Essential Thrombocythaemia

Key defining features

• Clonal megakaryocyte proliferation with enlarged, hyperlobulated forms on bone‑marrow biopsy, without significant fibrosis or left‑shift of other lineages.
• Persistent platelet count ≥ 450 × 10⁹/L, confirmed on repeat testing and peripheral smear examination showing platelet anisocytosis.
• Exclusion of secondary causes: no evidence of reactive thrombocytosis, BCR::ABL1‑positive disorders, polycythaemia vera, primary myelofibrosis or myelodysplasia.
• Detection of a myeloproliferative driver mutation (JAK2 V617F in ~50–60 percent; CALR in ~25–30 percent; MPL in ~3–11 percent), or another clonal marker, or absence of reactive cause.

Unknown trigger

• No specific environmental, infectious or lifestyle factor has been definitively implicated.
• Most cases arise sporadically.

Somatic driver mutations in key signalling genes

• JAK2 V617F in approximately 50–60 percent of patients.
• CALR (calreticulin) mutations in around 25–30 percent.
• MPL (thrombopoietin receptor) mutations in about 3–11 percent.
• Triple‑negative cases (10–15 percent) lack these three mutations; some may harbour rare non‑canonical variants detectable by extended sequencing.

Generally mutually exclusive

• Individual cases usually carry only one of the above mutations.
• Rare instances of dual mutations (for example, JAK2 plus CALR) have been documented.

Familial predisposition occurs in a small minority

• Some families exhibit autosomal dominant patterns, yet no single germline lesion has been universally identified.
• Occasional pedigrees carry inherited thrombopoietin or MPL mutations, confirming genetic susceptibility.

Shared pathogenic pathway

• All driver mutations activate the JAK–STAT cascade.
• This promotes cytokine‑independent growth of megakaryocytes and excessive platelet production.

Clonal Stem Cell Disorder

• ET is a chronic myeloproliferative neoplasm arising from a clonal expansion of haematopoietic stem cells.
• The hallmark is uncontrolled proliferation of megakaryocytes, leading to sustained thrombocytosis.
• Platelet production is excessive and often functionally abnormal, contributing to both thrombotic and haemorrhagic risks.

Driver Mutations and JAK-STAT Pathway Activation

• Somatic mutations drive the disease in ~90% of cases, affecting key genes involved in cytokine signalling:
  • JAK2 V617F (50–60%): Promotes cytokine-independent proliferation through constitutive activation of the JAK-STAT pathway.
  • CALR (25–30%): Mutations are linked to higher platelet counts and lower thrombotic risk compared to JAK2-mutant ET.
  • MPL (3–11%): Encodes the thrombopoietin receptor; mutations lead to aberrant JAK-STAT signalling.
• Around 10–15% of patients are “triple-negative,” lacking mutations in all three genes.

Familial and Hereditary ET

• Hereditary thrombocythaemia is rare and involves germline mutations:
  • Mutations in THPO lead to increased thrombopoietin production and chronic thrombocytosis.
  • Germline MPL mutations have also been reported in familial cases.

Platelet Dysfunction and Clinical Sequelae

• Thrombosis and bleeding occur due to both numerical and functional platelet abnormalities:
  • Thrombosis:
    • Enhanced platelet activation and aggregation.
    • Associated with higher thrombin generation and activated protein C resistance.
    • More common in patients with JAK2 mutations.
  • Bleeding:
    • Occurs particularly when platelet counts exceed 1500 × 10⁹/L.
    • Often due to acquired von Willebrand syndrome caused by depletion of high-molecular-weight VWF multimers.
    • Impaired platelet adhesion is the key defect.

Haematological and Morphological Features

• Bone marrow biopsy findings in ET typically show:
  • Marked megakaryocytic hyperplasia.
  • Enlarged, mature megakaryocytes with hyperlobulated (staghorn-like) nuclei.
  • Preserved erythroid and granulocytic lineages.
  • Minimal or absent reticulin fibrosis (helps differentiate from primary myelofibrosis).

