What is the cause of a patient's leukocytosis (elevated White Blood Cell (WBC) count) and thrombocytosis (elevated platelet count) with a WBC count of 22 x 10^9/L and a platelet count of 717 x 10^9/L?

Differential Diagnosis of Leukocytosis and Thrombocytosis

The combination of WBC 22 × 10^9/L and platelets 717 × 10^9/L most likely represents either a myeloproliferative neoplasm (particularly essential thrombocythemia or early polycythemia vera) or a reactive process, and these must be distinguished through bone marrow examination, driver mutation testing (JAK2, CALR, MPL), and exclusion of secondary causes. 1

Primary Diagnostic Considerations

Myeloproliferative Neoplasms (Most Important to Rule Out)

Essential Thrombocythemia (ET) is the leading consideration given the marked thrombocytosis. Diagnostic criteria require: 1

• Sustained platelet count ≥450 × 10^9/L (this patient meets criteria at 717)
• Bone marrow showing megakaryocyte proliferation with large, mature morphology and deeply lobulated (staghorn-like) nuclei 1, 2
• Presence of JAK2V617F, CALR, or MPL mutation in approximately 80% of cases 3
• Exclusion of other myeloid neoplasms including polycythemia vera, primary myelofibrosis, CML, and MDS 1

Polycythemia Vera (PV) must be excluded, as it commonly presents with leukocytosis and thrombocytosis. Key distinguishing features: 1

• Check hemoglobin/hematocrit (>16.5 g/dL in men, >16.0 g/dL in women suggests PV)
• PV shows trilineage proliferation (panmyelosis) on bone marrow with pleomorphic megakaryocytes 1, 2
• JAK2V617F mutation present in >95% of cases 1
• Absent or markedly reduced bone marrow iron stores 2

Early/Pre-fibrotic Primary Myelofibrosis should be considered: 1

• Distinguished by atypical megakaryocytes (small to large with aberrant nuclear/cytoplasmic ratio, hyperchromatic, irregularly folded nuclei, and dense clustering) 1
• May show grade 1 reticulin fibrosis with increased marrow cellularity 1

Chronic Myeloid Leukemia (CML) is an important consideration despite the atypical presentation: 4

• A rare subgroup of CML presents with marked thrombocytosis (>2,000 × 10^9/L) without significant leukocytosis, predominantly in young females 4
• BCR-ABL1 testing is mandatory to exclude this diagnosis 1
• These cases may be misdiagnosed as ET if Philadelphia chromosome testing is not performed 4

Reactive Thrombocytosis and Leukocytosis

Secondary causes must be systematically excluded: 1

Inflammatory/Infectious conditions:

• Adult-onset Still's disease characteristically causes marked leukocytosis (often >15-20 × 10^9/L with neutrophilia) and reactive thrombocytosis 1
• Look for: fever spikes, salmon-pink rash, sore throat, arthralgia, elevated ferritin, and ESR 1
• Chronic infections or inflammatory conditions (connective tissue disease, inflammatory bowel disease) 1

Other reactive causes to evaluate: 1

• Iron deficiency (check ferritin, iron studies)
• Recent surgery or trauma
• Occult malignancy (solid tumors, lymphoproliferative disorders)
• Post-splenectomy state
• Tissue necrosis or hemorrhage

Diagnostic Algorithm

Immediate Laboratory Evaluation

1. Complete blood count with differential: 1

   • Assess for neutrophilia (suggests reactive process or PV)
   • Evaluate hemoglobin/hematocrit (elevated suggests PV)
   • Review peripheral smear for immature cells, dysplasia, or leukoerythroblastosis

2. Inflammatory markers: 1

   • ESR, CRP (markedly elevated in reactive conditions)
   • Ferritin (very high in Still's disease, low in iron deficiency)

3. Molecular testing (essential): 1, 3

   • JAK2V617F mutation (present in ~60% of ET, >95% of PV)
   • CALR and MPL mutations if JAK2 negative (~20% and ~3% of ET respectively)
   • BCR-ABL1 testing to exclude CML

4. Exclude secondary causes: 1

   • Iron studies (ferritin, serum iron, TIBC)
   • Inflammatory workup if clinically indicated
   • Imaging to exclude occult malignancy or splenomegaly

Bone Marrow Examination

Bone marrow biopsy is required for definitive diagnosis: 1, 2

• Assess megakaryocyte morphology (large mature forms in ET vs. pleomorphic in PV vs. atypical clustering in PMF)
• Evaluate cellularity and trilineage proliferation
• Grade reticulin fibrosis (absent/minimal in ET, variable in others)
• Assess iron stores (absent in PV, normal in ET)
• Cytogenetic analysis to detect clonal abnormalities

Clinical Risk Assessment

If myeloproliferative neoplasm is confirmed, thrombotic risk stratification is critical: 1, 5

Thrombosis Risk Factors

• Age >60 years (most important) 1
• Prior thrombosis history (most important) 1
• JAK2V617F mutation (doubles thrombotic risk) 1
• Leukocytosis itself is an independent risk factor for thrombosis in both ET and PV 5, 6
• Cardiovascular risk factors 1

Important caveat: Extreme thrombocytosis (>1,000 × 10^9/L) is paradoxically associated with hemorrhagic risk rather than thrombotic risk due to acquired von Willebrand disease 1, 5, 3

Prognostic Implications

The combination of leukocytosis and thrombocytosis carries specific implications: 5, 6

• Elevated WBC count during follow-up correlates with both thrombosis (p=0.05) and major hemorrhage (p=0.01) 5
• Leukocytosis adds independent prognostic significance beyond traditional risk factors 6
• This association meets epidemiologic criteria for causation, not merely correlation 6

Common Pitfalls to Avoid

1. Do not assume reactive thrombocytosis without excluding MPN: Even with obvious inflammatory conditions, concurrent MPN can exist 1

2. Do not rely solely on platelet count for diagnosis: The morphology and distribution of megakaryocytes on bone marrow biopsy is critical for distinguishing ET from pre-fibrotic PMF 1, 2

3. Do not miss atypical CML presentation: Young females with marked thrombocytosis and minimal leukocytosis may have CML rather than ET 4

4. Do not overlook the significance of leukocytosis: WBC count >11 × 10^9/L is a minor criterion for PMF and an independent thrombotic risk factor in ET/PV 1, 5, 6

5. Do not forget iron studies: Iron deficiency can cause reactive thrombocytosis and must be corrected before diagnosing ET; conversely, absent iron stores support PV diagnosis 1, 2