Screen for extreme thrombocytosis (platelets >1000 × 10⁹/L), acute arterial or venous thrombosis, and myeloproliferative neoplasms requiring urgent treatment.
Platelets >1000 × 10⁹/L (extreme thrombocytosis) paradoxically cause bleeding AND thrombosis. Acquired von Willebrand syndrome occurs as high platelet mass consumes vWF. Simultaneously, platelet activation causes microvascular thrombosis. Urgent cytoreduction (hydroxycarbamide or platelet apheresis) required.
Acute thrombosis with thrombocytosis suggests JAK2+ myeloproliferative neoplasm (ET, PV). 30-40% of ET patients present with thrombotic event (stroke, MI, DVT, Budd-Chiari). Immediate aspirin 75 mg + anticoagulation + cytoreduction reduces recurrent thrombosis risk by 60%.
Erythromelalgia (red, burning extremities) is pathognomonic for ET. Caused by platelet-mediated arteriolar inflammation and microthrombi. Relieved within 30 minutes by aspirin (diagnostic test). Untreated, progresses to digital ischaemia and gangrene.
Reactive thrombocytosis (infection, inflammation, bleeding, malignancy) accounts for 80% of cases. Platelets rarely exceed 700 × 10⁹/L. Clonal thrombocytosis (ET, PV, CML) often exceeds 1000 × 10⁹/L and persists despite treating underlying cause.
Confirm persistent thrombocytosis and exclude transient reactive causes. A single elevated platelet count may be post-operative, post-bleeding, or post-infection.
Transient thrombocytosis is common post-infection (pneumonia, UTI), post-surgery, post-bleeding, or with active inflammation (RA flare, IBD). Platelets peak at 1-2 weeks, normalize within 3 months. Repeating FBC at 4 weeks differentiates reactive from clonal.
Iron deficiency causes reactive thrombocytosis in 50-75% of cases (ferritin <15 μg/L). Mechanism: reduced iron suppresses hepcidin, increasing platelet production. Treating iron deficiency normalizes platelets within 6-8 weeks. Always check ferritin in thrombocytosis.
Platelet count threshold: Reactive rarely exceeds 700 × 10⁹/L. If platelets >700 × 10⁹/L and persist >3 months, clonal thrombocytosis (ET) is highly likely even if no JAK2 mutation detected initially (10-15% of ET is JAK2-negative).
Blood film review can identify CML (left shift, basophilia), myelofibrosis (tear-drop cells, leucoerythroblastic picture), and ET (large abnormal platelets, megakaryocyte fragments). Essential for all persistent thrombocytosis.
Classify thrombocytosis as reactive (secondary) or clonal (primary myeloproliferative neoplasm). This determines investigation pathway and treatment urgency.
Reactive thrombocytosis is benign and does not increase thrombosis risk if platelets <1000 × 10⁹/L. No antiplatelet therapy needed. Treat the underlying cause (antibiotics for infection, iron for deficiency, NSAIDs for inflammation). Platelets normalize within 3 months in 90% of cases.
Essential thrombocythemia (ET) is the commonest myeloproliferative neoplasm (incidence 1-2 per 100,000/year). Median age at diagnosis is 60. Thrombosis risk is 2-4% per year (arterial > venous). Aspirin 75 mg daily reduces thrombosis by 60%. High-risk patients (age >60, prior thrombosis) require cytoreduction.
JAK2 V617F mutation is present in 95% of PV, 60% of ET, 50% of myelofibrosis. It activates JAK-STAT signaling, causing uncontrolled myeloid proliferation. CALR mutations (25% of ET) carry better prognosis than JAK2 (lower thrombosis risk). MPL mutations are rare (5%).
Distinguishing ET from reactive: ET platelets persist >3 months despite treating inflammation. Reactive platelets normalize. CRP is high in reactive (infection, RA), normal in ET. Splenomegaly suggests clonal (ET, PV). Iron deficiency coexists in 30% of ET cases (confounding factor).