Incidence and Prevalence

• Essential thrombocythaemia (ET) represents approximately one-third of BCR::ABL1-negative myeloproliferative neoplasms in regions with advanced healthcare infrastructure. 
• The annual incidence varies by geography and population demographics:
  • United States: Estimates range from 1 to 2.5 new cases per 100,000 persons annually, with a reported mean of 1.55 per 100,000 person-years.
  • Europe: Incidence ranges between 0.38 and 1.7 per 100,000 per year.
  • United Kingdom: Approximately 4.2 cases per 100,000 individuals annually, equating to an estimated 2,720 new diagnoses each year.
  • Due to its typically indolent course and near-normal life expectancy, the prevalence of ET exceeds its incidence, with estimates between 30 to 60 per 100,000 in the general population.

Demographic Characteristics

• Sex: ET is more commonly diagnosed in females, with a female-to-male ratio ranging from 1.25:1 to 2:1, depending on the dataset.
• Age: The median age at diagnosis differs slightly between regions:
  • United States: Median age around 67 years.
  • United Kingdom: Median age approximately 72 years.
     While most patients are older adults, up to 20% are diagnosed before the age of 40.
• Ethnicity: In the United States, incidence is higher among Black populations compared with non-Hispanic White, Hispanic, and Asian groups.

ET in Children

• Childhood-onset ET is exceedingly rare.
• Data from population-based studies in Denmark and British Columbia suggest an incidence of approximately 0.09 per million children under 14 years old per year. 

Clinical findings in paediatric ET include

• Most cases are either sporadic or hereditary thrombocytosis.
• Approximately one-third of affected children report symptoms, primarily headaches and paraesthesia.
• Splenomegaly is present in a subset.
• JAK2 V617F mutations are common in sporadic cases, whereas MPL mutations are more frequently seen in hereditary forms.
• Long-term follow-up studies (median duration ~11 years) have shown no progression to leukaemia or post-ET myelofibrosis, although isolated cases of non-fatal thrombotic events have occurred.
• Studies have also revealed variable rates of monoclonality and mutation positivity in affected female children, with reported JAK2 mutation rates ranging from 20% to 39%.

Incidental Discovery and Symptomatic Presentation

• A significant proportion of ET cases are identified incidentally following routine blood tests showing persistent thrombocytosis.
• Patients may report symptoms such as headaches, visual disturbances, dizziness, and atypical chest pain.
• Unlike polycythaemia vera, generalised pruritus is uncommon in ET (seen in <5% of patients).

Vasomotor Symptoms

• These are linked to microvascular platelet activation and include:
  • Erythromelalgia (burning pain and redness of hands/feet worsened by heat, improved with cooling).
  • Headache, dizziness, syncope.
  • Transient visual changes (e.g. amaurosis fugax).
  • Livedo reticularis (a lacy, purplish skin discolouration).
  • Paresthesia in the extremities.

Thrombotic History

• A history of arterial or venous thrombosis is a key feature:
  • Stroke, transient ischaemic attack (TIA), myocardial infarction.
  • Deep vein thrombosis, pulmonary embolism.
  • Retinal vein or artery occlusion, portal or hepatic vein thrombosis.
  • Digital ischaemia, which can begin with Raynaud-like symptoms and progress to necrosis.
• Risk factors associated with thrombosis in ET include:
  • Age >60 years, previous thrombotic events, cardiovascular risk factors, elevated WBC count (>11 x 10⁹/L), and the JAK2 V617F mutation.

Haemorrhagic History

• Bleeding events, while less frequent than thrombosis, may also be present:
  • Most commonly epistaxis or bruising.
  • Gastrointestinal bleeding is the most serious manifestation.
  • Associated with platelet counts exceeding 1 million/μL, high-dose aspirin (>325 mg/day), or NSAID use.
  • In rare cases, associated with acquired von Willebrand syndrome.

Obstetric History

• A detailed pregnancy history is crucial in female patients:
  • Elevated risk of first-trimester miscarriage (up to 43%).
  • Other complications include stillbirth, preterm labour, preeclampsia, and foetal growth restriction.
  • Use of low-dose aspirin, with or without heparin, may reduce the rate of pregnancy loss.
  • Platelet counts often fall during pregnancy, but this drop does not consistently correlate with complications.
  • The presence of the JAK2 V617F mutation may increase the risk of pregnancy-related complications.

