What are the primary and secondary causes in the differential diagnosis of thrombocytosis?

Differential Diagnosis of Thrombocytosis

Definition and Confirmation

Thrombocytosis is defined as a sustained platelet count ≥ 450 × 10⁹/L on multiple measurements, and the differential diagnosis divides into primary (clonal) and secondary (reactive) causes. 1

The first critical step is confirming true thrombocytosis by documenting elevated platelets on at least two separate occasions to exclude spurious elevation. 1

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Primary (Clonal) Thrombocytosis

Primary thrombocytosis represents clonal myeloproliferative neoplasms and accounts for approximately 12.5% of all thrombocytosis cases. 2 These disorders carry significantly higher thrombotic risk compared to secondary causes. 1

Essential Thrombocythemia (ET)

• Requires all four WHO criteria: sustained platelets ≥ 450 × 10⁹/L, bone marrow showing proliferation of enlarged hyperlobulated mature megakaryocytes, exclusion of other myeloid neoplasms (PV, PMF, CML, MDS), and presence of clonal marker (JAK2V617F) or absence of reactive cause if no clonal marker found. 1, 3
• JAK2V617F mutation is present in 50-60% of ET cases. 3
• CALR and MPL mutations should be tested if JAK2V617F is negative. 1
• Bone marrow biopsy shows mature megakaryocytic proliferation without left-shift of other lineages. 3

Polycythemia Vera (PV)

• JAK2V617F mutation present in >90% of cases. 3
• Hemoglobin thresholds: ≥ 18.5 g/dL in men or ≥ 16.5 g/dL in women. 3
• Critical pitfall: Iron deficiency can mask PV by normalizing hemoglobin; perform therapeutic iron trial before excluding PV in iron-deficient patients with thrombocytosis. 1, 3
• Serum erythropoietin levels are typically subnormal. 3

Primary Myelofibrosis (PMF)

• JAK2V617F mutation in approximately 50% of cases. 3
• Bone marrow shows atypical megakaryocytes with aberrant nuclear/cytoplasmic ratios, hyperchromasia, and bulbous nuclei, plus reticulin or collagen fibrosis. 3
• Frequently accompanied by leukoerythroblastosis, elevated LDH, anemia, and splenomegaly. 3

Chronic Myeloid Leukemia (CML)

• BCR-ABL1 testing is essential to exclude CML in all cases of suspected primary thrombocytosis. 3

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Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis accounts for 83.1% of all cases and rarely causes thrombosis even at very high platelet counts. 2, 3 The major causes with their approximate frequencies are:

Tissue Injury (32.2% of secondary cases) 2

• Surgery, trauma, burns
• Post-surgical states are recognized triggers. 3

Infection (17.1% of secondary cases) 2

• HIV, hepatitis C, Helicobacter pylori, parvovirus, cytomegalovirus. 3
• Pediatric empyema produces platelets >500 × 10⁹/L in 93% of cases, peaking at 2 weeks and normalizing by 3 weeks. 3

Chronic Inflammatory Disorders (11.7% of secondary cases) 2

• Connective tissue diseases (systemic lupus erythematosus, antiphospholipid antibody syndrome). 3
• Inflammatory bowel disease. 1
• Adult-onset Still's disease frequently presents with reactive thrombocytosis paralleling disease activity. 3

Iron Deficiency Anemia (11.1% of secondary cases) 2

• Can cause thrombocytosis even without anemia; iron replacement normalizes platelet counts when this is the sole driver. 3
• Microcytosis (MCV <80 fL) indicates iron deficiency requiring supplementation. 1

Post-Splenectomy or Functional Asplenia

• Produces sustained platelet elevation. 3

Malignancy

• Metastatic solid tumors and lymphoproliferative disorders. 1
• Malignancy-associated thrombocytosis confers increased thrombotic risk. 3

Medications

• Certain drugs are recognized causes of secondary thrombocytosis. 3

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Diagnostic Algorithm

Step 1: Confirm Thrombocytosis

• Document platelet count ≥ 450 × 10⁹/L on at least two separate occasions. 1

Step 2: Exclude Pseudothrombocytosis

• Review peripheral blood smear to exclude spurious elevation. 1

Step 3: Screen for Secondary Causes

• History: Recent surgery, trauma, splenectomy, active infection, inflammatory disease, malignancy. 1
• Iron studies: Ferritin, serum iron, TIBC to detect iron deficiency. 1, 3
• Inflammatory markers: ESR and CRP to identify chronic inflammation. 1
• ANA testing: To uncover autoimmune etiologies. 3

Step 4: Assess for Primary Thrombocytosis

• Platelet count >600 × 10⁹/L without identifiable secondary cause raises suspicion for primary thrombocytosis. 1
• Persistent thrombocytosis after resolution of potential secondary trigger supports primary etiology. 1

Step 5: Molecular Testing

• JAK2V617F testing is the first-line molecular assay. 1, 3
• If JAK2V617F negative, proceed with CALR and MPL mutation analysis. 1, 3

Step 6: Bone Marrow Evaluation

• Mandatory in patients >60 years or any age with systemic symptoms to identify megakaryocytic proliferation, exclude myelofibrosis, and rule out myelodysplastic syndromes or leukemias. 1, 3
• Not indicated in children with classic features of reactive thrombocytosis. 3
• Assess for megakaryocyte morphology, cellularity, reticulin fibrosis, and dysplasia. 3

Step 7: Additional Testing

• Hemoglobin/hematocrit to rule out polycythemia vera. 3
• BCR-ABL1 to exclude chronic myeloid leukemia. 3

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Key Diagnostic Pitfalls and How to Avoid Them

• Failing to perform bone marrow biopsy in patients >60 years can miss early myelofibrosis or myelodysplasia. 1
• Not conducting therapeutic iron trial in iron-deficient patients may lead to misclassification of concealed polycythemia vera as secondary thrombocytosis. 1
• Assuming concurrent reactive condition automatically excludes essential thrombocythemia; ET can coexist with reactive causes if core WHO criteria are satisfied. 1
• Moderate or massive splenomegaly suggests alternative cause rather than ET; mild splenomegaly may occur in younger ET patients. 4
• Constitutional symptoms (fever, weight loss), hepatomegaly, or lymphadenopathy indicate underlying disorder such as HIV, SLE, or lymphoproliferative disease rather than isolated ET. 4

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Clinical Significance

• Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis. 1
• Secondary thrombocytosis rarely leads to thrombosis even at very high platelet counts; antiplatelet therapy is not indicated. 3
• In pediatric empyema with platelets >500 × 10⁹/L, platelet function remains normal and no thromboembolic events occur. 3
• Median platelet count and incidence of thrombosis are significantly higher in primary versus secondary thrombocytosis. 2