What is the management approach for a patient with thrombocytosis, mild neutrophilia, and lymphocytosis on a peripheral blood smear?

Management of Thrombocytosis with Neutrophilia and Lymphocytosis

The immediate priority is to repeat the complete blood count in a non-EDTA tube and perform a comprehensive peripheral blood smear examination to exclude pseudothrombocytosis and identify the underlying etiology, which will determine whether this represents a reactive process, myeloproliferative neoplasm, or lymphoproliferative disorder. 1

Initial Diagnostic Workup

Confirm True Cell Count Abnormalities

• Repeat the platelet count immediately in heparin or sodium citrate tubes to exclude EDTA-dependent platelet agglutination, which can falsely elevate counts 1
• Perform peripheral blood smear examination to assess:
  • Platelet morphology (giant platelets suggest inherited disorders; normal to large platelets support reactive processes) 1
  • Lymphocyte morphology (atypical lymphocytes strongly suggest viral infection, particularly EBV, CMV, or acute HIV) 1
  • Neutrophil morphology (toxic granulation indicates bacterial infection; dysplasia suggests myeloid neoplasm) 2
  • Presence of immature myeloid precursors (left shift suggests reactive process or chronic myeloid neoplasm) 3
  • Teardrop erythrocytes (suggest myelofibrosis) 3

Essential Laboratory Testing

• Complete blood count with differential and reticulocyte count to distinguish isolated thrombocytosis from multi-lineage involvement 1
• HIV, hepatitis C, and hepatitis B testing in all adults, as these infections cause secondary cytopenias and cytoses 1
• CMV and EBV serologies given the lymphocytosis 1
• Ferritin level to assess for iron deficiency, which is associated with secondary thrombocytosis 4
• Inflammatory markers (CRP, ESR) to evaluate for chronic inflammatory disease 4

Differential Diagnosis Algorithm

If Atypical Lymphocytes Present

• Viral infection is the most likely diagnosis (EBV, CMV, acute HIV) 1
• The combination of reactive lymphocytes and toxic granulation strongly suggests an ongoing infectious process 2
• Obtain viral serologies and consider acute HIV testing 1
• Management: Treat the underlying infection and monitor CBC to assess response 2

If Normal Lymphocyte Morphology with Thrombocytosis and Neutrophilia

Distinguish between secondary thrombocytosis and myeloproliferative neoplasm:

Clinical Features Favoring Secondary Thrombocytosis

• Active malignancy 4
• Chronic inflammatory disease (inflammatory bowel disease, rheumatoid arthritis) 4
• History of splenectomy 4
• Iron deficiency anemia 4
• Higher body mass index 4
• Higher white blood cell and neutrophil counts 4

Clinical Features Favoring Essential Thrombocythemia or MPN

• History of arterial thrombosis 4
• Higher hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV) 4
• Absence of secondary causes 4

If Secondary Causes Identified

• Address the underlying condition (treat infection, manage inflammatory disease, correct iron deficiency) 4
• Monitor CBC to confirm resolution after treating the underlying cause 2
• No molecular testing is needed if clear secondary cause is present 4

If No Secondary Cause Identified or MPN Suspected

Mandatory Testing for MPN Workup

• Bone marrow aspiration and biopsy for morphological evaluation, which is essential for diagnosis 5
• Conventional cytogenetic analysis to detect clonal abnormalities 5
• BCR::ABL1 fusion testing (quantitative RT-PCR) to exclude chronic myeloid leukemia 5
• JAK2 V617F mutation testing (most common MPN mutation) 5, 3
• CALR and MPL mutation testing if JAK2 negative 3
• Next-generation sequencing panel for additional mutations (TET2, ASXL1, SRSF2, NRAS, KRAS, CBL) if diagnosis remains unclear 5, 3

Bone Marrow Findings Guide Diagnosis

• Granulocytic hyperplasia with dysplasia suggests chronic myelomonocytic leukemia or atypical CML 5
• Megakaryocytic hyperplasia without dysplasia suggests essential thrombocythemia 3
• Increased myeloid:erythroid ratio with marked granulocytic proliferation suggests advanced MPN 6
• Bone marrow fibrosis (assessed by Gomori's silver stain) suggests primary myelofibrosis 5

Critical Red Flags Requiring Immediate Hematology Consultation

• Age >60 years (increased risk of myelodysplastic syndrome or leukemia) 1
• Systemic symptoms (fever, weight loss, night sweats, bone pain) 1
• Splenomegaly, hepatomegaly, or lymphadenopathy on physical examination 5
• Immature myeloid precursors ≥10% in peripheral blood 6
• Persistent leukocytosis ≥13 × 10⁹/L (associated with aggressive disease course in MPN) 6
• Schistocytes on smear (indicate thrombotic microangiopathy requiring emergency intervention) 1

Management Based on Final Diagnosis

For Reactive/Secondary Thrombocytosis

• Treat the underlying cause (infection, inflammation, iron deficiency) 4
• No specific treatment for thrombocytosis itself unless platelet count >1000 × 10⁹/L with thrombotic risk 3
• Serial monitoring until counts normalize 2

For Myeloproliferative Neoplasm

• Risk stratification based on age, thrombosis history, and molecular profile 3
• Cytoreductive therapy (hydroxyurea) for high-risk patients 3
• Aspirin for thrombosis prevention in appropriate patients 3
• JAK2 inhibitors for symptomatic myelofibrosis 3

For Chronic Myelomonocytic Leukemia

• Allogeneic stem cell transplantation is the only curative option for eligible patients 5
• Hypomethylating agents (azacitidine, decitabine) for non-transplant candidates 5
• Supportive care with transfusions and growth factors as needed 5

Common Pitfalls to Avoid

• Missing pseudothrombocytosis by not repeating the count in non-EDTA tubes 1
• Assuming reactive process without excluding BCR::ABL1 fusion, which is mandatory in all cases of unexplained thrombocytosis with leukocytosis 5
• Ordering molecular testing before excluding secondary causes, which increases cost without diagnostic benefit 4
• Delaying bone marrow examination when MPN is suspected, as morphology is essential for diagnosis 5, 3
• Overlooking viral infections by not checking EBV, CMV, and HIV serologies in patients with lymphocytosis 1
• Ignoring persistent leukocytosis in known MPN patients, as this indicates disease progression and worse prognosis 6