What investigations should be done for a patient with persistent thrombocytosis (elevated platelet count) who has been asymptomatic for years?

Investigations for Persistent Asymptomatic Thrombocytosis

For a patient with persistent thrombocytosis lasting years without symptoms, the primary goal is to distinguish between primary (myeloproliferative neoplasm) and secondary thrombocytosis through targeted molecular testing and clinical evaluation, as this distinction fundamentally determines thrombotic risk and management.

Initial Laboratory Evaluation

Complete blood count with peripheral blood smear review by a qualified hematologist or pathologist is essential to assess for other cytopenias, abnormal cell morphology, and platelet characteristics that may suggest inherited thrombocytopenia or myeloproliferative disorders 1. The peripheral smear can reveal giant or small platelets indicating inherited conditions, or exclude pseudo-thrombocytopenia from EDTA-dependent platelet agglutination 1.

Key Blood Count Parameters

• Hemoglobin, MCV, RDW, and MPV: Higher values are associated with essential thrombocythemia (ET), while lower values suggest secondary causes 2
• White blood cell count and neutrophils: Elevated counts favor secondary thrombocytosis 2
• Reticulocyte count: Helps assess for hemolysis or bleeding as secondary causes 1

Molecular Testing for Primary Thrombocytosis

Molecular testing for JAK2, CALR, and MPL mutations should be performed if primary thrombocytosis is suspected, as 86% of patients with primary thrombocytosis have at least one molecular marker indicative of myeloproliferative neoplasms 3, 4. The overall yield of molecular testing is 52.4%, with 92.1% of positive results being JAK2, CALR, or MPL mutations 2.

• JAK2V617F mutation: Most common driver mutation in myeloproliferative neoplasms 5
• CALR mutations: Present in JAK2-negative essential thrombocythemia 1
• MPL mutations: Less common but diagnostic for myeloproliferative disorders 5

Clinical Assessment to Identify Secondary Causes

Before proceeding with expensive molecular testing, evaluate for clinical factors strongly associated with secondary thrombocytosis 2:

High-Yield Clinical Factors for Secondary Thrombocytosis

• Active malignancy: Strongly predicts secondary thrombocytosis 2
• Chronic inflammatory disease: Associated with secondary causes 2
• Iron deficiency anemia: Check ferritin levels; iron deficiency is a major cause of secondary thrombocytosis (11.1% of cases) 3, 2
• Splenectomy or functional asplenia: Definitive cause of secondary thrombocytosis 2
• Tissue injury: Accounts for 32.2% of secondary thrombocytosis cases 3
• Infection: Responsible for 17.1% of secondary cases 3

Bone Marrow Examination

Bone marrow aspirate and biopsy should be performed in selected patients, particularly those older than 60 years, those with systemic symptoms, or when splenectomy is being considered 1. Both morphologic assessment and flow cytometry should be included, with cytogenetic testing considered to identify clonal disorders 1.

Additional Targeted Testing

Tests of Potential Utility

• Ferritin level: Essential to exclude iron deficiency as a cause of secondary thrombocytosis 2
• C-reactive protein or ESR: To assess for chronic inflammatory conditions 3
• History of arterial thrombosis: Predictive of essential thrombocythemia (p<0.05) 2

Tests Generally Not Recommended

• Platelet-associated IgG (PaIgG): Not routinely recommended as it is elevated in both immune and non-immune thrombocytopenia 1
• Thrombopoietin (TPO) levels: Of unproven benefit 1
• Platelet survival studies: Of uncertain benefit 1
• Bleeding time: Of unproven benefit 1

Risk Stratification Algorithm

Once primary thrombocytosis is confirmed, risk stratification determines need for treatment 6, 4:

High-Risk Features Requiring Further Evaluation

• Age >60 years 6, 4
• History of prior thrombosis 6, 4
• JAK2 mutation positivity 6, 4
• Cardiovascular risk factors 4

Platelet Count Considerations

• Median platelet count is significantly higher in primary versus secondary thrombocytosis 3
• Extreme thrombocytosis (>1,000 × 10⁹/L) paradoxically increases bleeding risk rather than thrombotic risk in essential thrombocythemia 7, 4

Special Diagnostic Considerations

Reticulated platelet percentage and absolute count may identify patients at thrombotic risk: Chronic thrombocytosis patients with thrombosis have significantly higher reticulated platelet percentages (14.7% ± 10.1%) compared to asymptomatic patients (3.4% ± 1.8%, p<0.05) 8. However, this test is not widely available or routinely recommended in guidelines.

Common Pitfalls to Avoid

• Do not order comprehensive myeloid mutation panels in all patients with thrombocytosis: First exclude secondary causes through clinical assessment and basic laboratory testing 2
• Do not assume platelet count alone determines thrombotic risk: Risk stratification requires age, mutation status, and thrombotic history 6, 4
• Do not overlook iron deficiency: Check ferritin even if hemoglobin is normal, as iron deficiency commonly causes secondary thrombocytosis 3, 2
• Do not perform bone marrow biopsy routinely: Reserve for patients with unclear diagnosis, age >60 years, or when considering splenectomy 1