Causes of Isolated Thrombocytosis
Isolated thrombocytosis (platelet count ≥450×10⁹/L) is predominantly secondary (reactive) in 83% of cases, with tissue injury, infection, chronic inflammation, and iron deficiency being the most common causes; however, primary thrombocytosis—particularly essential thrombocythemia—must be excluded because it carries a significantly higher thrombotic risk and requires specific molecular testing and bone marrow evaluation. 1, 2
Primary vs. Secondary Thrombocytosis: The Critical Distinction
The first step is determining whether thrombocytosis is primary (clonal) or secondary (reactive), because this distinction drives all subsequent management decisions. 3, 4
Primary (Clonal) Thrombocytosis
Primary thrombocytosis accounts for 12.5% of cases and carries substantially higher thrombotic risk than secondary causes. 1, 2
Essential thrombocythemia (ET) is the most common primary cause, diagnosed when all four WHO criteria are met: sustained platelet count ≥450×10⁹/L, bone marrow biopsy showing megakaryocytic proliferation with large mature megakaryocytes, exclusion of other myeloid neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia), and demonstration of JAK2V617F or other clonal marker (CALR, MPL). 2
JAK2V617F mutation is present in 86% of essential thrombocythemia cases and >90% of polycythemia vera cases, making molecular testing essential for diagnosis. 2, 5
Polycythemia vera presents with elevated hemoglobin/hematocrit as the primary feature alongside thrombocytosis, with JAK2V617F mutation in >90% of cases. 2
Primary myelofibrosis is associated with JAK2V617F mutation in nearly 50% of cases, characterized by bone marrow fibrosis and atypical megakaryocytes. 2
Secondary (Reactive) Thrombocytosis
Secondary thrombocytosis accounts for 83% of cases and rarely causes vascular complications. 1, 4
The major causes in order of frequency are:
Tissue injury (32.2% of secondary cases)—including trauma, surgery, burns, and tissue necrosis. 1, 2
Infection (17.1%)—both acute bacterial/viral infections and chronic infections. 1, 2
Chronic inflammatory disorders (11.7%)—including inflammatory bowel disease, rheumatoid arthritis, and vasculitis. 1, 2
Iron deficiency anemia (11.1%)—can cause thrombocytosis even without overt anemia; microcytosis (MCV <80 fL) indicates iron deficiency requiring supplementation. 1, 2
Malignancy—solid tumors can produce cytokines that stimulate thrombopoiesis. 6, 4
Functional or surgical splenectomy—loss of splenic platelet sequestration. 6
Medications—including all-trans retinoic acid, epinephrine, and growth factors. 6
Diagnostic Algorithm for Isolated Thrombocytosis
Step 1: Confirm True Thrombocytosis
Verify platelet count ≥450×10⁹/L on repeat testing and exclude pseudothrombocytosis by reviewing the peripheral blood smear for platelet clumping. 2
Obtain complete blood count with differential to confirm isolated thrombocytosis versus concurrent abnormalities (elevated hemoglobin suggests polycythemia vera; leukocytosis or anemia suggests alternative diagnoses). 2
Step 2: Peripheral Blood Smear Examination
Review smear for platelet morphology, red cell abnormalities, and white cell morphology. 2
Giant platelets or abnormal megakaryocyte fragments suggest primary thrombocytosis. 5
Step 3: Identify Secondary Causes
Inflammatory markers: Obtain ESR and CRP to identify chronic inflammation. 2
Iron studies: Measure serum ferritin, iron, TIBC, and MCV to detect iron deficiency (even without anemia). 2
Clinical context: Assess for recent surgery, trauma, infection, active inflammatory disease, or known malignancy. 1, 2
Step 4: Molecular Testing When Primary Thrombocytosis is Suspected
Proceed to molecular testing if:
- No identifiable secondary cause is found
- Platelet count persistently >600×10⁹/L
- Concurrent splenomegaly, constitutional symptoms, or thrombotic events
- Age >60 years 2, 5
JAK2V617F mutation testing should be performed first; if negative, proceed to CALR and MPL mutation testing. 2
86% of essential thrombocythemia cases have at least one molecular marker (JAK2V617F, CALR, or MPL). 2, 1
Step 5: Bone Marrow Examination
Bone marrow biopsy is mandatory when:
- Age >60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies) 2
- Systemic symptoms present (fever, weight loss, night sweats, bone pain) 2
- Molecular marker positive (to confirm diagnosis and exclude other myeloproliferative neoplasms) 2
- Unexplained persistent thrombocytosis without identifiable secondary cause 5
- Bone marrow histology remains essential for distinguishing among myeloproliferative neoplasms, as molecular mutations are not disease-specific. 5
Thrombotic Risk Stratification
Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis, with median platelet counts and thrombosis incidence both significantly elevated in primary cases. 1, 2
High-Risk Features in Primary Thrombocytosis
- Age >60 years 2
- Prior thrombosis 2
- JAK2V617F mutation presence 2
- Cardiovascular risk factors (hypertension, diabetes, smoking) 2
- Leukocytosis >11×10⁹/L (confers 60% increase in thrombotic risk) 2
Paradoxical Bleeding Risk
- Extreme thrombocytosis >1,000/μL actually confers lower thrombotic risk but higher bleeding risk due to acquired von Willebrand syndrome. 2, 5
Critical Pitfalls to Avoid
Do not assume thrombocytosis is reactive without excluding primary causes, especially in patients >60 years or with persistent unexplained elevation. 5, 2
The presence of a reactive condition does not exclude essential thrombocythemia if WHO criteria are otherwise met; both can coexist. 2
Do not delay molecular testing in patients with persistent thrombocytosis >600×10⁹/L, as early diagnosis of myeloproliferative neoplasms impacts thrombotic risk management. 5, 2
Iron deficiency can cause thrombocytosis even without anemia; always check iron studies including MCV, ferritin, and TIBC. 2, 1
Leukocytosis in the setting of thrombocytosis significantly increases thrombotic risk and should prompt urgent evaluation for myeloproliferative neoplasms. 2