What is the differential diagnosis for a patient with a gradual increase in platelet count, but normal hemoglobin, white blood cell count, and other laboratory values?

Differential Diagnosis for Gradual Increase in Platelet Count with Normal Other Counts

A gradual, isolated increase in platelet count with normal hemoglobin and white blood cell counts most commonly represents either reactive thrombocytosis from an underlying inflammatory/infectious process, iron deficiency, or early essential thrombocythemia (ET), and requires immediate evaluation of the peripheral blood smear for morphologic clues to distinguish reactive from clonal myeloproliferative processes. 1

Initial Diagnostic Evaluation

Blood Smear Examination

• Examine the peripheral blood smear carefully for large/giant platelets, granulocytic left shift with dysplasia, or teardrop erythrocytes, which suggest a primary myeloproliferative neoplasm rather than reactive thrombocytosis. 1
• Look specifically for toxic changes in neutrophils such as vacuolization, which would indicate active bacterial infection requiring immediate intervention. 1

Key Clinical Features to Assess

• Obtain detailed history focusing on constitutional symptoms (fever, night sweats, weight loss), history of thrombosis at young age, splenomegaly or hepatomegaly on examination, and any identifiable reactive causes. 1
• Iron deficiency is a common cause of reactive thrombocytosis; in adults with iron deficiency anemia, thrombocytosis (>400 × 10⁹/L) occurs in approximately 13.3% of cases. 2

Primary Differential Diagnoses

Myeloproliferative Neoplasms (MPNs)

• Essential thrombocythemia and polycythemia vera are the most likely MPNs when platelets are elevated with normal other counts, as these conditions frequently present with isolated thrombocytosis initially. 1
• Suspect MPN if any of the following are present: persistent elevations without identifiable reactive cause, constitutional symptoms, history of thrombosis at young age, or splenomegaly/hepatomegaly. 1
• Order JAK2 V617F mutation testing immediately if MPN is suspected, as approximately 50-60% of essential thrombocythemia patients harbor this mutation. 1

Reactive Thrombocytosis

• Iron deficiency is the most common reactive cause of isolated thrombocytosis in adults, with mean platelet counts around 304 × 10³/μL in iron deficiency anemia patients. 2
• Inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, and adult-onset Still's disease commonly cause reactive thrombocytosis. 3, 4
• Post-splenectomy thrombocytosis occurs when platelet counts exceed 500 × 10⁹/L and can persist long-term due to removal of the splenic platelet pool. 5, 6
• Infections (particularly chronic infections), malignancy, and tissue damage are additional reactive causes. 4

Post-Surgical or Post-Splenectomy State

• Splenectomy causes both early marked thrombocytosis (from increased platelet production due to surgical trauma) and late persistent minor thrombocytosis (from removal of splenic platelet pool). 6
• Reactive thrombocytosis after splenectomy with platelet counts >500 × 10⁹/L can cause acquired von Willebrand factor abnormalities indistinguishable from those in myeloproliferative disorders. 7

Algorithmic Diagnostic Approach

Step 1: Determine Absolute Platelet Count and Duration

• Obtain complete blood count with manual differential to confirm platelet elevation and assess for any subtle abnormalities in other cell lines. 1
• Document duration of thrombocytosis; persistent elevation ≥3 months without clear reactive cause warrants hematology referral. 4

Step 2: Assess for Reactive Causes

• Check iron studies (ferritin, serum iron, TIBC, transferrin saturation) to exclude iron deficiency. 2
• Evaluate inflammatory markers (ESR, CRP) to assess for underlying inflammatory conditions. 3
• Review medication history and assess for recent surgery or splenectomy. 5, 6

Step 3: Risk Stratification for MPN

• If platelet count >400 × 10⁹/L persists without identifiable reactive cause, proceed with JAK2 V617F mutation testing. 1
• Assess thrombotic risk: high-risk patients are age >60 years or have prior thrombosis history; low-risk patients are age ≤60 years with no thrombosis history. 1

Step 4: Management Based on Findings

If JAK2 V617F Positive or MPN Suspected:

• All high-risk patients require cytoreductive therapy with hydroxyurea as first-line treatment, starting at 15 mg/kg/day orally with dose adjustments to maintain platelet count <400 × 10⁹/L. 1
• Add low-dose aspirin 81-100 mg daily for all high-risk patients unless contraindicated by extreme thrombocytosis (>1000-1500 × 10⁹/L) with acquired von Willebrand syndrome or active bleeding. 1, 7
• Target platelet count <400 × 10⁹/L in daily practice for essential thrombocythemia. 3

If Reactive Cause Identified:

• Treat underlying condition (iron supplementation for iron deficiency, anti-inflammatory therapy for inflammatory conditions). 2
• Monitor platelet counts during treatment; normalization of platelet count should occur with resolution of underlying cause. 7

Critical Pitfalls to Avoid

• Do not assume isolated thrombocytosis is benign without peripheral smear examination, as early MPN can present with normal hemoglobin and WBC initially. 1
• Extreme thrombocytosis (>1000 × 10⁹/L) paradoxically increases bleeding risk due to acquired von Willebrand syndrome from platelet-mediated removal of large vWF multimers; avoid aspirin in this setting. 7
• Failure to check iron studies misses the most common reactive cause of isolated thrombocytosis in adults. 2
• Monitor for hydroxyurea resistance, defined as failure to achieve platelet count <400 × 10⁹/L after 3 months of at least 2 g/day. 3

Monitoring Parameters

• Check complete blood count weekly initially until target counts achieved if on cytoreductive therapy, then every 2-4 weeks during maintenance. 1
• For reactive thrombocytosis, recheck platelet count after treating underlying cause to confirm normalization. 7