How do you investigate thrombocytosis (elevated platelet count)?

Investigation of Thrombocytosis

A thorough diagnostic workup for thrombocytosis should begin with distinguishing between primary (clonal) and secondary (reactive) causes, as this distinction fundamentally determines management and prognosis.

Initial Assessment

History and Examination

• Document recent infections, inflammatory conditions, surgeries, or bleeding episodes
• Check medication history (particularly for drugs associated with thrombocytosis)
• Assess for symptoms of underlying malignancy (weight loss, night sweats, abdominal discomfort)
• Look for splenomegaly, lymphadenopathy, or other signs of hematologic disorders
• Note any family history of blood disorders or thrombotic events

First-Line Investigations

1. Complete blood count with peripheral blood smear

   • Examine for abnormal platelet morphology, giant platelets, or other cell line abnormalities
   • Review previous CBCs to determine if thrombocytosis is acute or chronic

2. Basic laboratory tests

   • Inflammatory markers (CRP, ESR)
   • Iron studies (ferritin, transferrin saturation) to exclude iron deficiency
   • Renal and liver function tests

Secondary Causes Investigation

Secondary thrombocytosis accounts for approximately 83% of cases 1 and should be ruled out first:

• Inflammatory conditions: Check inflammatory markers, autoimmune panels if indicated
• Iron deficiency: Complete iron studies (ferritin, iron, TIBC, transferrin saturation)
• Infection: Blood cultures, specific serologies based on clinical presentation
• Post-surgical/trauma: Review recent surgical history
• Malignancy: Age-appropriate cancer screening, particularly for colorectal cancer in patients >60 years with unexplained thrombocytosis 2
• Drug-induced: Review medication history

Primary Thrombocytosis Investigation

If secondary causes are excluded or thrombocytosis persists despite addressing potential causes, investigate for primary thrombocytosis:

1. Molecular testing

   • JAK2 V617F mutation (most common in essential thrombocythemia)
   • CALR and MPL mutations if JAK2 negative
   • BCR-ABL to exclude chronic myeloid leukemia

2. Bone marrow examination

   • Not routinely required in all cases of thrombocytosis
   • Indicated when clinical suspicion for myeloproliferative neoplasm is high
   • Should include aspirate and trephine biopsy with cytogenetic analysis

Special Considerations

Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT)

• Consider in patients with thrombocytosis following COVID-19 vaccination
• Test D-dimer, anti-PF4 antibodies, and perform imaging if thrombosis is suspected 3

Myeloproliferative Neoplasms in Pregnancy

• Requires specialized testing and management
• Consider interferon-alpha therapy if treatment is needed during pregnancy 3

Heparin-Induced Thrombocytopenia

• Assess using 4T score if patient has been exposed to heparin
• Test for anti-PF4 antibodies if clinical suspicion is high 3

Diagnostic Algorithm

1. Confirm true thrombocytosis (platelet count >450 × 10^9/L)

   • Rule out pseudothrombocytosis by collecting blood in citrate or heparin tube

2. Evaluate for secondary causes

   • If identified, treat underlying condition and monitor platelet count

3. If no secondary cause identified or thrombocytosis persists:

   • Perform molecular testing for JAK2, CALR, and MPL mutations
   • Consider bone marrow examination

4. If molecular testing positive:

   • Diagnose appropriate myeloproliferative neoplasm
   • Risk-stratify for thrombotic complications

5. If molecular testing negative but high clinical suspicion:

   • Perform bone marrow examination
   • Consider additional genetic testing

Management Considerations

Treatment depends on the underlying cause:

• Secondary thrombocytosis: Treat underlying condition
• Primary thrombocytosis: Risk stratification for thrombotic events and consideration of cytoreductive therapy (e.g., anagrelide) 4 and antiplatelet agents

Common Pitfalls to Avoid

• Failing to distinguish between primary and secondary thrombocytosis
• Not investigating iron deficiency as both a cause of thrombocytosis and a potential sign of occult GI bleeding/malignancy
• Overlooking medication-induced thrombocytosis
• Premature diagnosis of essential thrombocythemia without excluding secondary causes
• Unnecessary bone marrow examination in cases of obvious secondary thrombocytosis

By following this systematic approach, clinicians can efficiently diagnose the cause of thrombocytosis and implement appropriate management strategies to reduce morbidity and mortality.