What is the appropriate workup and management for a patient presenting with thrombocytosis?

Workup for Thrombocytosis

Begin by testing for JAK2V617F mutation to distinguish primary myeloproliferative neoplasms from reactive thrombocytosis, as this is the critical first step in the diagnostic pathway. 1

Initial Diagnostic Approach

Confirm True Thrombocytosis

• Verify platelet count ≥450 × 10⁹/L on repeat testing to exclude spurious elevation 1, 2
• Review peripheral blood smear by a qualified hematologist or pathologist to assess platelet morphology and identify EDTA-dependent platelet agglutination 3
• Consistently giant platelets suggest inherited thrombocytopenia rather than thrombocytosis 3

Essential Clinical History

• Medication review: Document all current and recent medications, particularly heparin, quinidine/quinine, and sulfonamides 3
• Bleeding history: Assess for mucocutaneous bleeding, prior surgeries, and pregnancy outcomes to gauge hemostatic function 3
• Thrombosis history: Prior arterial or venous thrombotic events strongly predict essential thrombocythemia over reactive causes 2
• Systemic symptoms: Fever, weight loss, night sweats, or bone pain suggest underlying malignancy or myeloproliferative disease 3
• Secondary causes: Active infection, tissue injury, chronic inflammatory disorders (rheumatoid arthritis, inflammatory bowel disease), active malignancy, splenectomy, and iron deficiency anemia 4, 2

Physical Examination Findings

• Mild splenomegaly may occur in younger patients with essential thrombocythemia 3
• Moderate or massive splenomegaly indicates lymphoproliferative disease, portal hypertension, or primary myelofibrosis rather than essential thrombocythemia 3
• Lymphadenopathy or hepatomegaly suggests HIV, systemic lupus erythematosus, or lymphoproliferative disease 3

Laboratory Workup

Complete Blood Count Analysis

• Hemoglobin: Higher hemoglobin levels predict essential thrombocythemia; anemia proportional to bleeding suggests reactive thrombocytosis 2
• MCV and RDW: Higher MCV and RDW are associated with essential thrombocythemia 2
• White blood cell count: Elevated neutrophils suggest reactive thrombocytosis; normal counts favor essential thrombocythemia 2
• MPV: Higher mean platelet volume is associated with essential thrombocythemia 2
• Platelet morphology: Normal or slightly enlarged platelets are expected in essential thrombocythemia 3

Molecular Testing (Critical First Step)

• JAK2V617F mutation testing is mandatory to exclude essential thrombocythemia, polycythemia vera, and other myeloproliferative neoplasms 1, 5
• Approximately 80% of essential thrombocythemia patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL) in a mutually exclusive manner 6
• Among patients with primary thrombocytosis, 86% have at least one molecular marker indicative of myeloproliferative neoplasms 4
• The overall yield of molecular testing is 52.4%, with 92.1% of positive results being JAK2, CALR, or MPL mutations 2

Additional Laboratory Studies

• Ferritin: Iron deficiency is a common cause of secondary thrombocytosis and should be treated with iron replacement 1, 2
• C-reactive protein or ESR: Elevated inflammatory markers suggest chronic inflammatory disease as the cause 2
• HIV and hepatitis C testing: Mandatory in all adult patients regardless of risk factors, as these infections can cause thrombocytosis 3

Bone Marrow Examination: When Required

Mandatory Indications

• Age >60 years: Required to exclude myelodysplastic syndromes, leukemias, or other malignancies 3
• Clonal disorder cannot be excluded: When clinical assessment and mutation testing are inconclusive 1
• Atypical features present: Splenomegaly, lymphadenopathy, systemic symptoms, or abnormal smear findings 3
• Abnormal blood counts: Anemia not proportional to bleeding, leukopenia, or leukocytosis 3

Bone Marrow Testing Components

• Morphologic assessment with both aspirate and biopsy 3
• Flow cytometry to identify chronic lymphocytic leukemia-associated thrombocytosis 3
• Cytogenetic testing to exclude clonal disorders (abnormal karyotype seen in <10% of essential thrombocythemia cases) 6

Bone Marrow Morphology in Essential Thrombocythemia

• Increased number of mature-appearing megakaryocytes distributed in loose clusters 6
• Must exclude prefibrotic myelofibrosis, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis 6

