Causes of Elevated Platelets (Thrombocytosis)
Primary (Clonal) Thrombocytosis
Primary thrombocytosis arises from myeloproliferative neoplasms and requires sustained platelet counts ≥450 × 10⁹/L with bone marrow evidence of megakaryocyte proliferation. 1, 2
Essential Thrombocythemia (ET)
- ET is diagnosed when platelet count remains ≥450 × 10⁹/L on repeat testing, with bone marrow showing proliferation of enlarged, mature megakaryocytes without left-shift of other lineages. 3, 2
- JAK2 V617F mutation is present in 50-60% of ET patients, making it the primary molecular diagnostic marker. 2
- When JAK2 V617F is negative, proceed with CALR and MPL mutation testing to identify clonal disease. 2
- Diagnosis mandates exclusion of polycythemia vera, primary myelofibrosis, chronic myeloid leukemia, and myelodysplastic syndromes. 2
Polycythemia Vera (PV)
- PV harbors JAK2 V617F mutation in >90% of cases, with diagnostic hemoglobin thresholds ≥18.5 g/dL in men or ≥16.5 g/dL in women. 2
- Iron deficiency can mask PV by normalizing hemoglobin levels, making iron studies essential before excluding this diagnosis. 2
- Serum erythropoietin levels are typically subnormal in PV. 2
Primary Myelofibrosis (PMF)
- PMF shows JAK2 V617F mutation in approximately 50% of patients, with bone marrow demonstrating atypical megakaryocyte proliferation and reticulin or collagen fibrosis. 2
- PMF frequently presents with leukoerythroblastosis, elevated LDH, anemia, and splenomegaly. 2
Chronic Myeloid Leukemia (CML)
Secondary (Reactive) Thrombocytosis
Secondary thrombocytosis accounts for 83% of all cases and arises from identifiable underlying conditions that stimulate platelet production. 4
Tissue Damage and Trauma
- Surgery, burns, and trauma represent the most common cause of secondary thrombocytosis (32.2% of cases). 4
- Post-surgical states and trauma are recognized triggers of reactive thrombocytosis. 2
Infections
- Acute bacterial or viral infections cause secondary thrombocytosis through inflammatory cytokine production. 1
- Specific infections include HIV, hepatitis C, Helicobacter pylori, parvovirus, and cytomegalovirus. 2
- In pediatric empyema, platelet counts >500 × 10⁹/L occur in 93% of cases, peaking at 2 weeks and normalizing by 3 weeks without thromboembolic complications. 2, 5
Chronic Inflammatory Disorders
- Inflammatory bowel disease and rheumatoid arthritis cause sustained platelet elevation (11.7% of secondary cases). 4, 2
- Adult-onset Still's disease frequently presents with reactive thrombocytosis that parallels disease activity. 2
Malignancy
- Solid tumors and lymphoproliferative disorders cause thrombocytosis through inflammatory cytokine production. 1
- Malignancy-associated thrombocytosis confers increased thrombotic risk, warranting consideration of prophylaxis. 2
Iron Deficiency Anemia
- Iron deficiency causes secondary thrombocytosis in 11.1% of cases; iron replacement normalizes platelet counts when this is the sole driver. 4, 2
- Iron studies (ferritin, serum iron, TIBC) are mandatory to detect iron-deficiency-related thrombocytosis. 2
Post-Splenectomy or Hyposplenism
- Splenectomy or functional asplenia produces sustained platelet elevation. 2
Autoimmune Conditions
- Antiphospholipid antibody syndrome and systemic lupus erythematosus may induce thrombocytosis. 2
- Positive ANA testing can help uncover underlying autoimmune etiologies. 2
Drug-Induced
- Medications including corticosteroids, epinephrine, and erythropoiesis-stimulating agents are recognized causes of secondary thrombocytosis. 1, 2
Diagnostic Approach
Confirm true thrombocytosis by documenting sustained platelet count ≥450 × 10⁹/L on repeat measurement before initiating extensive workup. 2
Initial Laboratory Evaluation
- Review complete blood count for other cell line abnormalities (elevated hemoglobin suggests PV, leukoerythroblastosis suggests PMF). 1, 2
- Obtain peripheral blood smear to assess for dysplasia, immature cells, or morphologic abnormalities. 1
- Order iron studies (ferritin, serum iron, TIBC) to exclude iron deficiency as the cause. 2
- Measure inflammatory markers (CRP/ESR) to identify underlying inflammatory conditions. 2
Molecular Testing for Primary Thrombocytosis
- First-line molecular testing is JAK2 V617F assay; if negative, proceed with CALR and MPL mutation analysis. 2
- Approximately 86% of primary thrombocytosis patients have at least one molecular marker indicative of myeloproliferative neoplasms. 4
Bone Marrow Examination
- Bone marrow biopsy with aspirate is required when primary disorder is suspected to assess megakaryocyte morphology, cellularity, and fibrosis. 2
- Bone marrow examination is recommended for individuals older than 60 years or those with systemic symptoms to exclude myelodysplastic syndromes or acute leukemias. 2
- Bone marrow examination is not indicated in children with classic features of secondary thrombocytosis. 3, 5
Additional Testing
- BCR-ABL1 testing is essential to exclude chronic myeloid leukemia. 2
- Hemoglobin and hematocrit measurements help rule out polycythemia vera. 2
Thrombotic Risk Stratification
The median platelet count and incidence of thrombosis are significantly higher in primary thrombocytosis than secondary thrombocytosis. 4
Primary Thrombocytosis
- Primary thrombocytosis carries substantial thrombotic risk requiring risk stratification to guide cytoreductive therapy and antiplatelet agents. 2
Secondary Thrombocytosis
- Secondary thrombocytosis rarely leads to thrombosis, even at very high platelet counts. 2
- In pediatric empyema with platelets >500 × 10⁹/L, platelet function remains normal and no thromboembolic events occur. 2, 5
- Antiplatelet therapy is not indicated for secondary thrombocytosis unless other cardiovascular indications exist. 1, 2, 5
Management
Secondary Thrombocytosis
- Identify and treat the underlying condition; avoid unnecessary antiplatelet or cytoreductive agents. 2
- Re-measure platelet count after resolution of the primary disorder to confirm normalization. 2
- If thrombocytosis persists beyond the expected timeframe, consider bone marrow evaluation to exclude occult myeloproliferative neoplasm. 2
- No specific treatment is necessary for secondary thrombocytosis in children. 5
Primary Thrombocytosis
- Cytoreductive therapy (hydroxyurea or anagrelide) and low-dose aspirin (81-100 mg/day) may be indicated for high-risk patients based on thrombotic risk stratification. 1, 2
Common Pitfalls
- Avoid diagnosing essential thrombocythemia before excluding iron deficiency with trial of iron replacement, as occult polycythemia vera may be masked. 1
- In malignancy-related disseminated intravascular coagulation, a decreasing platelet trend from an initially elevated level may be the only sign of DIC, even if absolute count remains normal. 1
- Do not initiate antiplatelet therapy for secondary thrombocytosis, as it provides no benefit and increases bleeding risk. 5