Demographic and Personal Risk Factors

• Age ≥60 years is a recognised risk factor for both diagnosis and complications.
• Female sex predominates among ET patients.
• There is higher reported incidence among individuals of Black ethnicity in some populations.
• Family history of haematologic conditions may suggest hereditary thrombocythaemia.

Cytoreductive Therapy Considerations

• History should also explore the use of hydroxycarbamide and other cytoreductive therapies, particularly if skin changes (e.g., livedo reticularis) are noted.

General Observations on Presentation

• Many individuals are identified incidentally due to a raised platelet count on routine full blood count.
• A subset presents with clinical complications such as thrombosis, haemorrhage, or microvascular symptoms.
• Splenomegaly is the most consistent abnormal finding on physical examination, present in 10–35% of cases and typically mild in size.
• Hepatomegaly is rare; lymphadenopathy is distinctly uncommon.

Key Findings on Physical Examination

Splenomegaly

• Palpable spleen is often modest in size.
• Occurs in up to one-third of cases, more commonly in symptomatic patients.
• May present with left upper quadrant fullness or early satiety.

Microvascular Disturbances (Vasomotor Symptoms)

• Reflect disturbances in microcirculatory flow due to qualitative platelet abnormalities.
• Symptoms suggestive of this on examination include:
  • Erythromelalgia: Red, warm, painful extremities, particularly hands and feet; triggered by heat and relieved by cooling.
  • Livedo reticularis: A net-like, purplish discolouration of the skin, often affecting the lower limbs.
  • Digital ischaemia: May present as cold, cyanotic digits or ulceration; may evolve from Raynaud’s-like features.

Neurological Signs

• Neurological signs are typically subtle and transient but may include:
  • Headache (most common)
  • Lightheadedness or dizziness
  • Visual phenomena (e.g. scintillating scotomata, amaurosis fugax)
  • Rarely, syncope or seizures

Signs of Thrombotic Complications

• May be evident depending on the vascular territory affected:
  • Stroke or TIA: Hemiparesis, speech disturbance, visual field defects.
  • Retinal vessel occlusion: Reduced visual acuity or visual field loss.
  • Deep vein thrombosis: Calf tenderness, oedema.
  • Pulmonary embolism: Tachypnoea, hypoxia, pleuritic chest pain.
  • Portal vein thrombosis: Abdominal distension or splenomegaly.
  • Digital gangrene or ulceration: Suggests distal arterial thrombosis.

Signs of Haemorrhagic Events

• Usually mild on examination:
  • Petechiae, ecchymoses, or mucosal bleeding (e.g., epistaxis, gum bleeding).
  • More serious bleeding (e.g. gastrointestinal) may be occult or present with haemodynamic instability.

Pregnancy-Related Findings

• In pregnant patients, fetal loss or complications such as pre-eclampsia may be evident, although most findings are from history rather than examination.
• No specific physical findings reliably predict adverse outcomes, though some may have increased uterine size due to retained products in missed miscarriage.

Predictive and Risk Factors Noted on Examination

• Advanced age (especially >60 years) is associated with increased thrombotic risk.
• Male sex correlates with higher risk of venous thrombosis.
• Platelet counts >1,000 × 10⁹/L are associated with paradoxical bleeding risk due to acquired von Willebrand factor deficiency, though not apparent on examination without laboratory confirmation.

Rare or Unusual Findings

• Priapism: Very rare, may be related to thrombotic obstruction of penile vasculature.
• Pulmonary hypertension: Occasionally noted on clinical suspicion; often subclinical and confirmed on imaging.

Initial Clinical Assessment

• Symptoms such as headaches, dizziness, visual disturbances, or thrombotic/haemorrhagic events.
• History of first-trimester pregnancy loss or cardiovascular risk factors (e.g., hypertension, diabetes, smoking).
• Family history of thrombocytosis or haematological disorders.
• Physical examination should focus on signs of splenomegaly and vascular complications.

