Chronic myeloproliferative neoplasm with sustained thrombocytosis, thrombosis/hemorrhage risk, and JAK2/CALR/MPL mutations.
Also known as: ET, essential thrombocytosis, primary thrombocythemia
Overview
BCR-ABL1-negative Philadelphia-chromosome-negative chronic myeloproliferative neoplasm characterized by sustained peripheral thrombocytosis (≥450 × 10⁹/L), megakaryocytic hyperplasia in the bone marrow, and characteristic driver mutations (JAK2 V617F, CALR, or MPL) in most patients.
Epidemiology
Incidence ~1-2 per 100,000 per year. Bimodal age distribution: peak in women 50-60s and a smaller peak in young women (20-40s). Female predominance overall. Median survival 15-20+ years; survival approaches that of age-matched general population in low-risk ET.
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Question 1HematologyMedium
A 58-year-old woman is referred for a platelet count of 780 × 10⁹/L found on two CBCs three months apart. She reports intermittent burning, redness, and warmth in her fingertips that resolves with aspirin. She has no recent infection, surgery, or bleeding, and her exam shows only mild splenomegaly. Iron studies, ferritin, and CRP are normal, and a peripheral smear shows large platelets without a left shift or basophilia. Which of the following findings would best support a diagnosis of essential thrombocythemia?
AMarkedly low serum erythropoietin (EPO) level
BJAK2 V617F driver mutation on peripheral blood
CGrade 3 reticulin fibrosis on a marrow biopsy
DSmall hypolobated megakaryocytes on a marrow biopsy
EDetectable BCR-ABL1 fusion transcript in the blood
Reveal answer & full explanation
Correct answer: B — JAK2 V617F driver mutation on peripheral blood
AMarkedly low serum erythropoietin (EPO) level
BJAK2 V617F driver mutation on peripheral blood✓
CGrade 3 reticulin fibrosis on a marrow biopsy
DSmall hypolobated megakaryocytes on a marrow biopsy
EDetectable BCR-ABL1 fusion transcript in the blood
Why JAK2 V617F driver mutation on peripheral blood is correct
ET is a BCR-ABL1-negative myeloproliferative neoplasm; a clonal driver mutation in JAK2 (V617F, ~50-60%), CALR, or MPL is a WHO 2022 major criterion and the strongest molecular evidence of clonal thrombocytosis.
JAK2 V617F PCR is the first-line molecular test once reactive causes are excluded (normal iron studies, ferritin, and CRP here); finding it supports a clonal process rather than reactive thrombocytosis.
The vignette already excludes reactive thrombocytosis and shows erythromelalgia (burning red distal extremities relieved by aspirin), the textbook microvascular symptom of ET.
Why the others are wrong
Detectable BCR-ABL1 fusion transcript in the blood: its presence defines chronic myeloid leukemia and is a WHO exclusion criterion for ET, so a positive result argues against ET rather than supporting it.
Markedly low serum erythropoietin (EPO) level: this points toward polycythemia vera, in which autonomous erythrocytosis suppresses EPO; EPO is typically normal in ET, which has a normal red cell mass.
Grade 3 reticulin fibrosis on a marrow biopsy: significant fibrosis indicates primary myelofibrosis; ET marrow shows proliferation of mature, hyperlobulated megakaryocytes with at most minimal (grade 1) reticulin.
Small hypolobated megakaryocytes on a marrow biopsy — megakaryocyte proliferation is expected in ET, but ET megakaryocytes are large and mature with hyperlobulated nuclei; small hypolobated forms point away from ET toward a myelodysplastic syndrome or prefibrotic myelofibrosis, which must be excluded first.
Question 2HematologyMedium
A 58-year-old woman presents with several months of burning, reddened pain in her hands and feet that improves dramatically with aspirin. She has had occasional headaches and transient visual blurring. Physical exam shows mild splenomegaly. CBC reveals a platelet count of 1,050 × 10⁹/L with large platelets on the smear; hemoglobin and white count are normal. Iron studies and CRP are normal, BCR-ABL1 is negative, and JAK2 V617F testing is positive. Bone marrow biopsy shows proliferation of mature, hyperlobulated megakaryocytes. Which of the following best explains this patient's disease?
ACytokine-independent erythroid growth from a JAK2 exon 12 mutation
BRibosomal protein haploinsufficiency from an isolated 5q deletion
CConstitutive JAK-STAT activation in hematopoietic stem cells
DClonal expansion with ring sideroblasts from an SF3B1 mutation
Why Constitutive JAK-STAT activation in hematopoietic stem cells is correct
Essential thrombocythemia is a BCR-ABL1-negative myeloproliferative neoplasm driven by acquired somatic mutations in JAK2 (V617F, ~50-60%), CALR, or MPL.
These mutations constitutively activate JAK-STAT signaling independent of normal cytokine control, driving megakaryocyte proliferation and sustained platelet overproduction.
This vignette is classic ET: middle-aged woman, platelets over 1000 × 10⁹/L, JAK2 V617F-positive, and erythromelalgia (burning red extremities) that responds to aspirin.
Per WHO 2022, diagnosis requires sustained thrombocytosis, characteristic megakaryocyte morphology, exclusion of other myeloid neoplasms, and a JAK2/CALR/MPL mutation.
