Essential Thrombocytosis (ET)

JAK2, CALR, and MPL mutation–driven thrombocytosis — risk stratification, aspirin, cytoreductive therapy, and the challenge of distinguishing ET from pre-fibrotic MF

Key Points

• Essential thrombocytosis is defined by sustained platelet count ≥450,000/μL from a clonal megakaryocytic expansion — driver mutations include JAK2 V617F (~60%), CALR exon 9 (~25%), MPL W515K/L (~4%), and triple-negative (~12%); mutation type strongly influences prognosis.
• The WHO 2022 diagnosis requires platelet count ≥450,000/μL, bone marrow biopsy with proliferative megakaryocytic hyperplasia (large, mature megakaryocytes) without granulocyte or erythroid hyperplasia, and exclusion of reactive thrombocytosis and other MPNs — particularly pre-fibrotic primary myelofibrosis.
• Thrombosis (arterial predominates) and bleeding (at very high platelet counts, typically >1,500,000/μL — acquired vWF deficiency) are the primary clinical concerns; hemorrhage risk is the paradoxical reason high-platelet-count patients may have aspirin withheld.
• Risk stratification drives therapy: very-low-risk (age <60, JAK2-negative, no thrombosis) and low-risk patients need observation ± aspirin; high-risk patients (age ≥60 or prior thrombosis) need cytoreductive therapy, preferably hydroxyurea or ropeginterferon alfa-2b.
• CALR-mutated ET has a lower thrombosis risk but higher risk of myelofibrotic transformation compared to JAK2-mutated ET; triple-negative ET has the most uncertain prognosis and should be evaluated for hereditary thrombocytosis.
• Distinguishing ET from pre-fibrotic primary myelofibrosis (pre-PMF) requires an expert bone marrow biopsy review — both present with thrombocytosis, but pre-PMF has atypical megakaryocyte morphology and carries a substantially worse prognosis.

Molecular Biology, Diagnosis, and Differential

**Driver mutations in ET:** *JAK2 V617F (~60%):* Identical mutation to PV — constitutively activates JAK-STAT signaling. JAK2-mutated ET has higher hemoglobin and WBC, higher thrombosis risk (particularly arterial), lower risk of myelofibrotic transformation, and lower risk of blastic transformation compared to other mutation types. JAK2 V617F allele burden in ET is typically lower than in PV (often 1–50% vs. 50–100% in PV). *CALR exon 9 mutations (~25%):* Frameshift insertions/deletions in calreticulin (CALR) exon 9 — type 1 (52-bp deletion) and type 2 (5-bp insertion) are most common. CALR…

Risk Stratification and Treatment Framework

**IPSET-thrombosis score (revised ELN 2019):** The primary tool for ET risk stratification: | Risk Group | Criteria | Treatment | |---|---|---| | Very low | Age 1,500,000/μL): acquired von Willebrand disease (loss of high-molecular-weight vWF multimers, which adsorb onto the excess platelet surface) increases bleeding risk — screen with vWF ristocetin cofactor activity; withhold aspirin if activity <20–30% (cytoreduction to normalize platelets restores vWF function) **Microvascular symptoms:** Erythromelalgia (burning, redness of the extremities — exquisitely responsive to aspirin), digital…

Monitoring and Transformation

**Routine monitoring:** - CBC with differential every 3–6 months (adjust based on disease stability and therapy) - Bone marrow biopsy: at diagnosis (required for WHO criteria); repeat if progression suspected (new splenomegaly, cytopenias, constitutional symptoms, rising LDH) - Molecular monitoring: JAK2 V617F allele burden or CALR variant allele frequency on interferon (expected to decrease with molecular response); less informative on HU - LFTs, creatinine: annually on cytoreduction - Ferritin: iron deficiency from phlebotomy is not standard in ET (unlike PV where iron depletion is a goal)…