What is the appropriate work‑up for an adult with an elevated platelet count (thrombocytosis)?

Workup for Elevated Platelets (Thrombocytosis)

Initial Diagnostic Approach

The first step in evaluating thrombocytosis is to confirm a sustained platelet count ≥450×10⁹/L on repeat testing, followed by a comprehensive clinical assessment to distinguish primary (clonal) from secondary (reactive) causes, with peripheral blood smear review by a hematopathologist being essential to exclude pseudothrombocytosis and identify morphologic clues. 1

Confirm True Thrombocytosis

• Repeat the complete blood count to verify that the platelet elevation is sustained, as transient elevations may occur with acute stress, dehydration, or laboratory error 1, 2
• Obtain a peripheral blood smear reviewed by a qualified hematologist or pathologist to evaluate platelet morphology, exclude EDTA-dependent platelet clumping (pseudothrombocytosis), and assess for abnormalities suggesting myeloproliferative neoplasms 3, 1

Clinical History and Physical Examination

History must focus on:

• Personal and family history of thrombotic or bleeding events, as primary thrombocytosis carries significantly higher thrombotic risk than secondary causes 1, 2
• Constitutional symptoms including fever, night sweats, unintentional weight loss, or bone pain—any of these suggest primary myeloproliferative disease rather than reactive thrombocytosis 3, 1
• Complete medication review including over-the-counter drugs and supplements 1
• Recent or ongoing infections, tissue injury, surgery, or inflammatory conditions that commonly cause secondary thrombocytosis 2, 4
• Symptoms of iron deficiency (fatigue, pica, restless legs) or chronic blood loss 2

Physical examination should assess for:

• Splenomegaly—mild splenomegaly may occur in younger patients with primary thrombocytosis, but moderate or massive splenomegaly suggests chronic myeloid leukemia or myelofibrosis rather than essential thrombocythemia 3, 1
• Hepatomegaly or lymphadenopathy, which point toward lymphoproliferative disorders or systemic inflammatory conditions 3
• Signs of chronic inflammation, active infection, or malignancy 1, 2

Laboratory Investigations

First-Line Testing

• Complete blood count with differential to determine if thrombocytosis is isolated or accompanied by erythrocytosis (suggesting polycythemia vera), leukocytosis with left shift (suggesting chronic myeloid leukemia), or other cytopenias 1
• Peripheral blood smear examination by a hematopathologist to identify giant platelets, abnormal white cells, or red cell morphology suggestive of myeloproliferative neoplasms 3, 1
• Basic coagulation studies (PT, aPTT) to assess baseline hemostatic function, particularly if thrombosis or bleeding has occurred 1

Molecular Testing for Primary Thrombocytosis

• JAK2 V617F mutation analysis is essential when myeloproliferative neoplasm is suspected; this mutation is present in approximately 50-60% of essential thrombocythemia cases and helps distinguish primary from secondary thrombocytosis 1
• If JAK2 V617F is negative, testing for CALR and MPL mutations should follow, as these are found in most remaining cases of essential thrombocythemia 1
• The presence of any of these driver mutations strongly supports a diagnosis of myeloproliferative neoplasm 1

Evaluation for Secondary Causes

When secondary thrombocytosis is suspected, targeted testing should include:

• C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to screen for chronic inflammatory disorders, which account for approximately 12% of secondary thrombocytosis cases 2
• Iron studies (serum iron, ferritin, total iron-binding capacity, transferrin saturation) because iron deficiency anemia causes approximately 11% of secondary thrombocytosis 2
• Imaging studies (chest X-ray, CT scan) when malignancy or occult infection is suspected based on clinical features 2
• Stool occult blood testing if gastrointestinal blood loss is suspected as a cause of iron deficiency 2

Bone Marrow Examination

Bone marrow aspiration and biopsy with cytogenetic testing and flow cytometry are recommended when: 1

• Age >60 years with unexplained thrombocytosis, to exclude myelodysplastic syndrome or other age-related clonal disorders 1
• Abnormal findings on peripheral blood smear (immature cells, dysplastic features, leukoerythroblastic picture) 1
• Suspected myeloproliferative disorder based on clinical features, splenomegaly, or molecular testing 1
• Platelet count persistently >1,000×10⁹/L without clear secondary cause 2, 5
• Planning cytoreductive therapy or when diagnosis remains uncertain after initial workup 1

Flow cytometry is particularly helpful in identifying chronic lymphocytic leukemia as a cause of secondary thrombocytosis 3

Diagnostic Algorithm

1. Confirm sustained platelet count ≥450×10⁹/L on repeat CBC with peripheral smear review 1, 2

2. Assess clinical context:

   • If obvious secondary cause identified (active infection, recent surgery, known inflammatory disease, documented iron deficiency) → treat underlying condition and monitor platelet count 2, 4
   • If no clear secondary cause or concerning features present → proceed to step 3 1

3. Order JAK2 V617F mutation testing in all patients without obvious secondary cause 1

   • If positive → diagnose myeloproliferative neoplasm and proceed to bone marrow examination for classification 1
   • If negative → test for CALR and MPL mutations 1

4. If all driver mutations negative:

   • Evaluate thoroughly for secondary causes (inflammation markers, iron studies, imaging) 2
   • Consider bone marrow examination if age >60 years, splenomegaly present, or diagnosis remains uncertain 1

5. Thrombotic risk stratification is essential in confirmed primary thrombocytosis, as median platelet count and thrombosis incidence are significantly higher than in secondary thrombocytosis 3, 2

Critical Distinctions Between Primary and Secondary Thrombocytosis

Primary thrombocytosis typically presents with: 1, 2, 5

• Platelet counts often >1,000×10⁹/L (though can be lower)
• Presence of JAK2, CALR, or MPL mutations in 86% of cases
• Splenomegaly in many cases
• Paradoxical risk of both thrombosis AND hemorrhage
• Qualitative platelet abnormalities on function testing
• Median platelet count significantly higher than secondary causes

Secondary thrombocytosis typically presents with: 2, 4

• Platelet counts usually <1,000×10⁹/L
• Identifiable underlying cause (infection 17%, tissue injury 32%, chronic inflammation 12%, iron deficiency 11%)
• No driver mutations
• Normal platelet function
• Lower thrombotic risk
• Resolution with treatment of underlying condition

Common Pitfalls to Avoid

• Never assume thrombocytosis is reactive without excluding primary causes, particularly in patients with platelet counts >1,000×10⁹/L, splenomegaly, or unexplained thrombotic events 1, 5
• Do not skip peripheral smear review—automated counts cannot identify morphologic features of myeloproliferative neoplasms or exclude pseudothrombocytosis 3, 1
• Avoid unnecessary bone marrow examination in young patients with obvious secondary causes (active infection, recent surgery, documented iron deficiency) and platelet counts <700×10⁹/L 1, 4
• In children, recognize that secondary thrombocytosis is extremely common (3-13% of hospitalized children) and primary thrombocytosis is exceedingly rare (1 per million), so extensive workup is rarely needed unless platelet count is extreme or persistent 4
• Do not overlook acquired von Willebrand syndrome in patients with extreme thrombocytosis (>1,000×10⁹/L), which requires ristocetin cofactor and multimer analysis before initiating antiplatelet therapy 3