What is the appropriate workup for a patient with confirmed thrombocytosis?

Workup for Elevated Platelets (Thrombocytosis)

Begin by confirming true thrombocytosis with a repeat complete blood count and peripheral blood smear to exclude pseudothrombocytopenia and assess platelet morphology, then systematically distinguish between primary (clonal) and secondary (reactive) causes through targeted history, examination, and laboratory testing. 1, 2

Initial Confirmation and Assessment

• Verify the platelet count with a repeat CBC, as EDTA-dependent platelet agglutination can cause pseudothrombocytopenia 1
• Examine the peripheral blood smear to confirm true thrombocytosis, assess platelet size and morphology (giant or small platelets may indicate inherited disorders), and evaluate for other cell abnormalities 1
• Classify severity: mild (500,000-700,000/μL), moderate (700,000-900,000/μL), severe (>900,000/μL), or extreme (>1,000/μL) 3

Clinical History and Physical Examination

Key Historical Elements

• Age and prior thrombotic events are the strongest risk factors for thrombosis in primary thrombocytosis 4, 5
• Recent tissue injury, infection, surgery, or trauma (most common causes of secondary thrombocytosis at 32-42%) 2, 5
• Chronic inflammatory conditions (inflammatory bowel disease, rheumatoid arthritis) 2, 5
• Iron deficiency symptoms (accounts for 11% of secondary thrombocytosis) 2
• Malignancy history (13% of secondary cases) 5
• Medication history including recent heparin exposure (within 3 months) or COVID-19 vaccination (5-30 days prior) 6
• Bleeding history using a bleeding assessment tool, as paradoxical bleeding can occur with extreme thrombocytosis 1

Physical Examination Findings

• Splenomegaly suggests primary myeloproliferative neoplasm; obtain abdominal CT or ultrasound if suspected 1
• Signs of infection or inflammation 2
• Evidence of malignancy or tissue damage 5
• Bleeding manifestations (bruising, petechiae, mucosal bleeding) 6

Laboratory Workup Algorithm

First-Tier Testing (All Patients)

• Complete blood count with differential to assess for other cytopenias or erythrocytosis 7, 2
• Peripheral blood smear (already discussed above) 1
• Iron studies (serum iron, ferritin, TIBC) to exclude iron deficiency 2
• C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to assess for inflammation 5
• Comprehensive metabolic panel including lactate dehydrogenase (LDH) and potassium (elevated in primary thrombocytosis) 5

Second-Tier Testing (When Primary Thrombocytosis Suspected)

Suspect primary thrombocytosis when: platelet count >1,000/μL, no obvious secondary cause identified, or presence of splenomegaly 3, 2

• JAK2V617F mutation testing (present in ~50-60% of essential thrombocythemia cases) 8, 2
• CALR and MPL mutation testing if JAK2 negative (together account for most remaining ET cases) 8, 2
• Bone marrow aspiration and biopsy with morphologic assessment, flow cytometry, and cytogenetic testing 1, 2
  • Particularly important in patients >60 years, those with systemic symptoms, or when considering splenectomy 1
  • Essential for distinguishing between myeloproliferative neoplasms when molecular markers are present 2

Additional Testing Based on Clinical Context

• HIV and hepatitis C serology in all adults with suspected primary thrombocytosis, regardless of risk factors (can present identically to primary ITP) 1
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) if bleeding or thrombosis present, or if considering disseminated intravascular coagulation 7
• Helicobacter pylori testing (urea breath test or stool antigen preferred over serology) in adults where it may impact management 1
• Thyroid function tests and antithyroid antibodies as 8-14% of ITP patients develop thyroid disease longitudinally 1

Distinguishing Primary from Secondary Thrombocytosis

Features Favoring Primary (Clonal) Thrombocytosis

• Platelet count typically >1,000/μL (median significantly higher than secondary) 2, 5
• Presence of JAK2V617F, CALR, or MPL mutations (86% of primary cases have at least one molecular marker) 2
• Splenomegaly 1
• Elevated hematocrit, leukocyte count, LDH, and potassium 5
• Significantly increased thrombotic risk (both arterial and venous) 2, 5

Features Favoring Secondary (Reactive) Thrombocytosis

• Identifiable underlying cause (infection, inflammation, tissue damage, malignancy, iron deficiency) 2, 5
• Elevated inflammatory markers (CRP, ESR, fibrinogen) 5
• Lower platelet counts (typically <1,000/μL) 2
• Thrombosis only occurs with additional risk factors and is restricted to venous system 5

Critical Pitfalls to Avoid

• Do not assume thrombocytosis is reactive without excluding primary causes, especially when platelet count exceeds 1,000/μL or persists without clear etiology 2
• Do not delay molecular testing (JAK2, CALR, MPL) in suspected myeloproliferative neoplasms, as this has simplified diagnosis and is now standard of care 8, 2
• Do not overlook thrombotic risk assessment, as primary thrombocytosis carries significantly higher risk requiring different management 2, 5
• Do not routinely perform bone marrow biopsy before molecular testing, but do perform it when molecular markers are positive to classify the specific myeloproliferative neoplasm 1, 2
• Remember that 5% of vaccine-induced thrombotic thrombocytopenia (VITT) patients have normal platelet counts initially, requiring repeat testing in 2-3 days if clinical suspicion remains high 1