What are the causes and management of thrombocytosis?

Causes of Thrombocytosis

Thrombocytosis (platelet count >450×10⁹/L) is predominantly secondary (83% of cases), with primary causes accounting for only 12.5%, making it essential to systematically exclude reactive causes before pursuing bone marrow evaluation for myeloproliferative neoplasms. 1

Primary (Clonal) Thrombocytosis

Essential Thrombocythemia (ET)

Diagnosis requires meeting all four WHO criteria: 2

1. Sustained platelet count ≥450×10⁹/L during the work-up period 2
2. Bone marrow biopsy showing megakaryocytic proliferation with increased numbers of enlarged, mature megakaryocytes with deeply lobulated and hyperlobulated nuclei, without significant increase in neutrophil granulopoiesis or erythropoiesis 2
3. Exclusion of other myeloid neoplasms: No WHO criteria met for polycythemia vera (PV), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) 2
4. Demonstration of JAK2V617F or other clonal marker (found in 86% of primary thrombocytosis cases), or in the absence of clonal markers, no evidence of reactive thrombocytosis 2, 1

Other Myeloproliferative Neoplasms

• Polycythemia vera: JAK2V617F mutation present in >90% of cases, with elevated hemoglobin/hematocrit as the primary feature 2
• Primary myelofibrosis: JAK2V617F mutation in nearly 50% of cases, with characteristic bone marrow fibrosis and atypical megakaryocytes 2
• Chronic myeloid leukemia: Requires exclusion via BCR-ABL testing 2

Myelodysplastic Syndromes

• Bone marrow examination mandatory in patients >60 years or with systemic symptoms to exclude MDS, leukemias, or other malignancies 2, 3
• Look for dysgranulopoiesis, dyserythropoiesis, or predominance of small megakaryocytes with monolobated nuclei 2

Secondary (Reactive) Thrombocytosis

Most Common Causes (in order of frequency)

The major causes identified in a large retrospective study were: 1

1. Tissue injury (32.2%): Post-surgical, trauma, burns 2, 1
2. Infection (17.1%): Acute or chronic bacterial, viral, or fungal infections 2, 1
3. Chronic inflammatory disorders (11.7%): Connective tissue diseases, inflammatory bowel disease 2, 1
4. Iron deficiency anemia (11.1%): Even without anemia, iron deficiency alone can cause thrombocytosis 2, 1

Other Important Secondary Causes

• Malignancy: Metastatic cancer and lymphoproliferative disorders 2
• Post-splenectomy or functional asplenia: Congenital spleen agenesis can mimic essential thrombocythemia and requires screening for Howell-Jolly bodies on peripheral smear 4
• Chronic inflammation: Adult-onset Still's disease causes reactive thrombocytosis with leucocytosis 2

Diagnostic Algorithm

Initial Evaluation (Mandatory for All Patients)

1. Exclude pseudothrombocytosis: Repeat platelet count in heparin or sodium citrate tubes, as EDTA-dependent platelet agglutination can falsely lower counts 2, 3
2. Complete blood count with differential: Distinguish isolated thrombocytosis from pancytopenia (suggests bone marrow failure) 2, 3
3. Peripheral blood smear examination: Assess platelet morphology, identify Howell-Jolly bodies (asplenia), abnormal white cells, or red cell fragments 2, 3, 4

Red Flags Requiring Bone Marrow Examination

Proceed to bone marrow biopsy if any of the following are present: 2, 3

• Age >60 years 2, 3
• Splenomegaly, hepatomegaly, or lymphadenopathy 2, 3
• Abnormal hemoglobin, white blood cell count, or white cell morphology 3
• Constitutional symptoms (fever, weight loss, night sweats) suggesting infection or malignancy 2, 3
• Platelet count persistently >600×10⁹/L without obvious secondary cause 1

Molecular Testing

• JAK2V617F mutation testing should be performed when primary thrombocytosis is suspected, as it is present in 86% of cases 2, 1
• MPLW515L/K mutations are less common but can be found in ET and PMF 2
• BCR-ABL testing is mandatory to exclude CML 2

Evaluation for Secondary Causes

When bone marrow examination is not immediately indicated, systematically evaluate for: 2

• Iron studies: Serum ferritin, iron, TIBC to detect iron deficiency 2
• Inflammatory markers: ESR, CRP to identify chronic inflammation 2
• Infectious disease screening: HIV, hepatitis C, H. pylori in adults 3
• Imaging: Abdominal ultrasound to confirm spleen presence and assess for occult malignancy 4
• Review medication history: Exclude drug-induced causes 2

Clinical Significance and Thrombotic Risk

Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis: 1

• Median platelet count is higher in primary vs. secondary thrombocytosis 1
• Incidence of thrombosis is significantly elevated in primary thrombocytosis 1
• Secondary thrombocytosis rarely causes thrombotic complications unless platelet counts are extremely elevated or other risk factors coexist 5

Common Pitfalls to Avoid

• Do not assume thrombocytosis is reactive without excluding primary causes in patients with persistent elevation >450×10⁹/L 2
• Do not overlook congenital asplenia: Always screen for Howell-Jolly bodies and confirm spleen presence on imaging 4
• Do not delay bone marrow examination in patients >60 years even with apparent secondary causes, as both conditions can coexist 3
• The presence of a reactive condition does not exclude ET if WHO criteria are otherwise met 2

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