First-Line Laboratory Investigations

• Full Blood Count (FBC): Persistent thrombocytosis (≥450 × 10⁹/L) is the hallmark finding. White cell counts are typically normal or slightly raised, while haemoglobin levels may vary.
• Peripheral Blood Smear: Confirms thrombocytosis and may reveal platelet anisocytosis, including large or hypogranular forms. Occasional presence of immature granulocyte precursors (e.g., myelocytes) may be noted. Red cells are usually normocytic and normochromic but may appear microcytic in cases of iron deficiency. Features like Howell-Jolly bodies may suggest hyposplenism.
• Iron Studies: Essential to exclude iron deficiency, which is a common cause of reactive thrombocytosis. A low serum ferritin (<27 pmol/L) is diagnostic for iron deficiency.

Assessment of Inflammation and Secondary Causes

• C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), and Fibrinogen: Normal levels support a clonal cause, while elevated levels suggest an underlying inflammatory or reactive process.

Bone Marrow Evaluation

• Bone marrow aspirate and biopsy is required to confirm the diagnosis and exclude other myeloproliferative neoplasms. In essential thrombocythaemia (ET), marrow findings include:
  • Proliferation of mature, enlarged megakaryocytes with hyperlobulated nuclei.
  • Absence of significant granulocytic or erythroid proliferation.
  • No substantial reticulin fibrosis; at most, a minor (grade 1) increase may be seen.

Molecular and Genetic Testing

• JAK2 V617F Mutation: Present in approximately 50–60% of ET cases. Associated with increased thrombotic risk, especially in homozygous individuals or younger patients.
• CALR Mutations: Found in 25–30% of cases, typically associated with younger age, male sex, higher platelet counts, and lower thrombotic risk compared to JAK2-positive disease.
• MPL Mutations: Occur in about 3–11% of cases. May be linked with higher platelet counts, older age, and poorer myelofibrosis-free survival.
• Triple-negative ET (absence of JAK2, CALR, and MPL mutations) occurs in around 10–15% of cases. Additional mutations in genes such as ASXL1, EZH2, TET2, IDH1/2, or SRSF2 may support clonal disease in these patients.

Exclusion of Chronic Myeloid Leukaemia

• Molecular testing for the BCR::ABL1 fusion gene via FISH or PCR is necessary. A negative result helps rule out chronic myeloid leukaemia (CML), which may also present with isolated thrombocytosis but requires entirely different management.

Diagnostic Criteria

Major Criteria

• Platelet count ≥450 × 10⁹/L.
• Bone marrow biopsy showing isolated megakaryocytic proliferation without excess granulocytes or erythroid cells, and without significant reticulin fibrosis.
• Exclusion of other myeloid neoplasms such as CML, polycythaemia vera, primary myelofibrosis, and myelodysplastic syndromes.
• Detection of a clonal mutation (JAK2, CALR, or MPL).

Minor Criterion

• Absence of a reactive cause for thrombocytosis or identification of other clonal markers (e.g., ASXL1, EZH2, TET2, IDH1/2, SRSF2, SR3B1).

Non-Clonal Causes of Thrombocytosis

Reactive (Secondary) Thrombocytosis

• Common Triggers:
  • Iron deficiency anaemia
  • Infections or inflammatory diseases
  • Malignancy
  • Recent surgery or trauma
  • Haemorrhage or haemolysis
  • Functional or anatomical asplenia
• Laboratory Clues:
  • Raised CRP, fibrinogen, ESR, and/or ferritin
  • Normal bone marrow morphology without atypical megakaryocytes
• Clinical Context:
  • Thrombocytosis typically subsides when the underlying cause is resolved.
  • Risk of thrombosis or bleeding is generally low compared to clonal disorders.

Pseudothrombocytosis (Spurious)

• Mechanism:
  • Artefactual elevation in platelet counts due to cryoglobulinaemia or platelet clumping.
• Diagnostic Strategy:
  • Repeat blood testing at physiological temperature.
  • Manual blood smear review can confirm or refute spurious counts.

Clonal Myeloproliferative or Myelodysplastic Disorders

Chronic Myeloid Leukaemia (CML)

• Molecular Marker:
  • Presence of BCR::ABL1 fusion gene (Philadelphia chromosome).
• Haematological Features:
  • Often presents with significant leukocytosis, including myeloid precursors, basophils, and eosinophils.
  • Approximately 15–30% may have platelet counts exceeding 600 × 10⁹/L.
• Clinical Indicators:
  • Splenomegaly, fatigue, weight loss, and susceptibility to infections.
• Diagnostic Tools:
  • PCR or FISH testing for BCR::ABL1.

