What are the causes of thrombocytosis?

Causes of Thrombocytosis

Thrombocytosis (platelet count >450 × 10^9/L) is most commonly caused by secondary/reactive conditions (>80% of cases), with primary/clonal causes accounting for only about 12-15% of cases. 1

Primary (Clonal) Thrombocytosis

Primary thrombocytosis refers to clonal disorders where abnormal platelet production occurs due to genetic mutations in hematopoietic stem cells:

1. Essential Thrombocythemia (ET)

   • Characterized by sustained platelet count ≥450 × 10^9/L
   • Bone marrow shows proliferation of megakaryocytic lineage with enlarged, mature megakaryocytes
   • Diagnosis requires excluding other myeloid disorders
   • Associated with JAK2V617F mutation in ~50-60% of cases, CALR or MPL mutations in others 2

2. Other Myeloproliferative Neoplasms (MPNs)

   • Polycythemia vera (PV) - JAK2V617F mutation in >90% of cases
   • Primary myelofibrosis (PMF)
   • Chronic myeloid leukemia (CML) - BCR-ABL1 positive 2

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis accounts for approximately 83% of all cases 1. Major causes include:

1. Tissue Injury/Surgery (32.2% of secondary cases) 1

   • Post-surgical states
   • Trauma
   • Burns

2. Infections (17.1% of secondary cases) 1

   • Acute and chronic bacterial infections
   • Tuberculosis
   • Viral infections

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

   • Rheumatoid arthritis
   • Inflammatory bowel disease
   • Adult-onset Still's disease 2
   • Connective tissue diseases
   • Vasculitis

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

5. Post-splenectomy/Hyposplenism

   • Functional or anatomical asplenia

6. Malignancy

   • Solid tumors (lung, gastrointestinal, breast, ovarian)
   • Lymphoproliferative disorders

7. Medications

   • Corticosteroids
   • Epinephrine
   • Vincristine

8. Rebound Thrombocytosis

   • Following resolution of bone marrow suppression
   • After treatment of vitamin B12 or folate deficiency

9. Hemolytic Anemias

10. Pregnancy and Hormonal Factors

    • Oral contraceptives (estrogen-containing) 2

Clinical Significance and Complications

The risk of thrombotic complications is significantly higher in primary thrombocytosis compared to secondary causes 1:

• Primary thrombocytosis: Higher risk of both arterial and venous thrombosis
• Secondary thrombocytosis: Generally lower thrombotic risk unless other risk factors present

Diagnostic Approach

When evaluating thrombocytosis, consider:

1. Complete Blood Count

   • Higher hemoglobin, MCV, RDW, and MPV suggest ET
   • Higher WBC and neutrophil counts suggest secondary thrombocytosis 3

2. Clinical Assessment

   • History of arterial thrombosis suggests ET
   • Active malignancy, chronic inflammatory disease, splenectomy, or iron deficiency strongly suggest secondary thrombocytosis 3

3. Molecular Testing

   • Test for JAK2V617F, CALR, and MPL mutations if primary thrombocytosis is suspected
   • These mutations account for >90% of genetic abnormalities in ET 3

4. Bone Marrow Examination

   • Required for diagnosis of ET
   • Shows proliferation of megakaryocytes with mature morphology 2

5. Iron Studies

   • To rule out iron deficiency as a cause

Common Pitfalls

1. Overlooking secondary causes - Always rule out common reactive causes before pursuing extensive workup for primary thrombocytosis

2. Misdiagnosing ET - Remember that the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other diagnostic criteria are met 2

3. Incomplete evaluation - Failure to perform bone marrow examination when indicated can lead to missed diagnosis of myeloproliferative disorders

4. Overinvestigation - Molecular testing may be unnecessary in cases with clear secondary causes 3

By systematically evaluating patients with thrombocytosis and understanding the relative frequencies of different causes, clinicians can efficiently reach the correct diagnosis and implement appropriate management strategies.