What is the appropriate work-up for a patient presenting with thrombocytosis (elevated platelet count)?

Work-up for Thrombocytosis

Begin by confirming true thrombocytosis with a repeat complete blood count and peripheral blood smear, then immediately distinguish between primary (myeloproliferative neoplasm) and secondary (reactive) causes through targeted history, physical examination, and molecular testing for JAK2V617F, CALR, and MPL mutations. 1, 2

Initial Confirmation and Classification

• Confirm thrombocytosis by repeating the platelet count to exclude spurious elevation, and examine a peripheral blood smear to assess platelet morphology and evaluate other cell lines for clues to underlying etiology 2, 3
• Define severity: mild (450,000-700,000/μL), moderate (700,000-900,000/μL), severe (>900,000/μL), or extreme (>1,000/μL) 4
• Determine chronicity by reviewing previous complete blood counts to distinguish acute from chronic thrombocytosis 3

Clinical History and Physical Examination

Critical Historical Elements

• Assess for secondary causes including recent surgery or tissue injury (most common cause at 32.2%), active infection (17.1%), chronic inflammatory disorders (11.7%), iron deficiency anemia (11.1%), malignancy, or medications 2
• Evaluate thrombotic risk by documenting any history of thrombosis, bleeding episodes, or cardiovascular risk factors, as thrombosis incidence is significantly higher in primary versus secondary thrombocytosis 2, 5
• Screen for symptoms of myeloproliferative neoplasms including constitutional symptoms (fatigue, night sweats, weight loss), pruritus after bathing, erythromelalgia, or early satiety suggesting splenomegaly 1, 6
• Document medication history particularly aspirin, antiplatelet agents, or anticoagulants that may affect bleeding risk 1
• Obtain family history of thrombocytosis, myeloproliferative disorders, or thrombotic events 6

Physical Examination Focus

• Palpate for splenomegaly, which suggests primary thrombocytosis from a myeloproliferative neoplasm rather than reactive thrombocytosis 1, 6
• Examine for signs of infection, inflammation, or malignancy that could explain secondary thrombocytosis 2
• Assess for bleeding manifestations including petechiae, purpura, or mucosal bleeding, particularly in extreme thrombocytosis where acquired von Willebrand syndrome may occur 7

Laboratory Work-up Algorithm

First-Tier Laboratory Tests

• Complete blood count with differential to evaluate all cell lines: look for leukocytosis or erythrocytosis suggesting polycythemia vera, or anemia suggesting iron deficiency or chronic disease 2, 3
• Peripheral blood smear to assess platelet morphology, identify abnormal white blood cells, and evaluate red blood cell morphology 3
• Inflammatory markers including C-reactive protein and erythrocyte sedimentation rate to screen for chronic inflammatory conditions 2
• Iron studies (serum iron, ferritin, total iron-binding capacity) as iron deficiency accounts for 11.1% of secondary thrombocytosis 2
• Basic metabolic panel and liver function tests to identify organ dysfunction that may contribute to thrombocytosis 3

Molecular Testing for Primary Thrombocytosis

If clinical suspicion for primary thrombocytosis exists (persistent unexplained thrombocytosis, splenomegaly, or absence of secondary causes), immediately order molecular testing as 86% of primary thrombocytosis cases have at least one molecular marker 2, 6

• JAK2V617F mutation testing (most common mutation in myeloproliferative neoplasms, present in essential thrombocythemia, polycythemia vera, and primary myelofibrosis) 1, 6, 5
• CALR mutation testing if JAK2V617F is negative 1
• MPL mutation testing (MPLW515L/K) if both JAK2V617F and CALR are negative 1, 5

Additional Testing When Primary Thrombocytosis is Suspected

• Bone marrow aspiration and biopsy with cytogenetics is essential for definitive diagnosis when molecular markers are present or when clinical suspicion remains high despite negative molecular testing, as accurate evaluation of bone marrow histology remains a key diagnostic step 6, 5
• Serum erythropoietin level to help distinguish essential thrombocythemia from polycythemia vera (low in polycythemia vera) 6
• Acquired von Willebrand syndrome screening (ristocetin cofactor activity and multimer analysis) if platelet count exceeds 1,000/μL, as this affects bleeding risk and aspirin use 7

Risk Stratification for Primary Thrombocytosis

Once primary thrombocytosis is confirmed, immediately stratify thrombotic risk to guide treatment decisions 1:

High-Risk Features (Requiring Cytoreductive Therapy)

• Age >60 years 1
• History of prior thrombosis 1
• JAK2V617F mutation (increases thrombotic risk in essential thrombocythemia) 1, 5

Low-Risk Features

• Age ≤60 years 1
• No history of thrombosis 1
• JAK2V617F negative 1

Diagnostic Algorithm Summary

For platelet count >450,000/μL:

1. Repeat CBC and examine peripheral smear to confirm true thrombocytosis 2, 3
2. Obtain targeted history and physical focusing on secondary causes (infection, inflammation, iron deficiency, malignancy, tissue injury) and symptoms of myeloproliferative neoplasms 2, 6
3. Order first-tier labs: inflammatory markers, iron studies, metabolic panel 2, 3
4. If secondary cause identified: treat underlying condition and monitor platelet count 2
5. If no secondary cause identified or splenomegaly present: order JAK2V617F, CALR, and MPL mutation testing 1, 2, 6
6. If molecular markers positive or high clinical suspicion persists: refer to hematology for bone marrow biopsy 6, 5
7. If primary thrombocytosis confirmed: perform risk stratification based on age, thrombosis history, and JAK2 status 1

Common Pitfalls to Avoid

• Do not assume thrombocytosis is benign without excluding primary causes, as 12.5% of thrombocytosis cases are primary with significantly higher thrombotic risk 2
• Do not delay molecular testing in patients without obvious secondary causes, as 86% of primary thrombocytosis has identifiable molecular markers that guide diagnosis and treatment 2
• Do not rely solely on platelet count to distinguish primary from secondary thrombocytosis, as median platelet counts overlap significantly; molecular testing and bone marrow evaluation are essential 2, 5
• Do not overlook acquired von Willebrand syndrome in extreme thrombocytosis (>1,000/μL), as this affects both bleeding risk and aspirin therapy decisions 7
• Do not assume molecular testing alone is sufficient for diagnosis, as neither JAK2V617F nor MPL mutations are disease-specific or universally present; bone marrow histology remains essential for accurate classification 5

Referral Indications

Refer to hematology for:

• Confirmed or suspected primary thrombocytosis based on molecular testing or persistent unexplained thrombocytosis 1, 6
• Platelet count >1,000/μL regardless of etiology 7
• Thrombotic or bleeding complications 1, 5
• Need for bone marrow biopsy to establish definitive diagnosis 6, 5