What are the causes of thrombocytosis (elevated platelet count)?

Causes of Thrombocytosis (Elevated Platelet Count)

Thrombocytosis (platelet count >450×10⁹/L) is primarily caused by either primary (clonal) disorders or secondary (reactive) conditions, with reactive causes accounting for over 80% of cases. 1

Primary (Clonal) Thrombocytosis

Primary thrombocytosis occurs due to intrinsic abnormalities in the megakaryocyte lineage:

Myeloproliferative Neoplasms (MPNs)

• Essential Thrombocythemia (ET): Characterized by sustained platelet counts ≥450×10⁹/L, bone marrow showing megakaryocytic proliferation, and not meeting criteria for other MPNs 2
• Polycythemia Vera (PV): Features elevated red cell mass along with thrombocytosis
• Primary Myelofibrosis: May present with thrombocytosis in early stages
• Chronic Myeloid Leukemia (CML): Associated with BCR-ABL1 fusion gene

Molecular Markers

• JAK2 V617F mutation: Present in >90% of PV and approximately 50% of ET cases 2
• CALR mutations: Found in ET and myelofibrosis
• MPL mutations: Less common in MPNs

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis is more common (83.1% of cases) and occurs as a reaction to various conditions 1:

Major Causes (in order of frequency)

1. Tissue injury/Surgery (32.2%) 1

   • Post-surgical states
   • Trauma

2. Infections (17.1%) 1

   • Acute and chronic bacterial infections
   • Tuberculosis
   • Viral infections

3. Chronic Inflammatory Disorders (11.7%) 1

   • Rheumatoid arthritis
   • Inflammatory bowel disease
   • Connective tissue diseases

4. Iron Deficiency Anemia (11.1%) 1

   • Causes reactive thrombocytosis through multiple mechanisms
   • Associated with increased thromboembolic risk 3

5. Malignancy

   • Solid tumors (lung, breast, gastrointestinal)
   • Lymphomas

6. Post-splenectomy State

   • Due to removal of splenic sequestration function

7. Drug-induced

   • Corticosteroids
   • Epinephrine
   • Vincristine

8. Rebound from Thrombocytopenia

   • Following treatment of vitamin B12 or folate deficiency
   • After recovery from myelosuppressive therapy

Clinical Significance and Complications

Thrombotic Risk

• Primary thrombocytosis: Higher risk of both arterial and venous thrombosis compared to secondary causes 1
• Secondary thrombocytosis: Generally lower thrombotic risk, though iron deficiency-associated thrombocytosis may increase thromboembolic events 3

Bleeding Risk

• Paradoxically, severe thrombocytosis (>1,000×10⁹/L) may cause acquired von Willebrand syndrome and bleeding complications

Diagnostic Approach

Initial Evaluation

1. Confirm true thrombocytosis: Rule out pseudothrombocytosis (platelet clumping)
2. Review previous counts: Determine if acute or chronic
3. Complete blood count: Assess for other cytopenias or erythrocytosis

Further Testing

1. Inflammatory markers: ESR, CRP to identify inflammatory causes
2. Iron studies: Serum ferritin, iron, TIBC to rule out iron deficiency
3. Molecular testing: JAK2, CALR, and MPL mutations if primary thrombocytosis is suspected 2
4. Bone marrow examination: For suspected primary thrombocytosis, showing megakaryocytic proliferation 2

Management Considerations

Management depends on the underlying cause:

• Secondary thrombocytosis: Treat the underlying condition
• Primary thrombocytosis: Risk stratification for thrombotic complications and appropriate cytoreductive therapy

Common Pitfalls

1. Overlooking iron deficiency: Iron deficiency is a common and often overlooked cause of thrombocytosis that carries thromboembolic risk 3

2. Misdiagnosing primary vs. secondary: Distinguishing between primary and secondary thrombocytosis is crucial as treatment approaches differ significantly

3. Ignoring normal-range platelets that have significantly decreased: A substantial drop in platelets, even within normal range, may indicate developing DIC in cancer patients 2

4. Missing underlying malignancy: Thrombocytosis may be the presenting sign of occult solid tumors or hematologic malignancies 4