What is the appropriate workup for a patient with persistent leukocytosis (elevated White Blood Cell count) and thrombocytosis (elevated platelet count)?

Workup of Persistent Leukocytosis and Thrombocytosis in a 38-Year-Old

The primary concern in a 38-year-old with persistent high WBC and high platelets is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), specifically essential thrombocythemia (ET) or polycythemia vera (PV), which requires immediate bone marrow evaluation with cytogenetics and JAK2 mutation testing to guide treatment and prevent life-threatening thrombotic complications. 1

Initial Diagnostic Approach

Immediate Laboratory Testing

• Complete blood count with differential to quantify the degree of leukocytosis and thrombocytosis, and assess for other cytopenias 1
• Peripheral blood smear to evaluate for immature myeloid cells, leukoerythroblastosis, and megakaryocyte fragments that suggest primary bone marrow pathology 1
• JAK2 V617F mutation testing on peripheral blood, as this mutation is present in approximately 95% of PV cases and 50-60% of ET cases 1
• BCR-ABL testing by RT-PCR or FISH to exclude chronic myelogenous leukemia (CML), even though the patient is Philadelphia chromosome-negative by definition if this is negative 1

Secondary Causes to Exclude

Before pursuing MPN workup, rapidly exclude secondary causes that are far more common (87.7% of thrombocytosis cases) 2:

• Inflammatory markers: ESR, CRP, and fibrinogen to assess for chronic inflammation 2
• Infection workup: Blood cultures, urinalysis, chest X-ray if clinically indicated 3, 2
• Tissue damage assessment: Recent surgery, trauma, or ischemic events within the past 2-3 weeks 3, 2
• Malignancy screening: Age-appropriate cancer screening, particularly if constitutional symptoms present 2
• Iron studies: Serum ferritin, iron, and TIBC, as iron deficiency commonly causes reactive thrombocytosis 2

Critical distinction: Secondary thrombocytosis rarely exceeds 1000 × 10⁹/L and is not associated with thrombotic risk unless other risk factors are present, whereas primary thrombocytosis carries significant thrombotic risk 2

Bone Marrow Evaluation

When to Perform

Proceed immediately to bone marrow biopsy and aspiration if: 1

• Platelet count >450 × 10⁹/L persists after excluding secondary causes
• WBC count >11 × 10⁹/L without clear reactive etiology 4
• Any combination of elevated cell lines suggesting MPN
• JAK2 V617F mutation is positive

Required Bone Marrow Studies

• Cytogenetic analysis to confirm absence of Philadelphia chromosome and detect other chromosomal abnormalities 1
• Bone marrow histology to assess for megakaryocyte hyperplasia (characteristic of ET) and evaluate reticulin fibrosis grade 1
• Molecular testing panel including JAK2 exon 12 mutations (if JAK2 V617F negative), CALR mutations, and MPL mutations 1

Risk Stratification for Thrombosis

High-Risk Features Requiring Immediate Intervention

The combination of elevated platelets AND elevated WBC carries the highest thrombotic risk 5:

• WBC >11 × 10⁹/L: Hazard ratio 2.35 for thrombotic events, even when hematocrit is controlled 4
• Platelets >574-593 × 10⁹/L: Independently increases thrombotic risk 6, 5
• Combined elevation: When both WBC >8.48 × 10⁹/L AND platelets >574.5 × 10⁹/L, thrombotic event frequency is highest 5

Additional Thrombotic Risk Assessment

• Age >60 years or prior thrombotic event history automatically classifies as high-risk 1
• Cardiovascular risk factors: Hypertension, diabetes, smoking, hyperlipidemia 1
• Hematocrit level: If >45%, significantly increases thrombotic risk (HR 1.84) 4

Imaging Studies

Baseline Vascular Assessment

• Abdominal ultrasound to exclude subclinical splanchnic vein thrombosis or spleen infarcts, which may be present at diagnosis 1
• Splenomegaly assessment by palpation or imaging 1

If Thrombotic Symptoms Present

Immediate imaging based on symptom location 1:

• Head CT venogram or MRA for neurologic symptoms (cerebral venous sinus thrombosis)
• Abdominal ultrasound or CT venogram for abdominal pain (portal/splanchnic thrombosis)
• CT pulmonary angiography for dyspnea (pulmonary embolism)
• Duplex ultrasound for extremity symptoms (DVT)

Common Pitfalls to Avoid

• Do not dismiss persistent leukocytosis as "stress response" in a 38-year-old without clear acute illness—this age group requires MPN evaluation 3
• Do not wait for extreme thrombocytosis (>1000 × 10⁹/L) before investigating; ET diagnosis requires platelets >450 × 10⁹/L with appropriate bone marrow findings 1
• Do not overlook WBC count when focusing on platelets—leukocytosis is an independent and potentially more significant thrombotic risk factor than thrombocytosis 4, 5
• Avoid empiric antibiotics for unexplained leukocytosis without clear infection, as this leads to prolonged hospitalization and resistant organism colonization without benefit 3

Monitoring During Workup

• Serial CBC every 3-7 days to document persistence and trend of cytopenias 1
• Daily coagulation parameters if thrombocytosis is severe (>1000 × 10⁹/L) to monitor for acquired von Willebrand syndrome 1
• Symptom assessment for early thrombotic or hemorrhagic complications 1