Why the others are wrong
Activating MPL mutation driving thrombopoietin receptor signaling — MPL W515 mutations are a genuine ET driver in roughly 3-5% of cases, but JAK2, CALR, and MPL driver mutations are essentially mutually exclusive, and this patient's positive JAK2 V617F identifies her clone's driver; an MPL mutation would in any case act through the same downstream pathway, so the unifying mechanism remains constitutive JAK-STAT activation.
Cytokine-independent erythroid growth from a JAK2 exon 12 mutation — exon 12 mutations cause polycythemia vera with erythrocytosis, but this patient's hemoglobin is normal, making PV the wrong diagnosis.
Clonal expansion with ring sideroblasts from an SF3B1 mutation — this describes the MDS/MPN overlap RARS-T with dysplasia and ring sideroblasts, whereas the marrow here shows only megakaryocytic proliferation without dysplasia.
Ribosomal protein haploinsufficiency from an isolated 5q deletion — MDS with isolated del(5q) can present with a normal or elevated platelet count, typically in older women, but it is marked by a macrocytic anemia (driven largely by RPS14 haploinsufficiency) with hypolobated megakaryocytes in the marrow, whereas this patient has a normal hemoglobin, mature hyperlobulated megakaryocytes, and a positive JAK2 V617F typical of an MPN.
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Acquired somatic mutations in JAK2 (V617F, ~50-60%), CALR (exon 9, ~25-30%), or MPL (W515, ~3-5%) constitutively activate JAK-STAT signaling in hematopoietic stem cells, driving megakaryocyte proliferation and platelet overproduction. About 10-15% are 'triple-negative' with unidentified driver mutations. Increased platelet number and qualitative platelet dysfunction predispose to thrombosis; paradoxically, extreme thrombocytosis (>1500 × 10⁹/L) acquires von Willebrand factor and produces a bleeding diathesis.
Middle-aged woman with platelets >1000 × 10⁹/L, JAK2 V617F mutation, and erythromelalgia responsive to aspirin.
Differential diagnosis
Reactive (secondary) thrombocytosis — Iron deficiency, infection, inflammation, malignancy, splenectomy; platelets usually <1000; resolves with treatment of underlying cause
Polycythemia vera (PV) — Erythrocytosis (hemoglobin/hematocrit elevation); JAK2 V617F or exon 12 mutation in virtually all
Primary myelofibrosis (prefibrotic stage) — Megakaryocyte atypia and clustering, reticulin fibrosis on marrow biopsy; can mimic ET early
Chronic myeloid leukemia — Leukocytosis with left shift, basophilia; BCR-ABL1 (Philadelphia chromosome) positive
MDS/MPN overlap (e.g., RARS-T, atypical CML) — Dysplasia plus proliferative features; ring sideroblasts in RARS-T
Familial thrombocytosis — Germline THPO or MPL mutations; family history
Diagnostic workup
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)
Treatment
First-line
Risk stratify with the revised IPSET-thrombosis: age >60, prior thrombosis, JAK2 V617F (cardiovascular risk factors guide aspirin use but are no longer scored)
Low risk — observation OR low-dose aspirin (81 mg daily) if microvascular symptoms, JAK2-positive, or cardiovascular risk factors
Intermediate risk (age >60, JAK2 wild-type, no thrombosis) — low-dose aspirin, cytoreduction optional; High risk (prior thrombosis at any age, or age >60 with JAK2 V617F) — 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 (prior thrombosis at any age, OR age >60 with JAK2 V617F)
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
Venous thromboembolism, including splanchnic vein thrombosis (Budd-Chiari)
Bleeding from acquired von Willebrand syndrome at platelets >1500
Pregnancy loss, IUGR
Transformation to myelofibrosis (~5-10% at 15 years)
Transformation to acute myeloid leukemia (~2-5% at 15 years; risk increased after busulfan, P32, pipobroman or sequential cytoreductive agents; hydroxyurea alone not clearly leukemogenic)
Erythromelalgia, digital ischemia
PANCE pearls
Erythromelalgia (burning red distal extremities) is the textbook microvascular symptom; it responds dramatically to low-dose aspirin.
JAK2 V617F-positive ET carries higher thrombosis risk than CALR-mutated or triple-negative ET — and CALR-mutated ET tends to have higher platelet counts but lower thrombosis risk.
Platelets >1500 × 10⁹/L can produce acquired von Willebrand syndrome and a bleeding tendency — withhold aspirin and check vWF:RCo activity.
Hydroxyurea is teratogenic — switch to interferon-alfa in pregnancy.
Splanchnic vein thrombosis (Budd-Chiari, portal vein) in a young patient should prompt JAK2 V617F testing even without overt thrombocytosis.
References
WHO 2022 — Khoury JD et al. 5th edition WHO Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36:1703-1719.
ELN/IPSET-thrombosis — Barbui T et al. Development and validation of an International Prognostic Score for thrombosis in WHO-defined ET (IPSET-thrombosis). Blood 2012.
NCCN — NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms.
Revised IPSET-thrombosis — Barbui T et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015; 5:e369.
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