How should I evaluate and work up a patient with thrombocytosis (elevated platelet count)?

Workup for Thrombocytosis

Initial Verification and Assessment

Begin by confirming true thrombocytosis with a repeat complete blood count and peripheral blood smear examination to exclude pseudothrombocytopenia and assess platelet morphology. 1

• Verify the platelet count is genuinely elevated (>450 × 10⁹/L by WHO criteria) with a repeat CBC, as laboratory artifacts can cause false elevations 1
• Examine the peripheral blood smear personally or have a qualified hematologist/pathologist review it to confirm true thrombocytosis, assess platelet size and morphology, and evaluate for other cell line abnormalities 1
• Check for EDTA-dependent platelet clumping which can cause spurious results 2

Clinical History - Key Elements to Identify

Obtain a focused history targeting specific causes of secondary thrombocytosis and risk factors for primary myeloproliferative neoplasms.

For Secondary Causes:

• Recent or ongoing infection, particularly bacterial infections 3
• Tissue injury or trauma, surgery, burns (most common cause at 32.2% of secondary cases) 3
• Chronic inflammatory conditions (inflammatory bowel disease, rheumatoid arthritis, vasculitis) accounting for 11.7% of cases 3
• Iron deficiency anemia symptoms (accounts for 11.1% of secondary thrombocytosis) 3
• Active malignancy 3
• Recent medications including heparin exposure or COVID-19 vaccination 1
• Functional or surgical splenectomy 4

For Primary Causes:

• Personal or family history of thrombotic events (arterial or venous) 3
• Bleeding manifestations despite elevated platelets 5
• Constitutional symptoms: fever, night sweats, weight loss, pruritus after bathing 6

Physical Examination - Critical Findings

• Splenomegaly strongly suggests primary myeloproliferative neoplasm and warrants abdominal imaging (CT or ultrasound) 1
• Absence of splenomegaly does not exclude primary thrombocytosis but makes secondary causes more likely 6
• Look for signs of underlying infection, inflammation, or malignancy 3

Laboratory Workup Algorithm

First-Tier Testing (All Patients):

Order the following tests immediately to distinguish primary from secondary thrombocytosis:

• Complete blood count with differential to assess other cell lines 1
• Peripheral blood smear review (already mentioned but critical) 1
• Iron studies (serum iron, ferritin, TIBC) to identify iron deficiency 3
• C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to detect inflammation 3
• Comprehensive metabolic panel to assess for liver disease or renal dysfunction 3

Second-Tier Testing (Based on Initial Results):

If no clear secondary cause is identified and platelet count remains >450 × 10⁹/L:

• JAK2 V617F mutation testing (present in ~86% of primary thrombocytosis cases) 3, 1
• CALR and MPL mutation testing if JAK2 is negative 1
• HIV and hepatitis C serology in all adults regardless of risk factors 1
• Bone marrow aspiration and biopsy with cytogenetics if molecular markers are negative but clinical suspicion for myeloproliferative neoplasm remains high 3

Distinguishing Primary from Secondary Thrombocytosis

Features Favoring Primary (Essential Thrombocythemia/MPN):

• Platelet count typically >1,000 × 10⁹/L (though can be lower) 4, 5
• Presence of JAK2V617F, CALR, or MPL mutations 1
• Splenomegaly on examination or imaging 1
• Symptoms of thrombosis or paradoxical bleeding despite high platelets 3, 5
• Median platelet count significantly higher than secondary causes 3
• Plateletcrit ≥0.63% (80.6% sensitivity, 80.0% specificity) 7
• Large platelet count (LPLT) ≥23 × 10³/μL (64.5% sensitivity, 99.1% specificity) 7

Features Favoring Secondary (Reactive):

• Identifiable underlying cause (infection, inflammation, tissue injury, iron deficiency, malignancy) 3
• Platelet count usually <1,000 × 10⁹/L (mild to moderate elevation in 72-86% of cases) 4
• Absence of splenomegaly 1
• No molecular markers of MPNs 3
• Thrombotic complications rare (only 4% vs 56% in primary) 5

Risk Stratification

Primary thrombocytosis carries significantly higher thrombotic risk requiring different management than secondary thrombocytosis. 1

• Thrombotic events occur in 56% of patients with myeloproliferative disorders versus only 4% with reactive thrombocytosis 5
• However, no deaths directly attributable to thrombosis or bleeding have been documented when platelet counts are ≥1,000 × 10⁹/L in either group 5

Common Pitfalls to Avoid

• Do not assume extreme thrombocytosis (≥1,000 × 10⁹/L) automatically indicates primary disease - 82% of such cases are actually reactive 5
• Do not overlook iron deficiency as a cause, even without anemia 3
• Do not skip molecular testing (JAK2, CALR, MPL) when no obvious secondary cause exists, as 86% of primary cases will have at least one mutation 3
• In children, remember that primary thrombocytosis is extremely rare (1 per million) and reactive causes account for the vast majority of cases 4
• Do not rely solely on platelet count magnitude - both primary and secondary causes can produce extreme elevations 5