What is the approach to managing thrombocytosis (elevated platelet count)?

Approach to Thrombocytosis

The initial approach to thrombocytosis requires distinguishing between primary (clonal) and secondary (reactive) causes through a systematic evaluation of clinical context, complete blood count parameters, and selective molecular testing, with the understanding that secondary thrombocytosis accounts for approximately 83% of cases and rarely requires treatment beyond addressing the underlying condition.

Initial Assessment and Risk Stratification

Define the Severity

• Mild thrombocytosis: Platelet count 450-700 × 10⁹/L 1
• Moderate thrombocytosis: Platelet count 700-900 × 10⁹/L 1
• Extreme thrombocytosis: Platelet count >900 × 10⁹/L or >1,000 × 10⁹/L 2

Assess Thrombotic Risk Immediately

• History of arterial or venous thrombosis strongly predicts primary thrombocytosis (essential thrombocythemia) 3
• Median platelet count is significantly higher in primary versus secondary thrombocytosis 1
• Thrombotic complications occur predominantly in primary thrombocytosis, not reactive forms 4

Distinguish Primary from Secondary Thrombocytosis

Clinical Features Suggesting Secondary (Reactive) Thrombocytosis

These findings make primary thrombocytosis unlikely and molecular testing unnecessary 3:

• Active malignancy (any solid tumor or hematologic malignancy other than myeloproliferative neoplasm) 3
• Chronic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease, vasculitis) 3
• Recent splenectomy or functional asplenia 3
• Iron deficiency anemia (ferritin <30 ng/mL) 3
• Acute infection (bacterial, viral, fungal) - accounts for 17% of secondary thrombocytosis 1
• Tissue injury (surgery, trauma, burns, fractures) - accounts for 32% of secondary thrombocytosis 1
• Acute bleeding or hemolysis 1

Laboratory Parameters Favoring Secondary Thrombocytosis

• Elevated white blood cell count with neutrophilia 3
• Lower hemoglobin than expected 3
• Lower mean corpuscular volume (MCV) suggesting iron deficiency 3
• Lower mean platelet volume (MPV) 3
• Higher body mass index (associated with inflammatory state) 3

Clinical Features Suggesting Primary Thrombocytosis (Essential Thrombocythemia)

• History of arterial thrombosis (stroke, myocardial infarction, peripheral arterial occlusion) 3
• Microcirculatory symptoms: headaches, lightheadedness, acral paresthesias, erythromelalgia 2
• Splenomegaly on examination 2
• Absence of secondary causes listed above 3

Laboratory Parameters Favoring Primary Thrombocytosis

• Higher hemoglobin (may overlap with polycythemia vera) 3
• Higher MCV 3
• Higher RDW (red cell distribution width) 3
• Higher MPV 3
• Normal or low white blood cell count (unless transformation occurring) 3

Diagnostic Workup Algorithm

Step 1: Complete Blood Count with Differential

• Obtain hemoglobin, MCV, RDW, white blood cell count with differential, MPV 3
• Repeat platelet count to confirm persistent thrombocytosis (≥450 × 10⁹/L) 2

Step 2: Targeted Laboratory Testing Based on Clinical Context

If secondary causes are clinically evident, stop here and treat the underlying condition 3:

• Ferritin to exclude iron deficiency 3
• C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) if inflammatory disease suspected 1
• Peripheral blood smear to assess red cell morphology and platelet morphology 2

Step 3: Molecular Testing (Only if Primary Thrombocytosis Suspected)

Order molecular testing only when secondary causes are excluded and clinical/laboratory features suggest essential thrombocythemia 3:

• JAK2V617F mutation (present in ~60% of essential thrombocythemia) 2
• CALR mutation (present in ~20-25% of essential thrombocythemia) 2
• MPL mutation (present in ~3-5% of essential thrombocythemia) 2
• Approximately 80% of essential thrombocythemia patients harbor one of these three driver mutations in mutually exclusive fashion 2
• Overall yield of molecular testing is 52.4% when applied to all thrombocytosis cases, but 92.1% of positive results are JAK2, CALR, or MPL mutations 3

Step 4: Bone Marrow Examination (Selective Use)

Bone marrow biopsy is required to confirm essential thrombocythemia and exclude other myeloproliferative neoplasms 2:

• Indicated when: Molecular testing positive for JAK2/CALR/MPL mutations, or strong clinical suspicion despite negative molecular testing 2
• Key finding: Increased number of mature-appearing megakaryocytes distributed in loose clusters 2
• Critical exclusion: Must rule out prefibrotic myelofibrosis, which has different prognosis and management 2

Management Based on Diagnosis

Secondary (Reactive) Thrombocytosis Management

Treatment directed solely at underlying condition; platelet count itself requires no specific therapy 4:

• No antiplatelet therapy (aspirin) indicated for secondary thrombocytosis alone 4
• No cytoreductive therapy needed 5
• Secondary thrombocytosis, even with platelet counts >500 × 10⁹/L or >1,000 × 10⁹/L, is benign and not associated with thrombotic or hemorrhagic complications 4
• Platelet counts typically normalize within 2-3 weeks after resolution of underlying condition 4
• Monitor platelet count to confirm resolution and ensure diagnosis was correct 4

Primary Thrombocytosis (Essential Thrombocythemia) Management

Risk Stratification for Thrombosis

Four risk categories determine treatment intensity 2:

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 2
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 2
• Intermediate risk: Age >60 years, no thrombosis history, JAK2 wild-type 2
• High risk: History of thrombosis OR (age >60 years AND JAK2 mutation) 2

Treatment Algorithm

Very Low and Low Risk 2:

• Once-daily low-dose aspirin (75-100 mg) for very low risk 2
• Twice-daily low-dose aspirin for low risk (JAK2-mutated) 2
• No cytoreductive therapy unless extreme thrombocytosis (>1,500 × 10⁹/L) with acquired von Willebrand syndrome 2

Intermediate Risk 2:

• Once-daily low-dose aspirin 2
• Cytoreductive therapy optional, consider if additional risk factors present (cardiovascular risk factors, extreme thrombocytosis) 2

High Risk 2:

• Once-daily low-dose aspirin 2
• Cytoreductive therapy mandatory 2

First-Line Cytoreductive Therapy Options

• Hydroxyurea: Starting dose 15-20 mg/kg/day, adjust to maintain platelets <400 × 10⁹/L 2
• Pegylated interferon-α: Preferred in younger patients and pregnancy 2
• Target platelet count is <400 × 10⁹/L, not normalization 2

Second-Line Cytoreductive Therapy

• Anagrelide: Starting dose 0.5 mg four times daily or 1 mg twice daily for adults; maintain for one week then titrate; do not exceed 10 mg/day or 2.5 mg single dose 6
• Busulfan: For elderly patients intolerant of hydroxyurea and interferon 2

Special Situations

Extreme Thrombocytosis (>1,000 × 10⁹/L)

• Assess for acquired von Willebrand syndrome: Obtain ristocetin cofactor activity and von Willebrand factor multimer analysis 2
• If acquired von Willebrand syndrome present: Avoid aspirin until platelet count reduced with cytoreductive therapy 2
• Initiate cytoreductive therapy regardless of risk category if bleeding manifestations present 2

Thrombocytosis in Children

• Secondary thrombocytosis accounts for >95% of pediatric cases 5
• Primary thrombocytosis (essential thrombocythemia) is exceedingly rare in childhood 5
• No treatment needed for reactive thrombocytosis; aspirin is unwarranted 5
• Consultation with pediatric hematology only if extreme thrombocytosis with clinical/laboratory criteria for essential thrombocythemia, or hemorrhagic/thrombotic complication develops 5

Pregnancy and Thrombocytosis

• Pegylated interferon-α is the cytoreductive agent of choice during pregnancy 4
• Low-molecular-weight heparin for patients with history of venous thrombosis 4
• Aspirin continued unless extreme thrombocytosis with acquired von Willebrand syndrome 4

Critical Pitfalls to Avoid

• Do not order molecular testing for patients with obvious secondary causes (active malignancy, infection, iron deficiency, recent surgery) 3
• Do not treat secondary thrombocytosis with aspirin or cytoreductive therapy; no evidence of benefit and potential for harm 4, 5
• Do not assume thrombocytosis is benign in patients with history of thrombosis or microcirculatory symptoms; these require molecular testing 3, 2
• Do not normalize platelet counts as treatment goal in essential thrombocythemia; target is <400 × 10⁹/L to reduce thrombotic risk 2
• Do not diagnose essential thrombocythemia without bone marrow examination, as prefibrotic myelofibrosis can present identically but has worse prognosis 2