Examine for splenomegaly, signs of thrombosis, and microvascular symptoms suggesting myeloproliferative neoplasm.
Splenomegaly in thrombocytosis strongly suggests clonal disorder. Spleen sequestration paradoxically occurs in ET/PV despite high platelet count (extramedullary haematopoiesis). Reactive thrombocytosis does not cause splenomegaly unless the reactive cause itself does (e.g., lymphoma, infection).
Erythromelalgia (burning red extremities) is pathognomonic for ET. Occurs in 5-10% of ET patients. Caused by platelet aggregation in digital arterioles → inflammation, thrombosis. Relieved within 30 minutes by aspirin (diagnostic + therapeutic). Untreated → gangrene requiring amputation.
Plethora and pruritus after bathing are classic for PV. Plethora (ruddy face) is due to raised Hct (>0.52). Pruritus is mast cell-mediated histamine release (worsened by warmth). Present in 40% of PV patients. Neither occur in reactive thrombocytosis.
Thrombotic events (stroke, MI, DVT, Budd-Chiari) occur in 30-40% of ET/PV patients at presentation. Unusual site thrombosis (portal, splenic, cerebral veins) is highly suggestive of JAK2+ myeloproliferative neoplasm. Screen all thrombocytosis patients for prior thrombosis.
Investigate to differentiate reactive from clonal thrombocytosis. Target investigations based on clinical context and platelet count.
JAK2 V617F testing is diagnostic for myeloproliferative neoplasm. Positive in 95% of PV, 60% of ET, 50% of myelofibrosis. Sensitivity is high enough that bone marrow biopsy is often unnecessary if JAK2+ with compatible blood count. Test if platelets >600 persistent, or >450 with thrombosis/splenomegaly.
Iron deficiency is the commonest cause of reactive thrombocytosis in primary care. Ferritin <15 μg/L confirms deficiency. Mechanism: low iron → low hepcidin → increased thrombopoietin → thrombocytosis. Treating iron deficiency normalizes platelets in 80% of cases within 6-8 weeks.
CRP/ESR differentiate reactive from clonal. Reactive thrombocytosis has elevated CRP (infection, RA, malignancy). ET/PV have normal CRP (unless concurrent infection). If platelets >700 and CRP normal, ET is highly likely even if JAK2 negative initially.
Bone marrow biopsy is gold standard for ET diagnosis (WHO criteria: megakaryocyte hyperplasia, no BCR-ABL, no reactive cause). Performed by haematology, not primary care. Required if JAK2/CALR/MPL all negative (10% of ET cases), or to exclude myelofibrosis (reticulin staining).
Refer based on platelet count, persistence, JAK2 status, and thrombotic risk. Clonal thrombocytosis requires specialist management.
Platelets >1000 × 10⁹/L require same-day haematology even if asymptomatic. Paradoxical bleeding risk (acquired vWD) occurs as platelet mass consumes vWF. Simultaneously, thrombosis risk is high. Urgent cytoreduction (hydroxycarbamide or platelet apheresis) lowers platelets to safe range within days.
JAK2 V617F positive is diagnostic for myeloproliferative neoplasm and mandates haematology referral. 2WW pathway for suspected haematological cancer (NICE NG12). Haematology confirms diagnosis, risk-stratifies (IPSET score for ET), and initiates aspirin ± cytoreduction.
Reactive thrombocytosis (iron deficiency, infection, inflammation) does NOT require haematology referral if platelets <600 × 10⁹/L and normalizing with treatment. Treating the underlying cause is sufficient. Recheck FBC at 3 months to confirm normalization.
Young patients (<40) with persistent unexplained thrombocytosis warrant routine haematology referral even if JAK2 negative and platelets <700. ET can present at any age. Establishing diagnosis early enables decades of thrombosis prevention with aspirin ± cytoreduction.
