme, current aspirin or anticoagulant exposure and the time required for count control. Emergency plateletpheresis is considered only when a life-threatening thrombotic or bleeding event needs an immediate temporary count fall; hydroxycarbamide or interferon must control subsequent production.

Key points

ET is a sustained platelet count at least 450 × 10⁹/L with characteristic marrow megakaryocytes, a clonal marker and exclusion of reactive thrombocytosis and other myeloid neoplasms.
First-line assessment is repeat FBC and film, ferritin and iron, CRP or ESR, renal and liver tests and review for infection, inflammation, bleeding, cancer, surgery and splenic status.
Test JAK2 V617F first, then CALR and MPL when negative; test BCR-ABL1 when features are atypical or no clear MPN driver is found.
Bone-marrow trephine is central because ET must be separated from prefibrotic myelofibrosis and masked PV, which cannot be done reliably from platelets alone.
Thrombotic risk uses previous thrombosis, age, JAK2 and cardiovascular risk; the platelet number alone is a poor predictor of thrombosis.
Low-dose aspirin treats microvascular symptoms and prevents arterial events in appropriate risk groups, but withhold it in active bleeding or suspected acquired VWD.
High-risk ET usually receives cytoreduction, commonly hydroxycarbamide plus low-dose aspirin; interferon is preferred when pregnancy or reproductive concerns make hydroxycarbamide unsuitable.
Extreme thrombocytosis can bleed: check VWF activity and reduce the count rather than reflexively prescribing aspirin.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Driver-mutated stem-cell clone

Most ET has an acquired JAK2, CALR or MPL driver mutation that activates thrombopoietin or JAK-STAT signalling and expands megakaryocytes.

Additional clonal lesions

Co-mutations affect thrombosis, fibrotic progression and survival but do not replace marrow morphology in distinguishing ET from prefibrotic myelofibrosis.

Triple-negative disease

A minority lacks the three standard drivers; expert morphology and broader testing are required before labelling a persistent reactive platelet count clonal.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Megakaryocyte proliferation
Large mature hyperlobulated megakaryocytes expand in marrow and release excess platelets while granulocyte and red-cell proliferation remain less prominent than in other MPNs.
2
Thrombo-inflammatory activation
Abnormal platelets, leukocytes and endothelium promote arterial, venous and microvascular thrombosis, especially with JAK2 mutation and conventional cardiovascular risks.
3
Count-related VWF loss
At extreme platelet counts, adsorption and cleavage remove high-molecular-weight VWF multimers, causing acquired von Willebrand syndrome and paradoxical bleeding.
4
Clonal progression
Additional mutations can produce post-ET myelofibrosis with extramedullary haematopoiesis or, less commonly, transformation to acute myeloid leukaemia.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Incidental thrombocytosis

Most cases begin with a repeat platelet elevation, while reactive history, ferritin, inflammatory markers and film guide initial probability.

Microvascular syndrome

Burning red painful hands or feet, migraine-like headache, visual disturbance and paraesthesia can respond dramatically to aspirin.

Major thrombosisRed flag

Stroke, coronary, DVT, PE and portal, hepatic or cerebral venous events can occur even with a modest platelet count.

Acquired VWD bleedingRed flag

Epistaxis, gum or gastrointestinal bleeding with extreme thrombocytosis suggests loss of functional high-molecular-weight VWF.

Progression pattern

New cytopenia, teardrops, nucleated red cells, splenomegaly, weight loss or blasts suggests post-ET fibrosis or AML.

