What is the diagnostic procedure for a patient presenting with thrombocytosis?

Diagnostic Approach to Thrombocytosis

The diagnostic workup for thrombocytosis begins with confirming a platelet count ≥450 × 10⁹/L on at least two separate samples, followed immediately by molecular testing for JAK2V617F, CALR, and MPL mutations to distinguish primary (clonal) from secondary (reactive) thrombocytosis. 1

Initial Confirmation Steps

Verify the elevated platelet count is real, not artifactual:

• Confirm platelet count ≥450 × 10⁹/L on at least two separate blood samples 1, 2
• Examine the blood smear to exclude platelet clumping or aggregates that can falsely elevate automated counts 1
• Check for clots in the collection tube that may cause spurious results 1

Complete Blood Count with Peripheral Smear

Order a CBC with manual differential and peripheral blood smear review: 1

• Evaluate platelet morphology for size and granularity abnormalities 1
• Assess for other cell line abnormalities (leukocytosis, anemia, red cell morphology) 1
• Higher hemoglobin, MCV, RDW, and MPV suggest primary thrombocytosis (essential thrombocythemia) 2
• Higher WBC and neutrophil counts favor secondary thrombocytosis 2

Molecular Testing: The Critical First Step

Request immediate molecular testing for the three driver mutations: 1, 3

• JAK2V617F mutation (most common)
• CALR exon 9 mutations
• MPL mutations

These tests should be performed on whole blood or purified granulocytes 1. Approximately 80% of patients with essential thrombocythemia harbor at least one of these mutations in a mutually exclusive pattern 1. The discovery of these molecular markers has fundamentally simplified the diagnostic approach 3, 4.

Important caveat: About 92% of positive molecular findings in thrombocytosis are accounted for by JAK2, CALR, and MPL mutations 2. The overall yield of molecular testing in thrombocytosis is approximately 52% 2, meaning nearly half of patients will be mutation-negative and require clinical correlation.

Clinical Assessment to Distinguish Primary vs Secondary

Evaluate for clinical features that distinguish the two forms:

Features suggesting PRIMARY thrombocytosis (essential thrombocythemia): 5, 2

• History of arterial thrombosis (stroke, MI, peripheral arterial thrombosis) 2
• Platelet count typically >600-800 × 10⁹/L 5
• Absence of identifiable secondary causes 4

Features suggesting SECONDARY thrombocytosis: 4, 5, 2

• Tissue injury/damage (surgery, trauma, burns) - accounts for 32-42% of cases 4, 5
• Active infection - accounts for 17-24% of cases 4, 5
• Active malignancy - accounts for 13% of cases 5, 2
• Chronic inflammatory disorders (inflammatory bowel disease, rheumatoid arthritis, vasculitis) - accounts for 10-12% of cases 4, 5, 2
• Iron deficiency anemia - accounts for 11% of cases 4, 2
• Post-splenectomy state 2

Check ferritin levels, as iron deficiency is a common and treatable cause of secondary thrombocytosis 2.

Extended Molecular Panel (If Initial Testing Negative)

If JAK2/CALR/MPL are negative but clinical suspicion for myeloproliferative neoplasm remains high, consider extended mutational testing: 1

• TET2
• ASXL1
• DNMT3A
• SF3B1

However, a practical approach focusing on clinical characteristics (malignancy, inflammation, splenectomy, iron deficiency) can reduce unnecessary costly molecular testing in patients more likely to have secondary causes 2.

Risk Stratification for Primary Thrombocytosis

Once primary thrombocytosis is confirmed, stratify thrombotic risk: 1

• High risk: Age >60 years OR history of thrombosis
• Intermediate risk: Age <60 years with cardiovascular risk factors or JAK2V617F mutation
• Low risk: Age <60 years without thrombosis history

Apply the Triple A survival risk model (Age, Absolute neutrophil count, Absolute lymphocyte count) for prognostic stratification 1.

Screening for Thrombotic Complications

In confirmed primary thrombocytosis, screen for asymptomatic thrombosis: 1

• Doppler ultrasound of lower extremities in all patients to detect deep vein thrombosis 1
• Abdominal imaging (ultrasound or CT venography) to exclude splenic or portal vein thrombosis 1
• CT pulmonary angiography if respiratory symptoms present 1

Primary thrombocytosis carries significantly higher risk of both arterial and venous thrombosis compared to secondary thrombocytosis 4, 5. In secondary thrombocytosis, thromboembolic events are restricted to the venous system and occur only when additional risk factors are present 5.

Bleeding Risk Assessment

In extreme thrombocytosis (platelet count >1,000 × 10⁹/L): 1

• Evaluate for acquired von Willebrand syndrome (AVWS) by measuring VWF antigen, ristocetin cofactor activity, and factor VIII 1
• Perform platelet function tests if bleeding history exists despite elevated platelet count 1
• Exercise caution with aspirin, as platelet counts >1,000 × 10⁹/L paradoxically increase bleeding risk 1

Hematology Referral Criteria

Immediate hematology consultation is indicated for: 1

• Platelet count >1,000 × 10⁹/L
• Presence of any driver mutation (JAK2/CALR/MPL)
• History of thrombosis or unexplained bleeding
• Splenomegaly on examination

Common pitfall: Do not assume all thrombocytosis is reactive. While secondary thrombocytosis accounts for 83-88% of cases 4, 5, missing primary thrombocytosis has significant implications for thrombotic risk and requires specific management. The median platelet count and incidence of thrombosis are significantly higher in primary versus secondary thrombocytosis 4.