Essential thrombocythemia (ET)

Diagnostic Criteria (WHO 2022)

• Major: (1) sustained platelet count ≥450k; (2) BM proliferation of large mature megakaryocytes (no significant fibrosis, grade 1 or less); (3) not meeting WHO criteria for another myeloid neoplasm (PV, PMF, CML, MDS); (4) JAK2, CALR, or MPL mutation.
• Minor: presence of a clonal marker or absence of evidence for reactive thrombocytosis.
• Diagnosis: all 4 major, OR the first 3 major plus the minor criterion.
• Critical DDx: pre-fibrotic/early PMF (prePMF), distinguished by megakaryocyte morphology (PMF: clustered, hyperchromatic, bulbous nuclei vs ET: dispersed, hyperlobated). PrePMF has worse prognosis.
• Reactive thrombocytosis: infection, inflammation, tissue damage (most common), iron deficiency, post-splenectomy, hemorrhage, malignancy. Ferritin and hsCRP help distinguish.

Clinical Presentation

• Symptoms: headaches, dizziness, visual changes, vertigo, seizures; erythromelalgia; paresthesias; arterial > venous thrombosis; GI or mucosal bleeding and epistaxis (acquired vWD); first-trimester spontaneous abortion.
• Signs: splenomegaly (~25%), cutaneous ulcers.

CALR-mutant vs JAK2 V617F-mutant ET

• CALR-mutant ET: younger age of onset. CALR activates the megakaryocytic lineage, whereas JAK2 produces panmyelosis.
• CALR-mutant: isolated thrombocytosis (lower hemoglobin, lower WBC), lower thrombotic risk; survival differences by driver mutation are inconsistent.
• CALR-mutant ET has lower thrombotic risk than JAK2-mutant ET; driver mutation is not a consistent independent predictor of overall survival, and triple-negative ET (no JAK2/CALR/MPL) is not inferior to CALR and also has a lower thrombosis risk than JAK2-mutated ET; in ET, type 2/type 2-like CALR has the lowest thrombotic risk, while type 1/type 1-like CALR carries higher myelofibrotic-progression risk.

Risk Stratification, IPSET-thrombosis (revised)

• Very low risk: age ≤60 AND no prior thrombosis AND JAK2 V617F-negative, ~0.4%/yr thrombosis.
• Low risk: age ≤60 AND no prior thrombosis AND JAK2 V617F-positive, ~1.6%/yr.
• Intermediate risk: age >60 AND no prior thrombosis AND JAK2 V617F-negative, ~1.4 to 1.6%/yr.
• High risk: prior thrombosis OR (age >60 AND JAK2 V617F-positive), ~2.4 to 4.2%/yr (without vs with cardiovascular risk factors).

Classic Risk Stratification

• Low risk (all of): age <60, no history of thromboembolism, platelet count <1,500,000/uL, no cardiovascular risk factors.
• Intermediate risk: neither low- nor high-risk.
• High risk (one or both): age ≥60, history of thromboembolism.

Risk-Adapted Management

• Platelet-lowering agents: hydroxyurea, interferon-alfa (preferred if pregnant), anagrelide.
• Indications to start cytoreduction despite low-risk disease: new thrombosis, acquired vWD and/or disease-related major bleeding, symptomatic/progressive splenomegaly, symptomatic thrombocytosis, progressive leukocytosis, progressive disease-related symptoms (e.g., night sweats), vasomotor/microvascular disturbances not responsive to aspirin (e.g., chest pain).

Treatment

• Very-low / low risk: observation with or without low-dose ASA (avoid ASA in CALR-mutated low-risk without CV risk factors per some guidelines, debated).
• Intermediate: low-dose ASA with or without cytoreduction.
• High risk: cytoreduction plus ASA. 1st-line hydroxyurea (HU) or pegylated IFN alfa-2a (selected by age, pregnancy plans, comorbidity, preference); anagrelide 2nd-line. Ropeginterferon alfa-2b for ET, FDA approved Aug 31, 2026 for adults with ET (SURPASS-ET vs anagrelide in HU-resistant/intolerant ET, Mesa Lancet Haematol 2025, durable ELN response 43% vs 6% plus fewer serious AEs); label covers all adults with ET regardless of genotype or prior therapy (pivotal SURPASS-ET in HU-resistant/intolerant ET; phase 2b EXCEED-ET supportive, included treatment-naive patients). Bomedemstat (LSD1 inhibitor), phase 3 Shorespan-006 (vs best available therapy, HU-resistant/intolerant ET) and Shorespan-007 (vs HU, cytoreduction-naive ET) ongoing.
• Anagrelide: PDE3 inhibitor, reduces megakaryocyte maturation. PT1 (Harrison 2005), HU plus ASA superior to anagrelide plus ASA in high-risk ET (PVSG-defined, not JAK2-selected; more arterial events and MF progression with anagrelide). Reserved for intolerance. Note: ruxolitinib is NOT approved for ET.
• Platelet threshold for treatment: aim platelets <400 to 450k in high-risk ET. Avoid uncontrolled thrombocytosis, acquired vWD risk leads to bleeding.
• CALR vs JAK2: CALR-mutated ET, younger patients, lower thrombosis risk than JAK2; lowest with type 2/type 2-like insertions (type 1 deletions carry higher myelofibrotic-progression risk). Higher platelet counts typically.

Extreme Thrombocytosis & Acquired vWD

• With platelets ≥1,000,000 to 1,500,000/uL, screen for acquired von Willebrand syndrome (high-molecular-weight vWF multimers are adsorbed/cleaved), which paradoxically causes bleeding; aspirin can precipitate excessive bleeding in this setting.

Pregnancy and ET

• Many recommend aspirin for all pregnant women with ET unless a firm contraindication exists.
• If platelets ≥1000 × 10⁹/L, evaluate for acquired von Willebrand syndrome, since aspirin may cause excessive bleeding if present.
• Add low-molecular-weight heparin (LMWH) to low-dose aspirin if there is a prior major thrombosis or severe pregnancy complication.
• Consider interferon-alfa if platelets ≥1500 × 10⁹/L or with prior major bleeding. After delivery, consider LMWH for 6 weeks to prevent DVT.
• If cytoreduction is needed during pregnancy, do NOT use hydroxyurea; use peginterferon alfa-2a.
• In PV pregnancy, keep hematocrit within the gestation-specific normal range (it falls with plasma-volume expansion), not merely <45%, using venesection when needed.

Pregnancy Risk Triage for PV or ET

• Low-risk pregnancy: no prior disease-related complications, absence of hereditary thrombotic risk factors, age <35, platelets <1,000,000/mcL. Give low-dose aspirin throughout pregnancy and for 6 weeks postpartum.
• High-risk pregnancy (any of): prior major thrombosis or major disease-related hemorrhage (microvascular symptoms alone do not qualify), or two or more hereditary thrombophilic factors (weaker data); severe complications in a prior pregnancy (≥3 first-trimester losses or ≥1 second/third-trimester loss, birth weight <5th percentile, intrauterine death or stillbirth, preeclampsia necessitating preterm delivery <37 weeks); prior VTE or other strong VTE risk factor. Platelets >1,000,000/mcL should prompt acquired vWD assessment rather than automatic antepartum LMWH. Consider prophylactic-dose LMWH with low-dose aspirin throughout pregnancy and for 6 weeks postpartum.

Prognosis

• Often prolonged course, but overall survival is reduced versus matched controls (median ~18 years overall, over 35 years in younger patients); progression to MF or AML still contributes to mortality.
• Progression to AML <5%; progression to MF <25%.