Causes of Thrombocytosis
Thrombocytosis is primarily a secondary (reactive) phenomenon in 83% of cases, with tissue injury, infection, chronic inflammation, and iron deficiency being the most common causes, while primary thrombocytosis from myeloproliferative neoplasms accounts for only 12.5% of cases but carries significantly higher thrombotic risk. 1
Primary Thrombocytosis (12.5% of cases)
Primary thrombocytosis represents clonal myeloproliferative neoplasms with inherently elevated thrombotic risk compared to secondary causes 2:
Essential Thrombocythemia (Most Common Primary Cause)
- Requires sustained platelet count ≥450×10⁹/L, bone marrow biopsy showing megakaryocytic proliferation, exclusion of other myeloid neoplasms, and demonstration of JAK2V617F or other clonal markers (CALR or MPL mutations) 2, 3
- JAK2V617F mutation present in 64-86% of cases 2, 4
- CALR mutations in 23% and MPL mutations in 4% 4
- Median age at diagnosis is 59 years with median survival exceeding 35 years in younger patients 4
Polycythemia Vera
- Characterized by elevated hemoglobin/hematocrit as primary feature 2
- JAK2V617F mutation present in >90% of cases 2, 3
- Splenomegaly in 40-50% at diagnosis 3
Primary Myelofibrosis
- JAK2V617F mutation in nearly 50% of cases 2, 3
- Characteristic bone marrow fibrosis with atypical megakaryocytes 2
- Progressive splenomegaly 3
Chronic Myeloid Leukemia
- Marked leukocytosis with splenomegaly in 40-50% 3
- Requires Philadelphia chromosome t(9;22) or BCR-ABL1 detection 3
Secondary (Reactive) Thrombocytosis (83% of cases)
Secondary thrombocytosis is benign and resolves with treatment of underlying condition 1:
Most Common Causes (in order of frequency):
- Tissue injury: 32.2% of secondary cases 2, 1
- Infection: 17.1% 2, 1
- Chronic inflammatory disorders: 11.7% (rheumatoid arthritis, systemic lupus erythematosus) 2, 1, 4
- Iron deficiency anemia: 11.1% (can occur even without anemia) 2, 1
Other Secondary Causes:
- Splenectomy or functional asplenia 4, 5
- Solid tumors (lung cancer, other malignancies) 4, 6
- Medications 5
Diagnostic Algorithm
Initial Evaluation
- Complete blood count with differential and peripheral blood smear examination to exclude pseudothrombocytosis 2
- Iron studies (ferritin) to detect iron deficiency even without anemia 2, 6
- Inflammatory markers (ESR, CRP) to identify chronic inflammation 2
Clinical Red Flags Suggesting Primary Thrombocytosis:
- History of arterial thrombosis 6
- Higher hemoglobin, MCV, RDW, and MPV 6
- Median platelet count significantly higher than secondary causes 1
- Splenomegaly with thrombocytosis is never normal and mandates immediate hematologic workup 3
Clinical Features Suggesting Secondary Thrombocytosis:
- Active malignancy, chronic inflammatory disease, splenectomy, or iron deficiency 6
- Higher BMI, white blood cells, and neutrophils 6
When to Pursue Molecular Testing:
- JAK2V617F mutation testing should be performed immediately when primary thrombocytosis is suspected 3
- Molecular testing yield is 52.4%, with 92.1% being JAK2, CALR, or MPL mutations 6
- Bone marrow biopsy is mandatory in patients >60 years, with systemic symptoms, or when thrombocytosis presents with splenomegaly 2, 3
Critical Clinical Distinctions
The presence of a reactive condition does not exclude essential thrombocythemia if WHO criteria are otherwise met 2. This is a common pitfall—always complete the diagnostic workup even when secondary causes are identified.
Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis, with arterial thrombosis occurring in 11% and venous thrombosis in 7% of essential thrombocythemia patients 4. This makes distinguishing primary from secondary causes critical for mortality reduction 3.
In children, thrombocytosis is mild (platelet count 500,000-700,000/μL) in 72-86% of cases and is almost always secondary, with primary thrombocytosis being extremely rare (1 per million children) 5.