What are the causes of thrombocytosis?

Causes of Thrombocytosis

Thrombocytosis is divided into primary (clonal myeloproliferative neoplasms) and secondary (reactive) causes, with secondary thrombocytosis accounting for approximately 83% of cases and primary thrombocytosis for 12.5%. 1

Primary Thrombocytosis (Clonal/Myeloproliferative)

Primary thrombocytosis represents clonal disorders of the bone marrow with autonomous platelet production:

Essential Thrombocythemia (ET)

• Most common primary cause, requiring all four WHO criteria: sustained platelet count ≥450×10⁹/L, bone marrow showing megakaryocytic proliferation with enlarged mature megakaryocytes, exclusion of other myeloid neoplasms (PV, PMF, CML, MDS), and demonstration of JAK2V617F or other clonal marker 2, 3
• JAK2V617F mutation present in 86% of ET cases 3
• CALR and MPL mutations account for most remaining cases, with 92.1% of primary thrombocytosis having mutations in JAK2, CALR, or MPL 4
• Bone marrow shows large, mature-appearing megakaryocytes with deeply lobulated and hyperlobulated nuclei, dispersed throughout or in loose clusters 2

Polycythemia Vera (PV)

• JAK2V617F mutation present in >90% of cases, with elevated hemoglobin/hematocrit as the primary feature 3
• Thrombocytosis occurs as part of panmyelosis 2

Primary Myelofibrosis (PMF)

• JAK2V617F mutation in approximately 50% of cases 3
• Characterized by bone marrow fibrosis and atypical megakaryocytes 3

Other Myeloid Neoplasms

• Chronic myeloid leukemia (CML), myelodysplastic syndromes, and other malignancies can present with thrombocytosis 2

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis results from increased thrombopoietin production in response to various stimuli:

Tissue Injury and Surgery

• Most common cause of secondary thrombocytosis, accounting for 32.2% of cases 1, 3
• Includes trauma, burns, and postoperative states 1

Infection

• Accounts for 17.1% of secondary thrombocytosis cases 1, 3
• Nearly half of secondary thrombocytosis cases in some series are infectious 5
• Associated with fever, tachycardia, neutrophilia, leukocytosis, and hypoalbuminemia 5

Chronic Inflammatory Disorders

• Represents 11.7% of secondary thrombocytosis 1, 3
• Includes connective tissue diseases and other chronic inflammatory conditions 2
• Elevated inflammatory markers (ESR, CRP) support this diagnosis 3

Iron Deficiency

• Accounts for 11.1% of secondary thrombocytosis 1
• Can cause thrombocytosis even without anemia 3
• Iron studies (ferritin, serum iron, TIBC) should be performed to detect iron deficiency 3, 4

Malignancy

• Metastatic cancer and lymphoproliferative disorders cause reactive thrombocytosis 2
• Active malignancy strongly predicts secondary thrombocytosis 4

Splenectomy

• Functional or surgical splenectomy causes persistent thrombocytosis 2, 4

Other Causes

• Medications and drugs 2
• Hemolytic anemia 5
• Chronic hypoxia 2

Diagnostic Algorithm to Differentiate Primary from Secondary

Initial Laboratory Evaluation

• Complete blood count with differential to assess all cell lines 3
• Peripheral blood smear examination by qualified hematologist to identify abnormal cells, platelet morphology, and exclude pseudothrombocytosis 2, 3
• Iron studies (ferritin, serum iron, TIBC) to detect iron deficiency 3, 4
• Inflammatory markers (ESR, CRP) to identify chronic inflammation 3

Clinical Assessment for Secondary Causes

Strongly predictive of secondary thrombocytosis:

• Active malignancy 4
• Chronic inflammatory disease 4
• History of splenectomy 4
• Iron deficiency 4
• Recent surgery or tissue injury 1
• Active infection with fever, tachycardia, weight loss 5

Predictive of primary thrombocytosis:

• History of arterial thrombosis 4
• Higher hemoglobin, MCV, RDW, and MPV 4
• Platelet count >800×10⁹/L (extreme thrombocytosis) 1
• Persistent thrombocytosis >1 month 1

Molecular Testing

• JAK2V617F mutation testing should be performed when primary thrombocytosis is suspected after excluding secondary causes 3
• If JAK2V617F negative, consider CALR and MPL mutation testing 4
• Molecular testing has 52.4% overall yield, with 92.1% being JAK2, CALR, or MPL mutations 4

Bone Marrow Examination

• Mandatory in patients >60 years or with systemic symptoms to exclude myelodysplastic syndromes, leukemias, or other malignancies 3, 2
• Required when splenectomy is considered 2
• Should include aspirate, biopsy, flow cytometry, and cytogenetic testing 2
• Not necessary in typical presentations with clear secondary causes 2

Critical Distinctions

Platelet Count Patterns

• Median platelet count significantly higher in primary versus secondary thrombocytosis 1
• Extreme thrombocytosis (>800×10⁹/L) more common in primary thrombocytosis 1
• Secondary thrombocytosis typically mild (500-700×10⁹/L) in 72-86% of cases 6

Thrombotic Risk

• Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis 3, 1
• Incidence of thrombosis significantly higher in primary thrombocytosis 1

Important Caveat

• The presence of a condition associated with reactive thrombocytosis does not exclude ET if the first three WHO criteria are met 2, 3
• A JAK2V617F-negative patient with a concomitant reactive condition can still have ET if other criteria are fulfilled 2