Distinguishing Primary from Secondary Thrombocytosis

Clinical Predictors of Essential Thrombocythemia

• History of arterial thrombosis 2
• Higher hemoglobin, MCV, RDW, and MPV 2
• Median platelet count significantly higher than secondary thrombocytosis 4
• Absence of active malignancy, chronic inflammatory disease, splenectomy, or iron deficiency 2

Clinical Predictors of Secondary Thrombocytosis

• Active malignancy (32.2% of cases) 4
• Tissue injury (32.2% of cases) 4
• Infection (17.1% of cases) 4
• Chronic inflammatory disorders (11.7% of cases) 4
• Iron deficiency anemia (11.1% of cases) 4
• Higher body mass index, white blood cells, and neutrophils 2
• Splenectomy 2

Management Based on Diagnosis

Confirmed Reactive Thrombocytosis

• Treat the underlying cause: Iron replacement for iron deficiency, antibiotics for infection, management of inflammatory conditions 1
• No antiplatelet or cytoreductive therapy indicated at mild thrombocytosis levels (e.g., 365 × 10⁹/L) 1
• Recheck platelet count in 2-4 weeks after initiating treatment for the underlying cause 1
• If platelet count normalizes, no further hematologic workup is needed 1

Confirmed Essential Thrombocythemia

Risk Stratification

• Very low risk: Age ≤60 years, no thrombosis history, JAK2 wild-type 6
• Low risk: Age ≤60 years, no thrombosis history, JAK2 mutation present 6
• Intermediate risk: Age >60 years, no thrombosis history 6
• High risk: Thrombosis history OR age >60 years with JAK2 mutation 6

Treatment by Risk Category

• Low-risk patients: Once-daily low-dose aspirin for all patients; twice daily for very low-risk disease 6
• Intermediate-risk patients: Cytoreductive therapy is optional; consider aspirin plus observation 1, 6
• High-risk patients: Cytoreductive therapy with hydroxyurea plus aspirin is mandatory 1, 6
• First-line cytoreductive drugs: Hydroxyurea and pegylated interferon-α 6
• Second-line cytoreductive drug: Busulfan 6

Special Considerations in Cancer Patients

• Non-myeloproliferative malignancy increases thrombotic risk 1
• Antithrombotic prophylaxis should be considered based on validated risk scores 1
• At platelet count ≥50 × 10⁹/L, continue full therapeutic anticoagulation without modification if required for another indication 1
• At 365 × 10⁹/L, there is no contraindication to full-dose anticoagulation 1

Algorithmic Approach Summary

1. Confirm thrombocytosis (platelets ≥450 × 10⁹/L) and review peripheral blood smear 1, 2
2. Test for JAK2V617F mutation immediately to distinguish primary from reactive causes 1, 5
3. Assess for secondary causes: Active malignancy, infection, tissue injury, chronic inflammatory disease, iron deficiency, splenectomy 4, 2
4. Age-based stratification: Bone marrow examination mandatory if age >60 years 3
5. Evaluate for atypical features: If splenomegaly, lymphadenopathy, systemic symptoms, or abnormal smear present, proceed to bone marrow examination 3
6. If JAK2 negative and no secondary cause identified: Consider testing for CALR and MPL mutations 6
7. If persistent thrombocytosis without identified cause: Repeat JAK2V617F testing and consider hematology referral for bone marrow evaluation 1

Common Pitfalls to Avoid

• Do not delay JAK2 testing: This is the critical first step and should not be deferred pending other investigations 1
• Do not overlook iron deficiency: This is a common and easily treatable cause of secondary thrombocytosis 1, 2
• Do not assume low platelet counts exclude thrombotic risk: In essential thrombocythemia, thrombotic risk is determined by age, thrombosis history, and JAK2 mutation status, not platelet count alone 6
• Do not withhold anticoagulation in cancer patients: At platelet counts ≥50 × 10⁹/L, full therapeutic anticoagulation can be safely administered 1
• Do not order bone marrow biopsy reflexively: In patients <60 years with typical features and positive JAK2 mutation, bone marrow biopsy may not be necessary 1, 3