Treatment depends on whether thrombocytosis is reactive or clonal. Reactive thrombocytosis: treat cause. Clonal (ET/PV): aspirin for all, cytoreduction if high-risk.
ET/PV treatment ladder (haematology-managed):
Aspirin 75 mg reduces arterial thrombosis (stroke, MI) by 60% in ET/PV. Mechanism: irreversibly inhibits COX-1, preventing platelet aggregation. All ET/PV patients require aspirin unless bleeding risk (prior GI bleed, platelets >1500 with acquired vWD). PPI co-prescription if gastritis risk.
Hydroxycarbamide (hydroxyurea) is first-line cytoreductive agent. Inhibits DNA synthesis, reducing platelet count by 50-70%. Target platelets <400 × 10⁹/L. Reduces thrombosis by 85% in high-risk ET. Well-tolerated; main side effect is myelosuppression (monitor FBC monthly initially).
Risk stratification determines treatment. Low-risk ET (age <60, no thrombosis, platelets <1500): aspirin alone sufficient. High-risk ET (age >60 OR prior thrombosis OR platelets >1500): aspirin + cytoreduction mandatory. Age >60 alone doubles thrombosis risk (4% vs 2% per year).
Reactive thrombocytosis does NOT increase thrombosis risk unless platelets >1000 × 10⁹/L. Therefore, aspirin is not indicated for reactive causes. Treat the underlying cause (iron, infection, inflammation); platelets normalize and thrombosis risk returns to baseline.
Lifestyle interventions reduce thrombotic events in patients with ET/PV. Cardiovascular risk factor control is as important as aspirin.
Cardiovascular risk factors (smoking, hypertension, diabetes, hyperlipidaemia) are synergistic with thrombocytosis. Each additional risk factor doubles thrombosis rate. A 65-year-old with ET + smoking + hypertension has 20% 10-year stroke risk vs 4% with ET alone. Aggressive risk factor control is as important as aspirin.
Smoking cessation is the single most important lifestyle intervention. Smoking triples arterial thrombosis risk in ET (mechanism: endothelial dysfunction + platelet activation). Quitting reduces thrombosis risk by 50% within 1 year. NNT to prevent one stroke = 10 ET patients quit smoking for 5 years.
Hydration reduces blood viscosity and platelet aggregation. Dehydration increases Hct by 5-10%, worsening hyperviscosity (especially in PV). Patients with ET/PV should drink 2-2.5 L water daily. Dark urine is a sign of inadequate hydration.
Immobility (long flights, bed rest) increases venous stasis and DVT risk. ET/PV patients have 5× higher DVT risk than general population. Mobilization every 2 hours, compression socks, and LMWH prophylaxis for long-haul flights reduce DVT by 70%.
Monitor platelet trajectory, watch for thrombotic events, and re-refer if platelets rising or new symptoms. Chronic thrombocytosis requires long-term surveillance.
Platelet trajectory in reactive thrombocytosis should normalize within 3 months of treating the cause. If platelets remain >450 at 3 months despite iron repletion or infection resolution, clonal thrombocytosis (ET) is likely. Refer haematology for JAK2/CALR testing.
Thrombotic events on treatment indicate inadequate control. If patient has stroke/MI/DVT while on aspirin + cytoreduction, haematology escalates therapy (higher hydroxycarbamide dose, switch to anagrelide, add anticoagulation). Primary care role is early recognition and urgent referral.
Disease progression: 10-15% of ET evolves to myelofibrosis over 10-20 years. Signs: progressive splenomegaly, tear-drop cells on film, rising LDH, transition from thrombocytosis to thrombocytopenia. Myelofibrosis requires stem cell transplant evaluation (only curative therapy).
Annual cardiovascular review is mandatory. ET/PV patients have 2-4× higher CVD mortality than general population. Controlling BP, lipids, diabetes, and smoking status reduces cardiovascular events by 50%. QRISK underestimates risk in ET (does not include thrombocytosis as variable).