What are the differential diagnoses for an elevated platelet count and how should it be evaluated and managed?

Differential Diagnoses for Elevated Platelet Count

Thrombocytosis (platelet count >450,000/µL) is classified into primary (clonal) and secondary (reactive) causes, with secondary thrombocytosis accounting for the vast majority of cases in clinical practice. 1, 2

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Primary (Clonal) Thrombocytosis

Myeloproliferative Neoplasms

Essential thrombocythemia, polycythemia vera, primary myelofibrosis, and chronic myeloid leukemia are the principal myeloproliferative disorders causing primary thrombocytosis, diagnosed through bone marrow examination with JAK2 V617F, CALR, and MPL mutation testing. 3, 1

• Essential thrombocythemia – platelet count typically >1,000/µL with paradoxical thrombotic and hemorrhagic complications; requires bone marrow biopsy showing megakaryocyte proliferation and molecular testing for JAK2 V617F (present in 60%), CALR (25%), or MPL (~5%) mutations 3, 1

• Polycythemia vera – elevated hemoglobin/hematocrit with secondary thrombocytosis; JAK2 V617F mutation present in >95% of cases, or JAK2 Exon 12 mutations if V617F negative 3

• Primary myelofibrosis – thrombocytosis may occur early in disease course before progression to cytopenias; bone marrow shows reticulin/collagen fibrosis with JAK2, CALR, or MPL mutations 3

• Chronic myeloid leukemia – must be excluded via BCR-ABL1 testing (FISH or RT-PCR) in all patients with unexplained thrombocytosis 3

Key Diagnostic Features Distinguishing Primary from Secondary

• Splenomegaly – moderate to massive splenomegaly strongly suggests myeloproliferative neoplasm rather than reactive thrombocytosis 3, 1
• Abnormal platelet function tests – defective aggregation responses to multiple agonists are the rule in essential thrombocythemia/polycythemia vera but unusual in secondary thrombocytosis 4
• Bone marrow histology – remains the gold standard for distinguishing primary from secondary thrombocytosis, showing characteristic megakaryocyte clustering and atypia in myeloproliferative neoplasms 3, 1

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Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis is far more common than primary forms, occurring in 3–13% of hospitalized children and representing the majority of adult cases; it rarely causes thrombotic complications regardless of platelet count. 2, 5

Infection and Inflammation

• Acute and chronic infections – bacterial, viral, fungal, or parasitic infections trigger cytokine-mediated thrombopoiesis; platelet count normalizes after infection resolution 2, 5
• Chronic inflammatory conditions – inflammatory bowel disease, rheumatoid arthritis, vasculitis, and other autoimmune disorders cause sustained elevation of acute-phase reactants (CRP, ESR, IL-6, fibrinogen) with secondary thrombocytosis 2, 5

Iron Deficiency

• Iron deficiency anemia – one of the most common causes of reactive thrombocytosis; platelet count normalizes with iron repletion 2

Tissue Damage and Necrosis

• Post-surgical state – thrombocytosis peaks 7–14 days after major surgery 2
• Trauma – severe tissue injury, burns, or fractures stimulate reactive thrombocytosis 2
• Acute hemorrhage – blood loss triggers compensatory thrombopoiesis 2

Malignancy

• Solid tumors – lung, gastric, ovarian, and breast carcinomas may produce thrombopoietin or IL-6, causing paraneoplastic thrombocytosis 2, 5
• Lymphomas – Hodgkin and non-Hodgkin lymphoma can present with reactive thrombocytosis 2

Hyposplenism and Asplenia

• Surgical splenectomy – platelet count rises within days and may remain elevated for months 2
• Functional asplenia – sickle cell disease, celiac disease, inflammatory bowel disease cause splenic atrophy with persistent thrombocytosis 2

Medications

• All-trans retinoic acid (ATRA) – used in acute promyelocytic leukemia treatment 2
• Epinephrine – acute administration causes transient platelet count elevation 2
• Corticosteroids – chronic use may elevate platelet counts 2

Rebound Thrombocytosis

• Recovery from bone marrow suppression – chemotherapy, alcohol cessation, vitamin B12/folate repletion cause overshoot thrombocytosis 2

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Diagnostic Algorithm for Thrombocytosis

Step 1: Confirm True Thrombocytosis

• Repeat complete blood count to verify platelet count >450,000/µL 3
• Review peripheral blood smear to exclude platelet clumping (pseudothrombocytosis) 3

Step 2: Assess for Secondary Causes

• Measure inflammatory markers – CRP, ESR, fibrinogen, IL-6 elevation suggests reactive thrombocytosis 5
• Iron studies – serum iron, ferritin, TIBC, transferrin saturation to detect iron deficiency 2
• Infection workup – blood cultures, urinalysis, chest X-ray if clinically indicated 2
• Review medication list – identify drugs known to cause thrombocytosis 2
• Imaging – abdominal ultrasound or CT to assess spleen size and detect occult malignancy 3

Step 3: If Secondary Causes Excluded, Pursue Primary Thrombocytosis Workup

• BCR-ABL1 testing (FISH or RT-PCR) – mandatory first step to exclude chronic myeloid leukemia 3
• JAK2 V617F mutation – if negative, test for CALR and MPL mutations (for essential thrombocythemia/myelofibrosis) and JAK2 Exon 12 mutations (for polycythemia vera) 3
• Bone marrow aspirate and biopsy with reticulin stain – required for definitive diagnosis of myeloproliferative neoplasms 3, 1
• Bone marrow cytogenetics (karyotype ± FISH) – identifies clonal abnormalities 3

Step 4: Risk Stratification for Thrombosis (If Primary Thrombocytosis Confirmed)

• Age >60 years and prior thrombosis are the strongest risk factors for future thrombotic events in essential thrombocythemia 1
• JAK2 V617F mutation may confer additional thrombotic risk, though data are conflicting 1
• Extreme thrombocytosis (>1,000/µL) paradoxically increases hemorrhagic risk due to acquired von Willebrand disease 1, 6

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Management Principles

Secondary Thrombocytosis

No platelet-lowering therapy is required for reactive thrombocytosis regardless of platelet count; treatment focuses on the underlying condition. 2, 5

• Thrombotic complications are exceedingly rare in secondary thrombocytosis even with platelet counts >1,000/µL 5
• Low-dose aspirin (81 mg daily) may be considered within overall thromboembolism risk assessment but is not routinely indicated 5

Primary Thrombocytosis

Cytoreductive therapy (hydroxyurea, anagrelide, interferon-alpha) is reserved for high-risk patients (age >60 years, prior thrombosis, platelet count >1,500,000/µL with bleeding) in essential thrombocythemia. 3, 1, 6

• Asymptomatic low-risk patients – observation with serial monitoring every 3–6 months 3
• Symptomatic patients or high-risk features – initiate cytoreductive therapy targeting platelet count <400,000/µL 3, 1
• Low-dose aspirin – recommended for all essential thrombocythemia patients without contraindications to prevent microvascular thrombosis 1

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Critical Pitfalls to Avoid

• Do not assume thrombocytosis is reactive without excluding myeloproliferative neoplasms – splenomegaly, persistent unexplained thrombocytosis, or abnormal CBC parameters mandate bone marrow examination 3, 1
• Do not treat reactive thrombocytosis with cytoreductive agents – this exposes patients to unnecessary toxicity without benefit 2, 5
• Do not overlook iron deficiency – it is one of the most common and easily reversible causes of thrombocytosis 2
• Do not delay BCR-ABL1 testing – chronic myeloid leukemia requires immediate targeted therapy with tyrosine kinase inhibitors 3