Essential Thrombocythemia (ET)

Symptoms

• Asymptomatic — discovered on routine CBC in ~50%
• Vasomotor: headache, lightheadedness, dizziness, transient visual disturbances
• Erythromelalgia — painful, red, burning hands and feet relieved by aspirin
• Thrombosis — arterial (stroke, TIA, MI, peripheral) or venous (DVT, PE, splanchnic veins)
• Bleeding — usually with platelets >1500 × 10⁹/L (acquired von Willebrand syndrome): mucosal, GI
• Recurrent miscarriage and pregnancy complications
• Constitutional symptoms (fatigue, pruritus) less common than in PV/MF

Signs / physical exam

• Often normal physical exam
• Mild splenomegaly in ~30%
• Erythematous, warm distal extremities (erythromelalgia)
• Bruising, petechiae in bleeding phenotype

Classic findings

Middle-aged woman with platelets >1000 × 10⁹/L, JAK2 V617F mutation, and erythromelalgia responsive to aspirin.

Diagnostic criteria

WHO 2022 — ALL 4 major criteria, OR first 3 major + minor criterion: 1) Platelets ≥450 × 10⁹/L sustained 2) Bone marrow biopsy showing proliferation mainly of megakaryocytic lineage with increased numbers of mature, hyperlobulated megakaryocytes; no significant granulocytic or erythroid proliferation; very rarely minor reticulin fibrosis (grade 1) 3) WHO criteria for BCR-ABL1+ CML, PV, PMF, MDS, or other myeloid neoplasm not met 4) JAK2, CALR, or MPL mutation Minor criterion: presence of another clonal marker or absence of evidence for reactive thrombocytosis.

Labs

• CBC with smear — sustained platelets ≥450 × 10⁹/L; large platelets, megakaryocyte fragments
• Iron studies, ferritin, CRP — exclude reactive thrombocytosis
• JAK2 V617F PCR — first-line molecular test
• If JAK2 negative: CALR exon 9 and MPL W515 testing
• BCR-ABL1 — exclude CML
• LDH, uric acid, basic chemistries
• Bone marrow aspirate and biopsy with reticulin stain — required for diagnosis (megakaryocyte morphology distinguishes from prefibrotic PMF)
• Cytogenetics on marrow

Imaging

• Abdominal ultrasound for splenomegaly assessment (especially if splanchnic thrombosis)
• Other imaging guided by symptoms (Doppler, CTA, MRV)

First-line

• Risk stratify with IPSET-thrombosis: age >60, prior thrombosis, JAK2 V617F, cardiovascular risk factors
• Low risk — observation OR low-dose aspirin (81 mg daily) if microvascular symptoms, JAK2-positive, or cardiovascular risk factors
• Intermediate/high risk — cytoreduction with hydroxyurea PLUS low-dose aspirin
• Pre-treatment: aggressive control of cardiovascular risk factors (smoking, hypertension, lipids, glucose)

Very low / low-risk ET (age <60, no prior thrombosis)

• Observation if asymptomatic, JAK2-negative, no CV risk
• Low-dose aspirin 81 mg if microvascular symptoms or JAK2-positive
• Manage cardiovascular risk factors

High-risk ET (age >60 OR prior thrombosis)

• Cytoreduction: hydroxyurea is first-line (target platelets <400 × 10⁹/L)
• Plus low-dose aspirin (unless bleeding from acquired vWD)
• Therapeutic anticoagulation if prior venous thrombosis (warfarin or DOAC)

Hydroxyurea-intolerant or refractory

• Pegylated interferon-alfa-2a (preferred in younger patients and pregnancy)
• Anagrelide (PDE3 inhibitor that selectively reduces platelets — risk of cardiac/headache side effects, anemia)
• Ruxolitinib in select cases

Extreme thrombocytosis (>1500) with bleeding

• AVOID aspirin (acquired von Willebrand syndrome)
• Cytoreduction to lower platelets first
• Add aspirin once platelets <1000 if no ongoing bleeding

Pregnancy

• Low-dose aspirin throughout
• Prophylactic LMWH postpartum (6 weeks)
• Pegylated interferon if cytoreduction needed (avoid hydroxyurea — teratogen, anagrelide crosses placenta)

Second-line / adjunct

• Interferon-alfa for younger patients, pregnancy, or hydroxyurea intolerance
• Anagrelide as platelet-selective option
• Ruxolitinib in select MPN-overlap presentations