Chronic myeloproliferative neoplasm with sustained thrombocytosis, thrombosis/hemorrhage risk, and JAK2/CALR/MPL mutations.
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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?
- ADetectable BCR-ABL1 fusion transcript in the blood
- BMarkedly low serum erythropoietin (EPO) level
- CGrade 3 reticulin fibrosis on a marrow biopsy
- DJAK2 V617F driver mutation on peripheral blood
Reveal answer & full explanation
Correct answer: D — JAK2 V617F driver mutation on peripheral blood
- ADetectable BCR-ABL1 fusion transcript in the blood
- BMarkedly low serum erythropoietin (EPO) level
- CGrade 3 reticulin fibrosis on a marrow biopsy
- DJAK2 V617F driver mutation on peripheral 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.
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?
- AConstitutive JAK-STAT activation in hematopoietic stem cells
- BCytokine-independent erythroid growth from a JAK2 exon 12 mutation
- CActivating MPL mutation driving thrombopoietin receptor signaling
- DClonal expansion with ring sideroblasts from an SF3B1 mutation
Reveal answer & full explanation
Correct answer: A — Constitutive JAK-STAT activation in hematopoietic stem cells
- AConstitutive JAK-STAT activation in hematopoietic stem cells✓
- BCytokine-independent erythroid growth from a JAK2 exon 12 mutation
- CActivating MPL mutation driving thrombopoietin receptor signaling
- 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.
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Risk factors
- Older age (thrombosis risk)
- Prior thrombotic event
- JAK2 V617F mutation (higher thrombosis risk than CALR or triple-negative)
- Cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia)
- Leukocytosis
Pathophysiology
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.
Clinical presentation
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.
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 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
Complications
- Arterial thrombosis (stroke, MI, peripheral arterial occlusion)
- 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; higher with cytoreductive treatment exposure)
- 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.
- Always exclude reactive thrombocytosis (iron deficiency, inflammation, infection, occult malignancy, post-splenectomy) before invoking ET.
- 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 Neoplasms and Acute Leukaemias. Leukemia 2022.
- 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.