What is the initial workup for a patient presenting with isolated thrombocytosis?

Workup for Isolated Thrombocytosis

Begin with a complete blood count with peripheral blood smear examination, focused history targeting medication use, recent infections, tissue injury, and inflammatory conditions, followed by targeted laboratory testing to distinguish between primary (myeloproliferative neoplasm) and secondary (reactive) causes. 1

Initial Clinical Assessment

History and Physical Examination

• Medication review: Document all current medications, recent transfusions, and exposure to heparin products 1
• Symptom assessment: Query constitutional symptoms (fever, weight loss, night sweats), bleeding manifestations, and thrombotic events 1, 2
• Risk factor identification: Assess for tissue injury, recent surgery, infection, chronic inflammatory disorders, iron deficiency, smoking, obesity, diabetes, and presence of indwelling prostheses 3, 4
• Physical findings: Examine for splenomegaly, hepatomegaly, lymphadenopathy, fever, tachycardia, and signs of bleeding or thrombosis 1, 4
• Family history: Document bleeding disorders, thrombocytopenia, or known myeloproliferative neoplasms 1

Laboratory Workup

First-Tier Testing

• Complete blood count with differential: Evaluate for leukocytosis, neutrophilia, anemia, and other cytopenias that may suggest primary versus secondary causes 1, 4
• Peripheral blood smear: Essential for identifying morphologic abnormalities and excluding pseudothrombocytosis 1
• Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate to assess for inflammatory conditions 3, 4
• Iron studies: Serum ferritin, iron, and total iron-binding capacity, as iron deficiency anemia accounts for 11.1% of secondary thrombocytosis 3
• Liver and renal function tests: Assess for organ dysfunction that may contribute to thrombocytosis 1

Infectious and Inflammatory Screening

• Infection workup: Blood cultures, urinalysis, chest imaging if clinically indicated, as infection accounts for 17.1% of secondary thrombocytosis 3, 4
• HIV and hepatitis C testing: Recommended to identify secondary causes 5, 1
• Helicobacter pylori testing: Consider urea breath test or stool antigen test 5, 1

Molecular Testing for Primary Thrombocytosis

• JAK2 V617F mutation: Screen in all patients with unexplained thrombocytosis, as 86% of primary thrombocytosis cases have at least one molecular marker 3, 6, 2
• CALR and MPL mutations: Test if JAK2 is negative and clinical suspicion for myeloproliferative neoplasm remains high 6, 2
• Additional testing: Thyroid function tests, as 8-14% of patients may develop thyroid dysfunction 1

Bone Marrow Examination Indications

• Age >60 years: Recommended due to higher risk of myeloproliferative neoplasm 1
• Systemic symptoms: Presence of constitutional symptoms, abnormal signs, or splenomegaly 1
• Molecular marker negative: When JAK2, CALR, and MPL are negative but clinical suspicion remains 6, 2
• Consideration of splenectomy: Required before surgical intervention 1

Distinguishing Primary from Secondary Thrombocytosis

Features Suggesting Primary Thrombocytosis

• Platelet count typically >800 × 10⁹/L: Extreme thrombocytosis more common in essential thrombocythemia 3, 2
• Prolonged duration >1 month: Persistent elevation without clear secondary cause 3
• Presence of driver mutations: JAK2 V617F, CALR, or MPL mutations 3, 6, 2
• Higher thrombosis incidence: Significantly elevated compared to secondary causes 3
• Splenomegaly: May be present on examination 2

Features Suggesting Secondary Thrombocytosis

• Identifiable underlying cause: Tissue injury (32.2%), infection (17.1%), chronic inflammatory disorders (11.7%), iron deficiency (11.1%) 3
• Clinical context: Inpatient status, quadriplegia/paraplegia, indwelling prosthesis, dementia 4
• Associated findings: Fever, tachycardia, weight loss, hypoalbuminemia, neutrophilia, leukocytosis, anemia 4
• Rapid normalization: Platelet count normalizes quickly once underlying cause is treated 4

Risk Stratification and Management Implications

High-Risk Features Requiring Intervention

• Age ≥60 years: Increased thrombotic risk regardless of platelet count 7
• Prior thrombosis: At any age warrants cytoreductive therapy 7
• Extreme thrombocytosis >1,500 × 10⁹/L: Consider treatment even in younger patients 7
• Cardiovascular risk factors: Smoking, obesity, diabetes increase thrombotic risk 2, 7

Low-Risk Features Allowing Observation

• Age <60 years: Without prior thrombosis or cardiovascular risk factors 7
• Platelet count <1,500 × 10⁹/L: May observe with or without low-dose aspirin 7
• Secondary cause identified: Treat underlying condition rather than thrombocytosis itself 3, 4

Common Pitfalls to Avoid

• Failing to examine peripheral blood smear: Essential for excluding pseudothrombocytosis and identifying morphologic clues 1
• Missing secondary causes: Infection and tissue injury are the most common causes and require specific treatment 3, 4
• Inadequate molecular testing: 86% of primary thrombocytosis has identifiable mutations; test JAK2, CALR, and MPL sequentially 3, 6
• Overlooking iron deficiency: Accounts for 11.1% of secondary thrombocytosis and is easily treatable 3
• Premature bone marrow biopsy: Not necessary in all cases; reserve for patients >60 years, those with systemic symptoms, or molecular marker-negative cases with high clinical suspicion 1, 6