Increase in cell counts - thrombocytosis
Description
- Platelets >450 x10^9/L
- The whole task is one question: reactive or clonal?
| Reactive (~80-90%) | Clonal | |
|---|---|---|
| Platelet count | Usually <1000, but can exceed it | Any, often sustained >600 |
| Duration | Transient, tracks the trigger | Sustained over months |
| Spleen | Normal | Palpable in ~20-50% |
| Film | Normal platelet morphology | Giant/bizarre platelets, megakaryocyte fragments |
| Driver mutation | Absent | JAK2 / CALR / MPL |
| Thrombosis risk | Not increased | Increased |
| Ferritin/CRP | Often abnormal | Normal |
- *Extreme thrombocytosis (>1000) is more often reactive than clonal* - the number does not discriminate
- Spurious thrombocytosis: cryoglobulins, schistocytes, bacteria, leukaemic cell fragments counted as platelets
Epidemiology
- Thrombocytosis found in ~1-2% of unselected FBEs; the overwhelming majority reactive
- ET: incidence ~1-2.5/100,000/yr; median age ~60, but a distinct second peak in women aged 30-40; F>M overall
- Reactive thrombocytosis: universal after splenectomy, near-universal in significant iron deficiency and acute inflammation
Aetiopathogenesis
Reactive causes
- Iron deficiency - the single commonest, and often the only test needed
- Infection and inflammation - IL-6 -> hepatic thrombopoietin -> megakaryopoiesis
- Tissue damage - trauma, surgery, burns, pancreatitis, MI
- Post-splenectomy / hyposplenism - loss of the platelet pool; often permanent
- Look for Howell-Jolly bodies, target cells, acanthocytes
- Malignancy - especially lung, GI, ovarian, lymphoma. New thrombocytosis in an older smoker warrants thought
- Chronic inflammatory disease - RA, IBD, vasculitis, coeliac
- Rebound - after alcohol withdrawal, B12/folate replacement, chemotherapy recovery, treatment of ITP
- Haemolysis, blood loss, exercise, adrenaline
- Drugs - corticosteroids, vincristine, TPO-RAs, ATRA
Clonal causes
- Essential thrombocythaemia - the prototype
- Polycythaemia vera (iron deficiency may mask the erythrocytosis - check for it in "ET" with low ferritin)
- Prefibrotic primary myelofibrosis - often misdiagnosed as ET; worse outcome, needs the trephine
- CML - thrombocytosis can dominate; always exclude BCR::ABL1
- MDS/MPN with SF3B1 mutation and thrombocytosis (ring sideroblasts)
- 5q- syndrome
- Familial thrombocythaemia - germline THPO or MPL
Driver mutation biology
| Mutation | ET frequency | Phenotype |
|---|---|---|
| JAK2 V617F | ~55-60% | Higher Hb/WCC, highest thrombosis risk, older |
| CALR (exon 9 indel) | ~25% | Younger, higher platelets, lower thrombosis risk, better survival |
| MPL | ~3-5% | Older, more anaemia, marrow fibrosis |
| Triple negative | ~10-15% | Indolent; exclude reactive causes very carefully |
- All converge on constitutive JAK-STAT activation, cytokine-independent megakaryopoiesis
Diagnosis
Step 1 - is it real and is it sustained?
- Repeat the count; review the film; find old FBEs
- A single result is never enough for a clonal diagnosis
Step 2 - exclude reactive causes
- Ferritin, iron studies, CRP/ESR
- *Iron deficiency masks polycythaemia vera* - replace iron and repeat the count/Hb before concluding ET
- Infection screen, LFT, autoimmune serology, age-appropriate cancer screening, coeliac serology
- Splenectomy/hyposplenism from film and history
Step 3 - clonality
- JAK2 V617F first; if negative -> CALR and MPL
- BCR::ABL1 in every case (excludes CML)
- Bone marrow aspirate + trephine with reticulin stain and cytogenetics
- *Required* - distinguishes ET from prefibrotic PMF, and grades fibrosis
- EPO level and haematocrit to exclude PV
WHO criteria - essential thrombocythaemia
All 4 major, OR the first 3 major + the minor criterion
| Criterion | |
|---|---|
| Major 1 | Platelets >=450 x10^9/L |
| Major 2 | Marrow: megakaryocyte proliferation with enlarged, mature, hyperlobulated ("staghorn") forms; no significant granulocytic/erythroid left shift; no more than grade 1 reticulin |
| Major 3 | Does not meet criteria for CML (BCR::ABL1), PV, PMF, MDS or other myeloid neoplasm |
| Major 4 | JAK2, CALR or MPL mutation |
| Minor | Another clonal marker, or absence of evidence of reactive thrombocytosis |
Risk stratification - IPSET-thrombosis
| Category | Definition |
|---|---|