Polycythaemia Vera (PV)

• Pathophysiology:
  • A myeloproliferative neoplasm characterised by increased red cell mass, often with concomitant leukocytosis and thrombocytosis.
• Mutational Profile:
  • JAK2 V617F mutation found in >95% of cases.
• Key Clinical Signs:
  • Aquagenic pruritus, ruddy complexion, and erythromelalgia.
• Diagnostic Parameters:
  • Elevated haemoglobin/haematocrit, low erythropoietin levels, and hypercellular marrow with panmyelosis.

Primary Myelofibrosis (PMF) and Prefibrotic PMF

• Shared Features:
  • May present similarly to ET, especially in prefibrotic phase.
• Differentiating Characteristics:
  • PMF shows marrow fibrosis, atypical megakaryocytes, and peripheral leukoerythroblastosis.
  • Prefibrotic PMF lacks overt fibrosis but shows megakaryocytic atypia and has a worse prognosis than true ET.
• Prognostic Implication:
  • Misclassification can affect therapeutic decisions and expected survival.

Myelodysplastic Syndromes (MDS) with Thrombocytosis

• Overview:
  • Though typically associated with cytopenias, subtypes such as MDS with isolated 5q deletion and MDS/MPN overlap syndromes can manifest with thrombocytosis.
• Key Haematologic Findings:
  • Macrocytic anaemia, dysplastic neutrophils, and occasional ring sideroblasts.
  • Bone marrow demonstrates multilineage dysplasia.
• Confirmation:
  • Cytogenetic analysis is often necessary for diagnosis.

Inherited Forms

Familial Essential Thrombocythaemia

• Genetic Basis:
  • Germline mutations in genes such as TPO, MPL, JAK2, or CALR.
  • Mutations in TPO may lead to overproduction of thrombopoietin via enhanced mRNA translation.
• Inheritance Pattern:
  • Autosomal dominant; often identified through family history.
• Clinical Presentation:
  • Similar to sporadic ET, although often diagnosed at a younger age.
• Diagnosis:
  • Confirmed through genetic testing and family pedigree analysis.

Principles of Management

• ET treatment aims to reduce the risk of thrombosis and bleeding, alleviate symptoms, and delay or prevent transformation to myelofibrosis or acute leukaemia.
• There is no known curative treatment; management is risk-adapted.
• Cardiovascular risk factors (e.g., hypertension, hyperlipidaemia, smoking) should be assessed and optimised in all patients.
• Lifestyle modification and supportive care (e.g., analgesia, antipyretics) should be offered where appropriate.
• Platelet counts and symptoms should be monitored regularly, even in asymptomatic patients.

Risk Stratification

•  The IPSET-Thrombosis tool categorises patients into four risk levels based on age, thrombosis history, and JAK2 V617F mutation status:
  • Very low risk: Age ≤60, no thrombosis history, JAK2 negative.
  • Low risk: Age ≤60, no thrombosis history, JAK2 positive.
  • Intermediate risk: Age >60, no thrombosis history, JAK2 negative.
  • High risk: Any thrombosis history, or age >60 with JAK2 positive.

Management by Risk Group

Very Low-Risk Patients

• Observation is appropriate in asymptomatic individuals.
• Low-dose aspirin (once daily) is considered in the presence of vasomotor symptoms (e.g., headache, erythromelalgia).
• Aspirin is contraindicated in acquired von Willebrand syndrome (aVWS).

Low- and Intermediate-Risk Patients

• Low-dose aspirin is standard unless contraindicated.
• Clopidogrel may be substituted if aspirin is not tolerated.
• Twice-daily aspirin may be trialled for persistent symptoms.
• Cytoreductive therapy is not routinely indicated but may be considered for progressive thrombocytosis, leukocytosis, symptomatic splenomegaly, or persistent symptoms despite antiplatelet therapy.