Red flags requiring action

Focal neurological deficit, chest pain, acute limb pain, abdominal splanchnic thrombosis or hypoxia requires immediate thrombosis assessment and treatment.
Mucosal or major bleeding with an extreme platelet count suggests acquired von Willebrand syndrome; antiplatelet therapy may worsen it.
New anaemia, leucoerythroblastosis, progressive splenomegaly, constitutional symptoms or blasts suggests myelofibrotic or leukaemic transformation.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line reactive-cause screenFirst stepFirst line
Why
Confirm persistence and identify common non-clonal platelet drivers.
Interpretation and limitations
Repeat FBC and film, ferritin and iron, CRP or ESR, renal and liver tests and investigate infection, inflammation, bleeding, malignancy and splenic status clinically.
02
Sequential driver testing
Why
Demonstrate clonality and support thrombotic risk assessment.
Interpretation and limitations
Test JAK2 V617F, then CALR and MPL if negative; a driver supports an MPN but marrow morphology determines subtype.
03
Confirmatory bone-marrow trephineConfirmatory
Why
Distinguish true ET from prefibrotic myelofibrosis, masked PV, MDS or another myeloid neoplasm.
Interpretation and limitations
ET has enlarged mature hyperlobulated megakaryocytes without the atypical dense clusters and granulocytic proliferation typical of prefibrotic MF.
04
BCR-ABL1 and extended testing
Why
Exclude CML and establish clonality in atypical or triple-negative presentations.
Interpretation and limitations
Use BCR-ABL1 when basophilia, left shift or absent standard drivers raises concern; broader sequencing supports but does not replace morphology.
05
VWF activity and antigen
Why
Identify acquired VWD before aspirin, anticoagulation or procedure when bleeding or extreme platelets are present.
Interpretation and limitations
Reduced activity relative to antigen and loss of high-molecular-weight multimers supports acquired VWD; cytoreduction is causal treatment.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Reactive thrombocytosis

Infection, inflammation, iron deficiency, bleeding, malignancy, tissue injury and hyposplenism commonly raise platelets and usually resolve with the driver.

Prefibrotic myelofibrosis

Atypical dense megakaryocyte clusters, granulocytic proliferation, LDH, anaemia and spleen features identify a disease with different progression and prognosis.

Polycythaemia vera

Iron-deficient PV can present with thrombocytosis and apparently normal haemoglobin; JAK2, red-cell indices, erythropoietin and marrow reveal panmyelosis.

Chronic myeloid leukaemia

BCR-ABL1-positive CML may present with thrombocytosis, so molecular exclusion is needed when morphology or driver testing is atypical.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Persistent platelets above 450Exclude reaction and classify marrowFirst stepThrombocytosis persists on repeat FBC without an obvious transient cause.

1Assess film, iron, inflammation, infection, bleeding, malignancy, surgery and spleen.
2Test JAK2, then CALR and MPL, adding BCR-ABL1 when appropriate.
3Obtain expert marrow trephine and integrate morphology and genetics before assigning ET and risk.

02Low-risk ETChoose observation or aspirin safelyThere is no previous thrombosis and age, driver and cardiovascular factors indicate lower vascular risk.

1Assess microvascular symptoms, bleeding history and acquired VWD risk rather than treating the platelet number alone.
2Use low-dose aspirin for the indicated risk or symptoms when haemostasis is safe; observe selected very-low-risk disease.
3Control smoking, blood pressure, lipids, diabetes and immobility and review counts and symptoms at an agreed interval.

03High-risk ETAdd cytoreductionPrevious thrombosis, older age with JAK2 or another specialist indication creates high recurrence risk.

1Treat an acute event conventionally and address aspirin or anticoagulant indication and bleeding risk.
2Start hydroxycarbamide or interferon and titrate to safe platelets, leukocytes and symptom control.
3Second lineReassess intolerance, resistance, pregnancy plans and progression signs before switching to second-line therapy.

04Extreme count with bleedingCorrect acquired haemostasisVery high platelets coexist with mucosal or major bleeding or an urgent procedure.

1Withhold aspirin and obtain VWF activity, antigen and specialist functional testing with coagulation and group samples.
2Use urgent cytoreduction and haemostatic treatment; reserve plateletpheresis for selected life-threatening count-mediated events.
3Restart vascular prevention only after bleeding mechanism, VWF recovery and ongoing platelet control are reviewed.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Antiplatelet prevention and rapid relief of erythromelalgia and other platelet-mediated microvascular symptoms.