| Very low | Age <=60, no thrombosis history, JAK2 wild-type |
| Low | Age <=60, no thrombosis history, JAK2 mutated |
| Intermediate | Age >60, no thrombosis history, JAK2 wild-type |
| High | Prior thrombosis, OR age >60 with JAK2 mutation |
- Platelet count is not in the score - it does not predict thrombosis
Management
A. Reactive thrombocytosis
- *Treat the cause. No antiplatelet, no cytoreduction, whatever the number.*
- Even counts >1000 from iron deficiency or post-splenectomy do not need treatment
B. Clonal thrombocytosis (ET) - by IPSET-thrombosis risk
| Risk | Management |
|---|---|
| Very low | Observe; aspirin only if cardiovascular risk factors or microvascular symptoms |
| Low | Aspirin 100 mg daily |
| Intermediate | Aspirin; consider cytoreduction |
| High | Cytoreduction + aspirin |
- Twice-daily aspirin for persistent microvascular symptoms (erythromelalgia, acral paraesthesia, migraine-like visual disturbance) - aspirin's effect wears off within 24 h in high-turnover thrombocytosis
- Control cardiovascular risk factors in everyone - smoking, BP, lipids, diabetes
C. Cytoreductive agents
| Agent | Position | Toxicity |
|---|---|---|
| Hydroxyurea | First line >40-60 yr | Myelosuppression, oral/leg ulcers, skin cancer (sun protection, annual skin check), macrocytosis, nail pigmentation. Teratogenic |
| Interferon (peg-IFN alfa-2a, ropeginterferon) | Preferred in pregnancy and in younger patients; disease-modifying with molecular responses | Flu-like symptoms, depression, autoimmune thyroiditis/hepatitis. Contraindicated in significant psychiatric or autoimmune disease |
| Anagrelide | Second line | Headache, palpitations, diarrhoea early; fluid retention and cardiomyopathy; increases bleeding risk; *marrow fibrosis with long-term use*. Reduces platelets only |
| Busulfan | Elderly/refractory only | Leukaemogenic - avoid in anyone with a long life expectancy |
- Target platelets <400 x10^9/L in patients requiring cytoreduction
D. Special situations
- Extreme thrombocytosis (>1000-1500) -> acquired von Willebrand syndrome
- Check VWF activity before starting aspirin - bleeding, not clotting, is the risk here
- Cytoreduce first; withhold aspirin until platelets fall
- Pregnancy: aspirin throughout, interferon if cytoreduction needed, LMWH postpartum. Hydroxyurea and anagrelide contraindicated
- Surgery: optimise count preoperatively, thromboprophylaxis, restart aspirin early
- Perioperative and travel VTE prophylaxis
Associations
- Iron deficiency (the commonest association of all)
- Post-splenectomy and functional hyposplenism (coeliac disease, sickle cell)
- Occult malignancy - lung, GI, ovarian
- Chronic inflammatory disease - RA, IBD, vasculitis, chronic infection, TB
- Other MPNs - PV, prefibrotic and overt PMF, CML
- MDS/MPN-RS-T (SF3B1), 5q- syndrome
- Acquired von Willebrand syndrome
- Splanchnic vein thrombosis - Budd-Chiari and portal vein thrombosis; test JAK2 V617F in all such patients even with normal counts
- Familial (germline THPO, MPL)
Natural history & complications
- Reactive thrombocytosis resolves with the trigger and carries no thrombotic risk
- ET has the best survival of any MPN - median >20 years, near-normal in low-risk young patients
ET complications
- Thrombosis - the dominant cause of morbidity; arterial > venous
- Stroke, TIA, MI, peripheral arterial, splanchnic and cerebral venous
- Bleeding - paradoxical, from acquired von Willebrand syndrome at extreme counts
- Microvascular symptoms - erythromelalgia, headache, visual disturbance, acral paraesthesia. Highly aspirin-responsive
- Transformation
- Myelofibrosis ~4-10% at 15 years (higher with CALR, MPL, high reticulin at baseline)
- AML/MDS ~1-2% at 10 years, ~5% at 15 years (higher with prior alkylator or busulfan exposure)
- Pregnancy: increased miscarriage, placental infarction, IUGR
Adverse markers
- Age >60, prior thrombosis, leucocytosis, JAK2 V617F, anaemia
- Adverse somatic mutations - TP53, SRSF2, SF3B1, U2AF1, EZH2, IDH1/2
Monitoring
- FBE 3-monthly once stable; symptom review, cardiovascular risk factors
- Rising LDH, anaemia, progressive splenomegaly, weight loss -> repeat marrow for fibrotic transformation
- Annual skin surveillance on hydroxyurea
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