What is the appropriate workup for a patient with elevated platelet count (thrombocytosis)?

Workup for Elevated Platelets (Thrombocytosis)

Begin with a complete blood count with differential and peripheral blood smear to confirm true thrombocytosis (platelet count ≥450 × 10⁹/L) and distinguish primary from secondary causes, followed by JAK2V617F mutation testing if primary thrombocytosis is suspected. 1, 2

Initial Laboratory Assessment

• Confirm the platelet elevation with repeat complete blood count to exclude spurious results and review the peripheral smear to assess platelet morphology, identify platelet clumping (pseudothrombocytosis), and evaluate for other cytopenias that suggest primary bone marrow disorders 3, 1
• Measure inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) and ferritin to screen for reactive causes, as iron deficiency and inflammatory conditions account for the majority of secondary thrombocytosis cases 4, 5

Clinical History and Physical Examination

• Obtain detailed medication history specifically asking about heparin, quinidine, sulfonamides, chemotherapy agents, and over-the-counter medications that can affect platelet counts 3
• Assess for reactive causes including recent surgery, tissue injury, active infection, chronic inflammatory disorders (rheumatoid arthritis, inflammatory bowel disease), malignancy, bleeding, hemolysis, or prior splenectomy 4, 5
• Evaluate for thrombotic or bleeding symptoms including headaches, visual disturbances, erythromelalgia (burning pain in extremities), or mucosal bleeding, which suggest primary thrombocytosis 1, 6
• Document family history of bleeding disorders, thrombocytosis, or myeloproliferative neoplasms to assess for inherited conditions 3

Distinguishing Primary from Secondary Thrombocytosis

If Clinical Features Suggest Primary Thrombocytosis:

• Order JAK2V617F mutation testing as this mutation is present in approximately 50-60% of essential thrombocythemia cases and helps distinguish primary from reactive thrombocytosis 7, 1, 6
• Test for CALR and MPL mutations if JAK2V617F is negative, as these account for most remaining cases of essential thrombocythemia 1, 6
• Perform bone marrow aspiration and biopsy to confirm the diagnosis, exclude other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis), and rule out myelodysplastic syndrome, particularly if molecular markers are negative or if there are other cytopenias 7, 1
• Bone marrow histology should show proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes with deeply lobulated nuclei, without significant granulocytic left-shift or erythroid proliferation 7

If Clinical Features Suggest Secondary Thrombocytosis:

• Identify and treat the underlying condition as reactive thrombocytosis (even with platelet counts >1,000 × 10⁹/L) does not independently cause thrombosis and resolves with treatment of the primary disorder 4, 8, 9
• No specific platelet-directed therapy is required for secondary thrombocytosis, and antiplatelet agents are not indicated solely for elevated platelet counts in reactive conditions 8, 9

Risk Stratification for Primary Thrombocytosis

Once primary thrombocytosis is confirmed, stratify thrombotic risk:

• High-risk patients are defined as age >60 years OR prior history of thrombosis, regardless of platelet count 1, 2
• JAK2V617F mutation presence increases thrombotic risk in essential thrombocythemia and should be factored into management decisions 1, 2
• Extreme thrombocytosis (platelet count >1,000 × 10⁹/L) paradoxically increases bleeding risk due to acquired von Willebrand syndrome rather than thrombosis risk 1, 2

Special Considerations for Extreme Thrombocytosis

• Screen for acquired von Willebrand syndrome with ristocetin cofactor activity and von Willebrand factor multimer analysis if platelet count exceeds 1,000 × 10⁹/L, as this affects bleeding risk and contraindications to aspirin therapy 1
• Refer to hematology for any patient with platelet count >1,000 × 10⁹/L regardless of etiology 1

Exclusion Criteria for Essential Thrombocythemia

The diagnosis requires excluding:

• Polycythemia vera: Ensure hemoglobin is not elevated (normal red cell mass or hemoglobin <18.5 g/dL in men, <16.5 g/dL in women); if iron deficient, trial iron replacement to exclude occult polycythemia vera 7
• Chronic myeloid leukemia: Confirm absence of BCR-ABL fusion gene 7
• Primary myelofibrosis: Bone marrow should lack significant reticulin or collagen fibrosis, leukoerythroblastosis, or atypical megakaryocyte morphology characteristic of myelofibrosis 7
• Myelodysplastic syndrome: Exclude dysplastic changes in granulocytes or erythrocytes and specific cytogenetic abnormalities 7

Common Pitfalls

• Do not assume all thrombocytosis is reactive: Approximately 12-15% of thrombocytosis cases are primary myeloproliferative neoplasms, which carry significantly higher thrombotic risk and require different management 4
• Do not delay molecular testing: JAK2V617F testing should be performed early in the workup when primary thrombocytosis is suspected, as it can prevent unnecessary bone marrow biopsies in mutation-positive patients 7, 1
• Do not use antiplatelet therapy empirically: Aspirin is not indicated for secondary thrombocytosis and should only be used in primary thrombocytosis after careful risk-benefit assessment, particularly excluding acquired von Willebrand syndrome in extreme thrombocytosis 8, 9