Low-dose aspirin

Give 75 mg orally once daily when the thrombotic or microvascular indication outweighs bleeding risk; do not start during active bleeding or suspected acquired von Willebrand syndrome until assessed.

Review gastrointestinal bleeding, anticoagulation, pregnancy and VWF function with extreme platelets. Twice-daily dosing is specialist only and not a routine response to a high count.

First-line cytoreduction for many high-risk adults and those with severe count-mediated symptoms or acquired VWD.

Hydroxycarbamide

Start commonly at 500 mg orally once or twice daily and titrate with frequent FBC to safe platelet and leukocyte control, adjusting the starting and maintenance dose for renal function, age and cytopenia.

Monitor cytopenia, renal function, mouth or leg ulcers and skin cancer, avoid pregnancy and breastfeeding and use effective contraception; discuss fertility and interferon when reproductive plans matter.

Preferred cytoreduction in pregnancy and a first-line alternative for younger adults or hydroxycarbamide intolerance.

Pegylated interferon alfa

A common peginterferon alfa-2a start is 45 micrograms subcutaneously weekly, increasing gradually to 90 to 180 micrograms weekly according to counts and tolerance under the MPN protocol.

Monitor mood, autoimmune and thyroid disease, liver tests, cytopenia and flu-like toxicity and coordinate specialist product and pregnancy counselling.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Arterial and venous thrombosis

Stroke, myocardial infarction, DVT, PE and unusual-site venous thrombosis are major preventable events and may precede diagnosis.

Microvascular symptoms

Erythromelalgia, migraine-like headache, transient visual disturbance and acral paraesthesia reflect platelet-mediated small-vessel occlusion and can impair daily function.

Bleeding

Acquired VWD, platelet dysfunction, aspirin and anticoagulation can produce epistaxis, gastrointestinal bleeding and procedure-related haemorrhage despite the high platelet count.

Post-ET myelofibrosis or AML

Progressive anaemia, spleen, systemic symptoms, leucoerythroblastic film or blasts requires repeat marrow, genetics and a new treatment pathway.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During diagnosis and observation, repeat FBC and symptoms at a tempo-based interval and revisit reactive causes if the phenotype changes.
During cytoreduction, monitor FBC frequently during titration then extend when stable, with renal and liver review and documented adherence and toxicity.
At every review assess thrombosis, bleeding, microvascular symptoms, pregnancy plans, cardiovascular risk and aspirin or anticoagulant interaction.
Repeat VWF testing after cytoreduction when acquired VWD influenced aspirin, procedure or bleeding decisions.
Re-biopsy marrow for new anaemia, leucoerythroblastosis, progressive splenomegaly, constitutional symptoms or blasts.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Platelets do not equal thrombosis risk

Previous thrombosis, age, JAK2 and cardiovascular factors are more informative than the absolute count.

Marrow defines the subtype

Driver mutations overlap across MPNs, so trephine architecture separates ET from prefibrotic MF and masked PV.

CALR often changes risk

Younger CALR-mutated patients without vascular history can have very high platelets yet lower thrombotic risk than JAK2-positive disease.

Extreme counts can cause bleeding

Acquired VWD makes reflex aspirin unsafe and improves when the platelet count is reduced.

Plateletpheresis is temporary

It is reserved for selected life-threatening events because counts rebound unless cytoreduction controls production.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing ET before excluding iron deficiency and inflammation.
02
Using JAK2 positivity alone to distinguish ET from PV or myelofibrosis.
03
Treating the platelet count as the whole thrombotic score.
04
Giving aspirin during acquired VWD bleeding.
05
Using plateletpheresis as chronic therapy.
06
Continuing teratogenic hydroxycarbamide during pregnancy.