High-Risk Patients

• Should receive both low-dose aspirin and cytoreductive therapy.
• Hydroxycarbamide is the first-line cytoreductive agent.
• Alternatives:
  • Peginterferon alfa-2a (especially in younger patients or those with pregnancy potential).
  • Anagrelide or busulfan may be considered second-line, with caution due to toxicity and potential leukemogenicity.

Cytoreductive Therapy

Hydroxycarbamide

• Oral cytoreductive drug; titrated to maintain platelet count between 100–400 ×10⁹/L.
• Avoided in pregnancy due to teratogenicity.
• Side effects include cytopenias, mucocutaneous ulcers, and possible hepatic dysfunction.
• No consistent evidence links it to increased leukaemia risk in ET.

Peginterferon alfa-2a

• Non-teratogenic and non-leukemogenic.
• Preferred in younger patients, women of childbearing potential, and pregnancy.
• May reduce JAK2 and CALR allele burden.
• Side effects include flu-like symptoms, depression, and fatigue.

Anagrelide

• Lowers platelet count but with a higher risk of fibrotic progression and cardiovascular toxicity.
• May be considered second-line in patients intolerant to other agents.

Busulfan

• Used mainly in older patients or where other agents fail.
• Risk of leukaemic transformation is debated; not recommended by current guidelines.

Pregnancy Management

• Management requires joint haematology–obstetric care.
• First-line therapy: low-dose aspirin, particularly beneficial in JAK2-positive patients.
• Cytoreduction (if needed): peginterferon alfa-2a is preferred.
• Avoid hydroxycarbamide, anagrelide, and busulfan during pregnancy and lactation.
• High-risk patients with prior thrombosis:
  • Arterial thrombosis: Aspirin + peginterferon.
  • Venous thrombosis: Peginterferon + LMWH (e.g., enoxaparin).

Management of Thrombosis History

• Arterial thrombosis: Consider twice-daily low-dose aspirin and cytoreductive therapy.
• Venous thrombosis: Add systemic anticoagulation to aspirin and cytoreduction, balancing bleeding risk.

Plateletpheresis

• Rarely used; reserved for emergencies (e.g., severe thrombocytosis with neurological symptoms, life-threatening bleeding).
• Temporarily reduces platelet count; must be followed by cytoreductive therapy.

Surgical Patients

• Increased risk of bleeding and thrombosis.
• Antiplatelet therapy usually stopped 7–10 days before major surgery and restarted postoperatively.
• Preoperative optimisation of platelet count with cytoreduction is recommended.

Acquired von Willebrand Syndrome (aVWS)

• Should be suspected in bleeding patients or if platelet count >1000 × 10⁹/L.
• Ristocetin cofactor activity <30% confirms diagnosis.
• Aspirin should be avoided; consider cytoreduction to lower platelet count and reduce bleeding risk.

Refractory or Intolerant Disease

• Switch cytoreductive agent based on side effect profile and comorbidities.
• Peginterferon, anagrelide, or busulfan may be options.
• Clinical trials or off-label use of agents like ruxolitinib may be considered in select patients.

Monitoring and Follow-up

• Regular monitoring for:
  • Platelet and white cell counts
  • Disease symptoms and splenomegaly
  • Signs of transformation to myelofibrosis or acute leukaemia
• Bone marrow biopsy is indicated if transformation is suspected.

Overall Survival

• Most individuals with essential thrombocythaemia (ET) experience a life expectancy that is near-normal or modestly reduced in comparison with the general population.
• Median overall survival (OS) estimates vary by age:
  • ≤40 years: approximately 35 years
  • 41–60 years: approximately 22 years
  • 60 years: approximately 11 years
• A large population-based study of over 8,700 patients reported a median OS of 12.1 years, with a 1.5% cumulative incidence of acute myeloid leukaemia (AML) transformation, typically occurring around 5.8 years after diagnosis.
• A multivariable analysis involving 891 patients revealed the following independent predictors of inferior survival:
  • Age >60 years (Hazard Ratio [HR] 6.7)
  • Prior thrombotic events (HR 2.81)
  • Anaemia (haemoglobin <12 g/dL; HR 2.95)
  • Leukocytosis (WBC >11 × 10⁹/L; HR 2.01)
• Another cohort study (n=605) similarly identified age ≥60, anaemia, leukocytosis ≥15 × 10⁹/L, and previous venous thrombosis as factors associated with decreased survival.

