Causes of Thrombocytosis (Elevated Platelet Count)
Thrombocytosis is predominantly a secondary (reactive) phenomenon occurring in 83% of cases, with primary myeloproliferative neoplasms accounting for only 12.5% of patients with platelet counts >450 × 10⁹/L. 1
Primary (Clonal) Thrombocytosis
Primary thrombocytosis represents clonal disorders of hematopoietic stem cells and carries significantly higher thrombotic risk than secondary causes. 2, 1
Essential Thrombocythemia (ET)
- ET is the most common primary cause, accounting for 45% of primary thrombocytosis cases, characterized by sustained platelet count ≥450 × 10⁹/L with bone marrow megakaryocytic proliferation. 2
- Diagnosis requires detection of clonal markers: JAK2V617F (present in 50-60% of ET patients), CALR mutations, or MPL mutations—86% of primary thrombocytosis patients have at least one molecular marker. 2, 1
- Dysregulation involves defective thrombopoietin binding by platelets and megakaryocytes, resulting in increased plasma free thrombopoietin and increased megakaryocyte sensitivity to thrombopoietin. 3
Other Myeloproliferative Neoplasms
- Polycythemia vera presents with elevated platelets alongside increased red cell mass, often with leukocytosis, lower ESR, lower fibrinogen, and lower serum potassium. 2
- Primary myelofibrosis, chronic myeloid leukemia, and other myeloproliferative disorders can also cause primary thrombocytosis. 2
Thrombotic Risk in Primary Disease
- Median platelet count and incidence of thrombosis are significantly higher in primary versus secondary thrombocytosis. 1
- TAFI (thrombin-activatable fibrinolysis inhibitor) activity is significantly elevated in clonal thrombocytemia compared to reactive thrombocytosis, explaining the increased thrombotic tendency. 4
- Bleeding and thrombosis are the major causes of morbidity and mortality in ET and other MPDs, though platelet count alone does not correlate well with clinical complications. 3
Secondary (Reactive) Thrombocytosis
Secondary thrombocytosis accounts for 83.1% of all cases and is generally benign with low thrombotic risk. 1
Tissue Injury and Inflammation
- Tissue injury is the leading cause of secondary thrombocytosis, accounting for 32.2% of cases. 1
- Chronic inflammatory disorders (connective tissue diseases, inflammatory bowel disease) cause 11.7% of secondary thrombocytosis, with elevated acute phase reactants including C-reactive protein, fibrinogen, ESR, and interleukin-6. 2, 1, 5
Infection
- Infection accounts for 17.1% of secondary thrombocytosis cases. 1
- In children with empyema, platelet count >500 × 10⁹/L occurs in 93% of patients, reaching maximum at 2 weeks and normalizing after 3 weeks—this is benign and requires no antiplatelet therapy. 6
Iron Deficiency Anemia
- Iron deficiency anemia is a frequently overlooked cause, accounting for 11% of secondary thrombocytosis cases. 2, 1
Malignancy
- Solid tumors and lymphoproliferative disorders can cause secondary thrombocytosis, often with elevated leukocyte count and evidence of underlying malignant process. 2
Hematologic Conditions
- Hemolytic anemia and post-hemorrhagic states can cause secondary thrombocytosis. 2
- Post-splenectomy or functional hyposplenism leads to thrombocytosis due to loss of splenic platelet sequestration. 2
- Rebound thrombocytosis after treatment of thrombocytopenia can occur. 2
Physiologic and Transient Causes
- Pregnancy and hormonal influences can cause secondary thrombocytosis. 2
- Exercise-induced thrombocytosis can be transient. 2
Vascular Thrombosis-Associated
- Myeloproliferative neoplasms are observed in 30-40% of patients with Budd-Chiari syndrome or portal vein thrombosis, caused by increased platelet aggregation and thrombin generation. 6
- In splanchnic vein thrombosis patients, characteristic thrombocytosis may be masked by portal hypertension leading to hypersplenism and hemodilution. 6
Diagnostic Approach
Initial Evaluation
- Confirm true thrombocytosis with complete blood count and differential, then assess for obvious secondary causes (infection, inflammation, iron deficiency, malignancy, recent surgery/trauma). 2
- Laboratory tests showing increased acute phase responses (C-reactive protein, fibrinogen, ESR, interleukin-6) are useful in diagnosing secondary thrombocytosis. 5
When to Suspect Primary Disease
- Obtain molecular testing for JAK2V617F, CALR, and MPL mutations if no clear secondary cause is identified OR if platelet count >1000 × 10⁹/L. 2
- Bone marrow biopsy is recommended to confirm diagnosis and exclude other myeloid neoplasms if molecular markers are positive or clinical suspicion is high for MPN. 2
- The paradoxic clinical complications of hemorrhage and thrombosis, presence of splenomegaly, and qualitative platelet abnormalities point to neoplastic disorder. 7
Management Implications
Secondary Thrombocytosis
- Secondary thrombocytosis is common but benign; antiplatelet therapy is not necessary even with platelet counts >500 × 10⁹/L. 6
- No reports of thrombotic complications were found in six studies totaling 1,007 children with secondary thrombocytosis due to various causes. 6
- Thrombosis due to secondary thrombocytosis is rare at any platelet count, though it should be considered within overall thromboembolism risk assessment. 5
- If treatment is initiated for secondary thrombocytosis, low-dose aspirin is sufficient. 5
Primary Thrombocytosis
- Treatment of symptomatic patients with platelet-lowering agents or antiplatelet drugs may be indicated and effective, though the role of therapy in asymptomatic individuals remains controversial. 7
- The goal is to determine the cause and prevent thrombosis, particularly in cases of primary thrombocytosis. 1
Critical Pitfalls
- Do not assume thrombocytosis is benign without excluding primary myeloproliferative neoplasms, especially when platelet count exceeds 1000 × 10⁹/L or when thrombotic events occur. 2, 1
- Do not initiate antiplatelet therapy for secondary thrombocytosis, as it provides no benefit and increases bleeding risk. 6
- In patients with splanchnic vein thrombosis, do not rely solely on platelet count to exclude MPN—hypersplenism may mask thrombocytosis; obtain JAK2 mutation testing. 6