What is the appropriate management for a patient with persistent leukocytosis (elevated white blood cell count) and thrombocytosis (elevated platelet count)?

Management of Persistent Leukocytosis and Thrombocytosis

The first priority is to exclude chronic myeloid leukemia (CML) through immediate BCR-ABL testing, as this requires urgent tyrosine kinase inhibitor therapy; if CML is excluded, proceed with risk stratification for myeloproliferative neoplasms and initiate cytoreductive therapy with hydroxyurea for high-risk patients (age >60 years or prior thrombosis history) while adding low-dose aspirin unless contraindicated. 1

Immediate Diagnostic Steps

Obtain peripheral blood BCR-ABL testing (FISH or PCR) immediately to confirm or exclude CML, as this fundamentally changes management. 1 If the Philadelphia chromosome or BCR-ABL1 fusion gene is detected, start imatinib immediately without waiting for additional workup. 1

For Philadelphia-negative cases, the diagnostic workup should include:

• Bone marrow biopsy with morphologic evaluation, as this remains the cornerstone of diagnosis and is essential to distinguish between essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic myelofibrosis 2, 3
• JAK2, CALR, and MPL mutation testing, as approximately 90% of ET patients express one of these driver mutations 2
• Complete blood count with differential to assess the degree of leukocytosis and thrombocytosis 1

Risk Stratification for Myeloproliferative Neoplasms

Risk stratification determines treatment intensity and is based primarily on age and thrombosis history, not on blood count levels alone. 4, 5

High-Risk Criteria (Requiring Cytoreductive Therapy):

• Age >60 years and/or prior history of thrombosis 4, 5, 2
• In ET specifically: age >60 years with JAK2 mutation 4

Low-Risk Criteria:

• Age ≤60 years with no prior thrombosis history 4, 6
• In ET: further stratified to "very low risk" if JAK2 wild-type 4, 2

Important caveat: While leukocytosis >9.5 × 10⁹/L at diagnosis is associated with increased thrombotic risk (hazard ratio 1.8), the benefit of initiating cytoreductive therapy based solely on elevated blood counts has not been evaluated in prospective studies. 4, 7 Age and thrombosis history remain the primary drivers of treatment decisions. 4, 2

Treatment Algorithm

For High-Risk Patients:

Initiate hydroxyurea as first-line cytoreductive therapy with a starting dose of 15-20 mg/kg/day (or 500-1000 mg daily), targeting platelet count <400-450 × 10⁹/L and white blood cell count in the normal range. 5, 1, 6, 2

• Hydroxyurea reduces baseline WBC levels by approximately 35%, which diminishes the association between leukocytosis and thrombosis 7
• Add low-dose aspirin 81-100 mg daily unless contraindicated 4, 5, 6, 2
• Monitor complete blood count weekly until stable, then every 2-4 weeks 1, 6

For Low-Risk Patients:

Low-risk patients with JAK2 mutation should receive low-dose aspirin 81-100 mg daily; observation alone is appropriate for very low-risk patients (JAK2 wild-type). 4, 6

Initiate cytoreductive therapy in low-risk patients only if they develop:

• Symptomatic thrombocytosis 4, 1
• Progressive leukocytosis 4, 1
• Symptomatic or progressive splenomegaly 4
• Disease-related symptoms (pruritus, night sweats, fatigue) 4

Special Considerations and Pitfalls

Extreme Thrombocytosis (>1,000 × 10⁹/L):

• Screen for acquired von Willebrand disease before initiating aspirin, as this paradoxically increases bleeding risk 5, 6
• Refer to hematology regardless of etiology 5
• Avoid aspirin in young CML patients due to acquired von Willebrand syndrome risk 1

Symptomatic Leukocytosis or Thrombocytosis:

For patients presenting with symptoms attributable to elevated counts:

• Leukocytosis: Hydroxyurea 50-60 mg/kg/day until WBC <10-20 × 10⁹/L, with consideration of leukapheresis if WBC >100 × 10⁹/L 4, 1
• Thrombocytosis: Hydroxyurea 2-4 g/day to restore platelet count <400 × 10⁹/L 4, 1
• Anagrelide or apheresis are alternative options 4

Second-Line Therapy:

If hydroxyurea is ineffective or not tolerated, use pegylated interferon-α (preferred for younger patients) or consider ruxolitinib for PV patients with inadequate response. 4, 6, 2

Cardiovascular Risk Management

Aggressively manage all modifiable cardiovascular risk factors including hypertension, diabetes, hyperlipidemia, and smoking cessation, as these compound thrombotic risk. 6

Avoid estrogen-containing contraceptives; prefer non-hormonal or progesterone-based alternatives in women with thrombocytosis. 6

Monitoring Strategy

For CML (if BCR-ABL positive):

• BCR-ABL transcript levels every 3 months 1
• Bone marrow cytogenetics at 6 and 12 months from therapy initiation 1

For ET/PV:

• Complete blood count every 2-4 weeks initially, then every 4-12 weeks once stable 6
• Annual bone marrow evaluation if clinically indicated 6
• Target platelet count <400,000/μL for patients on cytoreductive therapy 5

Critical Pitfall to Avoid

Do not assume persistent leukocytosis in hospitalized patients represents infection requiring prolonged antibiotics. In critically ill patients with major trauma, surgery, or cerebrovascular events, persistent leukocytosis often reflects the persistent inflammation-immunosuppression and catabolism syndrome (PICS) rather than active infection, and empiric broad-spectrum antibiotics are frequently ineffective and promote resistant organism colonization. 8 This scenario differs fundamentally from primary myeloproliferative disorders and requires different management.