Thrombotic Risk

• Thrombosis is a major cause of morbidity and mortality in ET, involving both venous and arterial events, such as deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction.
• The revised International Prognostic Score for Thrombosis in ET (revised IPSET-thrombosis) incorporates four independent risk factors:
  • Age >60 years (HR 1.50)
  • Previous thrombosis (HR 1.93)
  • Presence of cardiovascular risk factors (e.g. hypertension, diabetes, smoking; HR 1.56)
  • JAK2 V617F mutation (HR 2.04)
• Interestingly, a platelet count exceeding 1,000 × 10⁹/L has been associated with a reduced risk of arterial thrombosis, likely due to acquired von Willebrand syndrome, which alters haemostatic balance.

Risk of Disease Transformation

• ET carries the lowest risk of transformation among the BCR::ABL1-negative myeloproliferative neoplasms.
• Cumulative 15-year risk estimates:
  • AML transformation: 2–5.3%
  • Progression to post-ET myelofibrosis: 4–11%
• Independent predictors of AML transformation include:
  • Low haemoglobin
  • Marked thrombocytosis (platelet count ≥1,000 × 10⁹/L)
• Neither the presence of the JAK2 V617F mutation nor the use of cytoreductive therapy has been associated with increased transformation risk.
• While JAK2, CALR, and MPL mutations do not significantly affect overall survival, specific mutations influence disease behaviour:
  • JAK2 and MPL mutations are associated with increased risk of thrombosis.
  • MPL mutations may also confer a higher risk of fibrotic progression.

Leukaemic Transformation

• Transformation to acute myeloid leukaemia (AML) is a recognised but uncommon late complication of ET.
• Reported 15-year cumulative risk ranges from 2% to 5.3%.
• Risk factors associated with progression to AML include:
  • Anaemia at diagnosis (e.g. haemoglobin <12 g/dL)
  • Platelet count ≥1,000 × 10⁹/L
  • Older age at diagnosis
• Neither the presence of JAK2 V617F mutation nor the use of cytoreductive therapy has been consistently shown to increase AML risk.

Progression to Myelofibrosis

• Transformation to post-ET myelofibrosis occurs more frequently than transformation to AML but remains relatively rare.
• The 15-year cumulative risk is reported between 4% and 11%.
• Factors contributing to fibrotic progression include:
  • Presence of MPL mutations
  • Higher baseline leukocyte count
  • Lower haemoglobin levels
• Symptoms may evolve to include progressive splenomegaly, constitutional symptoms, and bone marrow fibrosis on biopsy.

Thrombotic Events

• Thrombosis represents a major source of morbidity and mortality in ET, with an intermediate overall likelihood.
• Both arterial and venous thromboses occur due to:
  • Abnormal platelet function (qualitative defects)
  • Elevated platelet count (quantitative abnormality)
• Reported thrombotic complications include:
  • Stroke
  • Transient ischaemic attacks
  • Myocardial infarction
  • Deep vein thrombosis
  • Pulmonary embolism
  • Hepatic or portal vein thrombosis
  • Retinal artery/vein occlusion
  • Digital ischaemia, which may progress to necrosis

Haemorrhagic Complications

• Bleeding risk is also elevated in ET and is typically linked to extreme thrombocytosis (>1,000 × 10⁹/L), which may lead to acquired von Willebrand syndrome.
• Bleeding events are usually mucocutaneous but can occasionally be severe, especially in patients treated with high-dose aspirin or with pre-existing coagulation abnormalities.
• Common bleeding manifestations include:
  • Epistaxis
  • Easy bruising
  • Gastrointestinal bleeding
  • Menorrhagia

Pregnancy-Related Complications

• ET is associated with adverse pregnancy outcomes in a significant proportion of cases.
• Complications may include:
  • First trimester spontaneous abortion
  • Intrauterine growth restriction (IUGR)
  • Intrauterine fetal death (particularly in the third trimester)
• Mechanisms are likely related to microvascular placental thrombosis and impaired placental perfusion.
• Pregnancies should be managed in collaboration with haematology and obstetrics specialists, often involving low-dose aspirin and/or interferon alfa.

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