Essential Thrombocytopenia

Summary

Essential Thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) defined by sustained overproduction of platelets by clonal megakaryocytes in the bone marrow, leading to a persistently elevated platelet count (> 450 × 10⁹/L).

Note: the lesson title says "Essential Thrombocytopenia," but the correct disease is Essential Thrombocythemia — too many platelets, not too few.

• Cause: driver mutations in JAK2 (V617F), CALR, or MPL.
• Age: typically > 50 years; female predominance.
• Key risks: thrombosis (arterial > venous) and bleeding (when platelets are very high).
• Classic clue: erythromelalgia — burning, red, painful hands/feet relieved by aspirin.
• Treatment: low-dose aspirin ± cytoreduction (hydroxyurea) based on risk.

Definition & Epidemiology

Definition

• A Philadelphia-negative myeloproliferative neoplasm (MPN) characterized by sustained thrombocytosis (platelets > 450 × 10⁹/L) due to clonal proliferation of megakaryocytes.
• Belongs to the same family as Polycythemia Vera (PV) and Primary Myelofibrosis (PMF).

Epidemiology

• Incidence: ~1–2 per 100,000/year.
• Age: bimodal — peak around 50–60 years; a smaller peak in young women (~30 yrs).
• Sex: slight female predominance.
• Most indolent of the MPNs — long median survival (often > 15–20 years).

Etiology & Pathophysiology

Driver mutations (mutually exclusive in ~90%)

• JAK2 V617F — most common (~50–60%). Causes constitutive activation of the JAK-STAT pathway → uncontrolled megakaryocyte proliferation.
• CALR (calreticulin) — ~20–25%. Younger patients, higher platelets, lower thrombosis risk.
• MPL (thrombopoietin receptor) — ~3–5%.
• "Triple-negative" — ~10–15%, no identifiable driver.

Pathophysiology

• Mutation → JAK-STAT activation → megakaryocytes proliferate independent of thrombopoietin.
• Massive platelet release → blood becomes hyperviscous & prothrombotic.
• Paradox: at very high counts (> 1,000–1,500 × 10⁹/L), platelets adsorb large vWF multimers → acquired von Willebrand disease → bleeding risk.

Clinical Features

Most patients are asymptomatic at diagnosis — discovered incidentally on a routine CBC. When symptoms occur, they fall into three groups:

1. Vasomotor / Microvascular symptoms

• Erythromelalgia — burning red painful hands/feet, dramatically relieved by aspirin (classic).
• Headache, dizziness, blurred vision, paresthesias, tinnitus.

2. Thrombosis (arterial > venous)

• Stroke / TIA, MI, peripheral arterial occlusion.
• DVT, PE, or splanchnic vein thrombosis (Budd-Chiari, portal vein) — suspect MPN in young patients with splanchnic clots.

3. Bleeding (when platelets > 1,000–1,500 × 10⁹/L)

• Mucocutaneous bleeding from acquired von Willebrand disease.
• Aspirin must be used cautiously at very high counts.

Exam findings

• Mild splenomegaly in ~25–50%.
• No significant hepatomegaly, no lymphadenopathy.

Diagnosis

Step 1 — Confirm true thrombocytosis

• CBC: platelets persistently > 450 × 10⁹/L (on at least 2 occasions).
• Peripheral smear: increased platelets, often giant/abnormal; WBCs and RBCs typically normal.

Step 2 — Exclude reactive (secondary) thrombocytosis

• Iron studies (rule out iron deficiency).
• CRP/ESR (infection, inflammation).
• Review for recent bleeding, surgery, splenectomy, malignancy.

Step 3 — Molecular & bone marrow studies

• Driver mutation panel: JAK2 V617F → CALR → MPL.
• BCR-ABL — must be negative (excludes CML).
• Bone marrow biopsy: hypercellular with proliferation of large, mature, hyperlobulated ("stag-horn") megakaryocytes; no significant reticulin fibrosis.

WHO Diagnostic Criteria (simplified)

Major criteria — all 4 required:

1. Platelets > 450 × 10⁹/L.
2. Bone marrow: megakaryocyte proliferation with large, mature forms.
3. Does not meet criteria for CML, PV, PMF, MDS, or other myeloid neoplasm.
4. Presence of JAK2, CALR, or MPL mutation.

Minor: clonal marker or absence of reactive cause (used when major criterion 4 is absent).

Differential Diagnosis

Any persistent platelet count > 450 × 10⁹/L needs a workup. The differential splits into clonal (MPN) vs. reactive causes.

Other MPNs to exclude

• CML — leukocytosis with left shift, BCR-ABL positive.
• Polycythemia Vera — high Hb/Hct, JAK2-positive; can also raise platelets.
• Primary Myelofibrosis — teardrop RBCs, marrow fibrosis, leukoerythroblastic smear.
• MDS (5q-) — can have isolated thrombocytosis with dysplasia.

Management

Treatment is risk-stratified. Goals: prevent thrombosis, control bleeding, relieve symptoms. ET is not curable (except by transplant) but very treatable.

Risk Stratification (IPSET-thrombosis, simplified)

• High risk: age > 60 OR prior thrombosis OR JAK2-positive with cardiovascular risk factors.
• Low risk: none of the above.

Treatment by Risk

Cytoreductive Agents

• Hydroxyurea — first-line for most high-risk patients.
• Interferon-α (peg-IFN) — preferred in pregnancy and young patients (non-teratogenic, non-leukemogenic).
• Anagrelide — second-line; reduces megakaryocyte maturation. Side effects: palpitations, headache, fluid retention.

Complications & Prognosis

Complications

• Thrombosis — leading cause of morbidity (stroke, MI, DVT, splanchnic vein thrombosis).
• Bleeding — mainly when platelets > 1,000–1,500 × 10⁹/L (acquired vWD).
• Transformation (uncommon, late):
  • To myelofibrosis (post-ET MF) — ~5–10% at 15 years.
  • To AML — ~1–5% at 15 years (higher with alkylating agents).
• Pregnancy loss due to placental thrombosis.

Prognosis

• Most indolent of the MPNs.
• Median survival approaches that of the general population if well-managed.
• CALR-mutated patients tend to have a better prognosis than JAK2-mutated.