What are the causes of thrombocytosis in adults?

Causes of Thrombocytosis in Adults

Thrombocytosis is predominantly a secondary (reactive) phenomenon in adults, with tissue injury, infection, chronic inflammation, and iron deficiency accounting for the majority of cases, though primary myeloproliferative neoplasms must be systematically excluded due to their significantly higher thrombotic risk and mortality implications. 1, 2

Primary vs. Secondary Thrombocytosis: Critical Distinction

The fundamental classification separates primary (clonal) from secondary (reactive) thrombocytosis, as primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis, making this distinction critical for mortality reduction. 1, 3

Primary Thrombocytosis (12.5% of cases)

Primary thrombocytosis represents clonal myeloproliferative neoplasms (MPNs): 2

• Essential thrombocythemia (ET) is the most common primary cause, requiring 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). 1, 3

• JAK2V617F mutation is present in 86% of ET cases, making molecular testing essential for diagnosis. 1, 2

• Polycythemia vera presents with elevated hemoglobin/hematocrit and JAK2V617F mutation in >90% of cases, with splenomegaly in 40-50% at diagnosis. 3

• Primary myelofibrosis is associated with JAK2V617F mutation in nearly 50% of cases, characteristic bone marrow fibrosis, atypical megakaryocytes, and progressive splenomegaly. 3

• Chronic myeloid leukemia (CML) typically presents with marked leukocytosis, splenomegaly in 40-50% of cases, and requires detection of Philadelphia chromosome t(9;22) or BCR-ABL1 transcripts. 3

Secondary Thrombocytosis (83.1% of cases)

Secondary thrombocytosis is far more common and results from reactive processes: 2

• Tissue injury accounts for 32.2% of secondary thrombocytosis cases, including trauma, surgery, burns, and tissue necrosis. 1, 2

• Infection accounts for 17.1% of cases, representing nearly half of all secondary thrombocytosis in some cohorts, and is associated with higher mortality risk despite more rapid platelet count normalization. 1, 2, 4

• Chronic inflammatory disorders account for 11.7% of cases, including rheumatoid arthritis, inflammatory bowel disease, and vasculitis. 1, 2

• Iron deficiency anemia accounts for 11.1% of cases, and can cause thrombocytosis even without anemia, requiring iron studies for detection. 1, 2

• Active malignancy is strongly associated with secondary thrombocytosis and should be excluded. 5

• Splenectomy or functional asplenia causes persistent thrombocytosis through loss of platelet sequestration. 5

Diagnostic Algorithm for Thrombocytosis

Step 1: Confirm True Thrombocytosis

• Obtain complete blood count with differential to confirm platelet count ≥450×10⁹/L and assess for pancytopenia, leukocytosis, or isolated thrombocytosis. 1, 3

• Peripheral blood smear examination is mandatory to exclude pseudothrombocytosis, identify immature myeloid cells, abnormal white cells, red cell fragments, and platelet morphology. 1, 3

Step 2: Identify Clinical Red Flags for Primary Thrombocytosis

Splenomegaly with thrombocytosis is never normal and mandates immediate hematologic workup, as this combination strongly suggests MPN. 3

Additional red flags include: 5

• History of arterial thrombosis (predictive of ET)
• Extreme thrombocytosis >1,000/μL (though paradoxically associated with lower thrombotic risk but higher bleeding risk in ET)
• Persistent unexplained thrombocytosis lasting >1 month
• Constitutional symptoms (fever, weight loss, night sweats suggesting underlying malignancy or myelodysplasia)

Step 3: Assess for Secondary Causes

Before pursuing expensive molecular testing, systematically evaluate for secondary causes: 5

• Active malignancy (strongly associated with secondary thrombocytosis)
• Chronic inflammatory disease (rheumatoid arthritis, inflammatory bowel disease)
• History of splenectomy (definitive cause of persistent thrombocytosis)
• Iron deficiency: Evaluate mean corpuscular volume (MCV <80 fL indicates iron deficiency requiring supplementation) and ferritin levels, as iron deficiency can cause thrombocytosis even without anemia. 1, 5
• Active infection: Consider in patients with fever, tachycardia, weight loss, hypoalbuminemia, neutrophilia, leukocytosis, and anemia, particularly in those with quadriplegia/paraplegia, indwelling prosthesis, dementia, or diabetes. 4
• Recent tissue injury: Surgery, trauma, burns within past 3 months

Step 4: Laboratory Differentiation

Laboratory parameters that distinguish ET from secondary thrombocytosis: 5

• Higher hemoglobin, MCV, RDW, and MPV suggest ET
• Higher white blood cells and neutrophils suggest secondary thrombocytosis
• Inflammatory markers (ESR, CRP) should be obtained to identify chronic inflammation 1

Step 5: Molecular Testing and Bone Marrow Evaluation

If secondary causes are excluded or clinical suspicion for primary thrombocytosis remains high: 1, 3, 2

• JAK2V617F mutation testing should be performed immediately when primary thrombocytosis is suspected, as it is present in 86% of ET cases and >90% of polycythemia vera cases.

• CALR and MPL mutation testing should be performed if JAK2 negative, as 92.1% of primary thrombocytosis cases have mutations in JAK2, CALR, and/or MPL. 5

• Bone marrow biopsy with aspirate is mandatory when thrombocytosis presents with splenomegaly, in patients >60 years, with systemic symptoms, or when molecular markers are detected. 1, 3

Risk Stratification and Clinical Significance

The median platelet count and incidence of thrombosis are significantly higher in patients with primary thrombocytosis than in those with secondary thrombocytosis. 2

Risk factors for thrombosis in primary thrombocytosis include: 1

• Age >60 years
• Prior thrombosis
• JAK2V617F mutation presence
• Cardiovascular risk factors
• Leukocytosis >11×10⁹/L (confers 60% increase in thrombotic risk)

Common Pitfalls to Avoid

• Never assume thrombocytosis is reactive without systematically excluding primary causes, particularly in patients with persistent elevation >1 month or extreme thrombocytosis. 2, 5

• Never overlook splenomegaly, as its presence with thrombocytosis mandates immediate hematologic workup for MPN. 3

• Never skip iron studies, as iron deficiency can cause thrombocytosis even without anemia and is easily correctable. 1, 5

• Never ignore infection as a cause, particularly in high-risk patients (indwelling devices, immunocompromised, diabetes), as infection-associated thrombocytosis carries higher mortality risk. 4

• Never order expensive molecular testing before excluding obvious secondary causes (active malignancy, chronic inflammatory disease, splenectomy, iron deficiency), as this practical approach reduces overinvestigation. 5