What are the causes of thrombocytosis?

Causes of Thrombocytosis

Thrombocytosis is primarily caused by secondary (reactive) conditions in approximately 83% of cases, while primary thrombocytosis accounts for only about 12.5% of cases. 1

Primary Thrombocytosis

Primary thrombocytosis refers to clonal disorders where thrombocytosis is a primary event accompanying hematological diseases:

1. Myeloproliferative Neoplasms (MPNs):

   • Essential Thrombocythemia (ET)
   • Polycythemia Vera (PV)
   • Primary Myelofibrosis (PMF)
   • Chronic Myeloid Leukemia (CML)

2. Molecular Markers:

   • JAK2 V617F mutation (found in >90% of PV and ~50% of ET and PMF cases) 2
   • CALR mutations
   • MPL mutations
   • About 86% of primary thrombocytosis cases have at least one molecular marker 1

3. Other Myeloid Disorders:

   • Myelodysplastic Syndrome (MDS) with isolated deletion 5q
   • MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) 3

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis accounts for the majority of cases and can be caused by:

1. Tissue Injury (32.2% of secondary cases) 1:

   • Surgery
   • Trauma
   • Burns

2. Infections (17.1% of secondary cases) 1:

   • Bacterial infections
   • Viral infections (including HIV and COVID-19)

3. Chronic Inflammatory Disorders (11.7% of secondary cases) 1:

   • Rheumatoid arthritis
   • Inflammatory bowel disease
   • Connective tissue diseases

4. Iron Deficiency Anemia (11.1% of secondary cases) 1

5. Other Common Causes:

   • Splenectomy or functional asplenia
   • Malignancy (solid tumors)
   • Medications (corticosteroids, epinephrine)
   • Rebound from thrombocytopenia
   • Acute hemorrhage
   • Hemolytic anemia

Clinical Significance

1. Thrombotic Risk:

   • Primary thrombocytosis carries a significantly higher risk of thrombosis compared to secondary thrombocytosis 1
   • History of arterial thrombosis is predictive of essential thrombocythemia 4

2. Laboratory Findings:

   • Primary thrombocytosis: Higher hemoglobin, MCV, RDW, and MPV
   • Secondary thrombocytosis: Higher BMI, WBC count, and neutrophil count 4

3. Severity Classification:

   • Mild: 500,000-700,000/μL
   • Moderate: 700,000-900,000/μL
   • Severe: >900,000/μL
   • Extreme: >1,000/μL 5

Diagnostic Approach

1. Rule out secondary causes first:

   • Assess for active malignancy, chronic inflammatory disease, recent splenectomy, and iron deficiency 4
   • Check for infections, tissue injury, and medication effects

2. If no secondary cause is identified, evaluate for primary thrombocytosis:

   • Test for JAK2 V617F, CALR, and MPL mutations
   • Perform bone marrow biopsy to assess megakaryocyte morphology
   • Rule out BCR-ABL1 to exclude CML

3. Apply WHO diagnostic criteria for specific MPNs:

   • ET diagnosis requires sustained platelet count ≥450×10⁹/L, characteristic bone marrow findings, exclusion of other myeloid neoplasms, and demonstration of clonal markers or exclusion of reactive thrombocytosis 2

Pitfalls to Avoid

1. Don't assume all thrombocytosis is benign - while most cases are reactive, primary thrombocytosis carries significant thrombotic risk

2. Don't overlook the possibility of ET in patients with conditions associated with reactive thrombocytosis - the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other diagnostic criteria are met 2

3. Don't rely solely on molecular testing - approximately 14% of primary thrombocytosis cases lack detectable molecular markers 1

4. Don't miss iron deficiency as a common and treatable cause of thrombocytosis