What are the causes of thrombocytosis (elevated platelet count)?

Causes of Elevated Platelets (Thrombocytosis)

Thrombocytosis is predominantly a secondary (reactive) phenomenon in 83% of cases, with primary clonal disorders accounting for only 12.5% of patients presenting with platelet counts >450 × 10⁹/L. 1

Primary (Clonal) Thrombocytosis

Primary thrombocytosis represents clonal myeloproliferative neoplasms (MPNs) that carry significantly higher thrombotic risk compared to secondary causes. 1

Essential Thrombocythemia (ET)

• Most common primary cause, accounting for 45% of primary thrombocytosis cases 2
• Requires sustained platelet count ≥450 × 10⁹/L with bone marrow showing megakaryocytic proliferation 2
• 86% of primary thrombocytosis patients have at least one molecular marker (JAK2V617F, CALR, or MPL mutations) 1
• JAK2V617F mutation present in 50-60% of ET patients 3
• CALR and MPL mutations found in JAK2-negative cases 3

Other Myeloproliferative Neoplasms

• Polycythemia vera: Elevated platelets alongside increased red cell mass, JAK2V617F mutation in >90% of cases 3
• Primary myelofibrosis: JAK2V617F in ~50%, characterized by atypical megakaryocytes and bone marrow fibrosis 3
• Chronic myeloid leukemia: Requires BCR-ABL1 testing for exclusion 3

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis accounts for the vast majority of cases and carries minimal thrombotic risk, even at very high platelet counts. 3

Tissue Damage and Trauma

• Most common cause of secondary thrombocytosis at 32.2% of cases 1
• Post-surgical states and trauma 3
• Burns 4

Infections

• Second most common cause at 17.1% of secondary cases 1
• Acute bacterial or viral infections 4
• Chronic infections: HIV, hepatitis C, Helicobacter pylori, parvovirus, cytomegalovirus 3
• Pediatric empyema causes platelets >500 × 10⁹/L in 93% of cases, peaking at 2 weeks and normalizing by 3 weeks without thromboembolic complications 3

Chronic Inflammatory Disorders

• Accounts for 11.7% of secondary thrombocytosis 1
• Inflammatory bowel disease 2
• Rheumatoid arthritis 4
• Adult-onset Still's disease (thrombocytosis parallels disease activity) 3
• Connective tissue diseases 2

Iron Deficiency Anemia

• Frequently overlooked cause, accounting for 11.1-11% of secondary cases 2, 1
• Iron replacement normalizes platelet counts when this is the sole driver 3
• Critical pitfall: Iron deficiency can mask polycythemia vera by normalizing hemoglobin levels 3

Malignancy

• Solid tumors and lymphoproliferative disorders 2
• Malignancy-associated thrombocytosis confers increased thrombotic risk 3
• Paraneoplastic thrombocytosis observed in 33.9% of patients with reactive thrombocytosis in cancer populations 5

Post-Splenectomy or Hyposplenism

• Produces sustained platelet elevation 3
• Functional asplenia has similar effect 2

Drug-Induced

• Corticosteroids 4
• Epinephrine 4
• Erythropoiesis-stimulating agents in cancer patients 4

Other Causes

• Hemolytic anemia 2
• Post-hemorrhagic states 2
• Rebound thrombocytosis after treatment of thrombocytopenia 2
• Pregnancy and hormonal influences 2
• Exercise-induced (transient) 2

Diagnostic Algorithm

Step 1: Confirm True Thrombocytosis

• Document sustained platelet count ≥450 × 10⁹/L on repeat testing 3
• Exclude pseudothrombocytosis via peripheral blood smear 2

Step 2: Assess for Secondary Causes

• Iron studies (ferritin, serum iron, TIBC) to detect iron deficiency 3
• Inflammatory markers (CRP, ESR) for chronic inflammation 4
• Review for recent infections, trauma, surgery, or malignancy 4
• Medication review for drug-induced causes 3

Step 3: Molecular Testing (if no clear secondary cause or platelet count >1000 × 10⁹/L)

• First-line: JAK2V617F mutation testing 3
• If JAK2 negative: CALR and MPL mutation analysis 3
• BCR-ABL1 testing to exclude chronic myeloid leukemia 3

Step 4: Bone Marrow Evaluation

• Required when molecular markers are positive or clinical suspicion is high for MPN 2
• Assess megakaryocyte morphology, cellularity, and fibrosis 3
• Not indicated in children with classic immune thrombocytopenia features 3

Clinical Significance and Risk Stratification

Thrombotic Risk

• Primary thrombocytosis carries significantly higher thrombotic risk with higher median platelet counts compared to secondary causes 1
• Secondary thrombocytosis rarely leads to thrombosis, even at very high platelet counts 3
• In pediatric empyema with platelets >500 × 10⁹/L, platelet function remains normal with no thromboembolic events 3

Management Implications

• Secondary thrombocytosis: Treat underlying condition; antiplatelet therapy not indicated 3, 4
• Primary thrombocytosis: Risk-stratify for cytoreductive therapy (hydroxyurea, anagrelide) and low-dose aspirin (81-100 mg/day) 4
• Monitor platelet count after treating underlying cause to confirm resolution; if thrombocytosis persists beyond expected timeframe, consider bone marrow evaluation for occult MPN 3

Key Pitfalls to Avoid

• Do not assume iron deficiency is the sole cause without trial of iron replacement, as occult polycythemia vera may be masked 4
• Do not overlook malignancy-associated thrombocytosis, which may warrant thromboprophylaxis 3
• Do not prescribe antiplatelet therapy for secondary thrombocytosis unless other cardiovascular indications exist 4
• In cancer patients with initially elevated platelets, a decreasing trend may indicate disseminated intravascular coagulation even if absolute count remains normal 4