What are the primary and secondary causes of thrombocytosis and what is the recommended diagnostic work‑up?

Causes of High Platelet Count

Thrombocytosis is primarily caused by reactive (secondary) processes in 83% of cases—including infection, tissue injury, chronic inflammation, and iron deficiency—while primary clonal disorders (essential thrombocythemia, polycythemia vera, primary myelofibrosis) account for only 12.5% of cases. 1

Primary (Clonal) Causes

Primary thrombocytosis results from myeloproliferative neoplasms where the platelet elevation is due to clonal proliferation of megakaryocytes:

Essential Thrombocythemia (ET)

• Sustained platelet count ≥450 × 10⁹/L is required for diagnosis 2, 3
• JAK2 V617F mutation is present in approximately 50-60% of cases 2, 4, 3
• Bone marrow shows proliferation mainly of megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes without significant left-shift of other cell lines 2
• CALR and MPL mutations should be tested if JAK2 V617F is negative 3
• Must exclude polycythemia vera, primary myelofibrosis, CML, and myelodysplastic syndromes 2

Polycythemia Vera (PV)

• JAK2 V617F mutation is present in more than 90% of cases 2
• Hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women is diagnostic 3
• Iron deficiency can mask the diagnosis by normalizing hemoglobin levels 3
• Serum erythropoietin levels are subnormal 3

Primary Myelofibrosis (PMF)

• JAK2 V617F mutation is present in nearly 50% of cases 2, 4
• Megakaryocyte proliferation with atypia (small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous, or irregularly folded nuclei) 2, 4
• Reticulin or collagen fibrosis present on bone marrow biopsy 2
• Associated with leukoerythroblastosis, elevated LDH, anemia, and splenomegaly 2

Secondary (Reactive) Causes

Secondary thrombocytosis accounts for the vast majority of cases and resolves when the underlying condition is treated 5, 1:

Infection and Inflammation

• Acute and chronic infections are responsible for 17.1% of secondary thrombocytosis cases 1
• HIV, hepatitis C, Helicobacter pylori, parvovirus, and cytomegalovirus can all cause thrombocytosis 2, 4
• Chronic inflammatory disorders account for 11.7% of cases 1
• In pediatric empyema, 93% develop platelet counts >500 × 10⁹/L, peaking at 2 weeks and normalizing by 3 weeks 2

Tissue Injury and Surgery

• Tissue injury is the most common cause of secondary thrombocytosis, accounting for 32.2% of cases 1
• Post-surgical states and trauma trigger reactive thrombocytosis 2
• Splenectomy or functional asplenia causes sustained elevation 2

Iron Deficiency Anemia

• Iron deficiency accounts for 11.1% of secondary thrombocytosis cases 1
• Iron replacement therapy should normalize platelet counts if this is the sole cause 5

Malignancy

• Metastatic cancer and lymphoproliferative disorders cause reactive thrombocytosis 2
• Paraneoplastic thrombocytosis may occur 6
• Patients with malignancy-associated thrombocytosis have increased thrombotic risk requiring consideration of prophylaxis 5

Autoimmune and Connective Tissue Diseases

• Antiphospholipid antibody syndrome, lupus, and other autoimmune conditions 2
• Adult-onset Still's disease commonly presents with reactive thrombocytosis correlating with disease activity 5
• ANA testing can identify underlying autoimmune causes 4

Medications

• Certain drugs can induce secondary thrombocytosis 2

Diagnostic Work-Up Algorithm

Step 1: Confirm True Thrombocytosis

• Verify sustained platelet count ≥450 × 10⁹/L on repeat testing 2, 3

Step 2: Assess for Secondary Causes

• Complete blood count with differential to evaluate for anemia, leukocytosis, or other cytopenias 7
• Iron studies (ferritin, serum iron, TIBC) to identify iron deficiency 5, 1
• Inflammatory markers (CRP, ESR, fibrinogen, IL-6) are elevated in reactive thrombocytosis 6
• Evaluate for infection, recent surgery, trauma, or active inflammatory disease 1
• Screen for malignancy if clinically indicated 5

Step 3: If Secondary Causes Are Absent or Platelet Count >1000 × 10⁹/L, Test for Primary Thrombocytosis

• JAK2 V617F mutation testing is the first-line molecular test 4, 3, 7
• If JAK2 V617F is negative, test for CALR and MPL mutations 3
• Bone marrow biopsy with aspirate is required to evaluate megakaryocyte morphology, cellularity, and fibrosis 2, 4, 3
• Bone marrow examination is unnecessary in children with typical features of immune thrombocytopenia 2

Step 4: Exclude Other Myeloproliferative Neoplasms

• BCR-ABL1 testing to exclude chronic myeloid leukemia 2
• Hemoglobin and hematocrit to exclude polycythemia vera 2, 3
• Assess for dysplasia to exclude myelodysplastic syndrome 2

Clinical Significance and Thrombotic Risk

• Median platelet count and thrombosis incidence are significantly higher in primary versus secondary thrombocytosis 1
• Primary thrombocytosis carries a markedly increased risk of thrombosis, which is the predominant complication affecting prognosis and quality of life 7, 8
• Secondary thrombocytosis rarely causes thrombosis regardless of platelet count 2, 6
• In pediatric empyema with platelet counts >500 × 10⁹/L, platelet function remains normal and thromboembolic complications do not occur 2
• Antiplatelet therapy is not necessary for secondary thrombocytosis 2, 5

Management Principles

For Secondary Thrombocytosis

• Identify and treat the underlying cause; avoid unnecessary antiplatelet or cytoreductive therapy 5
• Recheck platelet count after treating the underlying condition to confirm resolution 5
• Reassess if thrombocytosis persists beyond the expected timeframe and consider bone marrow evaluation to exclude occult myeloproliferative neoplasm 5

For Primary Thrombocytosis

• Risk stratification for thrombosis guides treatment decisions 7, 8
• Cytoreductive therapy and antiplatelet agents are used based on thrombotic risk 8