What causes high platelet counts (thrombocytosis)?

Causes of High Platelet Count (Thrombocytosis)

Thrombocytosis (platelet count ≥450 × 10⁹/L) is predominantly secondary (reactive) in approximately 83-88% of cases, with primary (clonal) causes accounting for only 12-13% of patients. 1, 2

Primary (Clonal) Thrombocytosis

Primary thrombocytosis represents clonal myeloproliferative neoplasms (MPNs) and carries significantly higher thrombotic risk than secondary causes. 3, 4

Key primary causes include:

• Essential thrombocythemia (ET) - the most common primary cause, accounting for 45% of primary thrombocytosis cases, characterized by sustained platelet count ≥450 × 10⁹/L with bone marrow showing megakaryocytic proliferation and JAK2V617F or other clonal markers 3, 1

• Polycythemia vera - presents with elevated platelets alongside increased red cell mass and often leukocytosis 3, 4

• Primary myelofibrosis - distinguished by reticulin/collagen fibrosis and characteristic megakaryocyte morphology with aberrant nuclear features 3

• Chronic myeloid leukemia - excluded by absence of BCR-ABL fusion gene 3

• Myelodysplastic syndromes - particularly those with del(5q) or other specific cytogenetic abnormalities 3

• Rare hereditary thrombocytosis - familial forms with genetic mutations 5

Critical diagnostic point: 86% of primary thrombocytosis patients have at least one molecular marker (JAK2V617F, CALR, or MPL mutations) indicative of MPNs, making molecular testing essential. 1

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis results from physiologic stimulation of platelet production and accounts for the vast majority of cases. 1, 2

Major causes by frequency:

• Tissue injury/damage (32-42%) - including surgery, trauma, burns, and tissue necrosis 1, 2

• Infection (17-24%) - acute or chronic infectious processes 1, 2

• Chronic inflammatory disorders (10-13%) - including connective tissue diseases, inflammatory bowel disease 3, 1, 2

• Iron deficiency anemia (11%) - a frequently overlooked but common cause 3, 1

• Malignancy (13%) - both solid tumors (metastatic cancer) and lymphoproliferative disorders 3, 1, 2

• Post-splenectomy or functional hyposplenism - loss of splenic platelet sequestration 3, 4

• Hemolytic anemia and post-hemorrhagic states - increased bone marrow stimulation 4

• Rebound thrombocytosis - following recovery from thrombocytopenia or chemotherapy 4

Transient causes:

• Exercise-induced thrombocytosis - temporary elevation that resolves with rest 4

• Pregnancy and hormonal influences - physiologic changes during gestation 4

Pseudothrombocytosis (False Elevation)

Before pursuing extensive workup, exclude laboratory artifacts that falsely elevate platelet counts: 4, 6

• EDTA-dependent platelet clumping - requires peripheral blood smear examination to identify platelet aggregates 6

• Microspherocytes, schistocytes, or red cell fragments - counted as platelets by automated analyzers 5

• Cryoglobulins or bacteria - interfere with automated counting 5

• Inadequate anticoagulant volume in polycythemia - reduced plasma volume with standard anticoagulant causes artifactual results 6

Distinguishing Primary from Secondary Thrombocytosis

Primary thrombocytosis is associated with significantly higher platelet counts (often >1000 × 10⁹/L) and markedly increased thrombotic risk, whereas secondary thrombocytosis rarely causes thrombosis unless additional risk factors are present. 1, 2

Laboratory features favoring primary thrombocytosis: 2

• Higher absolute platelet count (median significantly elevated)
• Lower erythrocyte sedimentation rate
• Lower fibrinogen levels
• Lower serum potassium
• Higher lactate dehydrogenase
• Presence of JAK2V617F, CALR, or MPL mutations 1

Laboratory features favoring secondary thrombocytosis: 2

• Elevated acute phase reactants (C-reactive protein, fibrinogen, ESR, IL-6) 7
• Elevated leukocyte count with left shift
• Evidence of underlying inflammatory or infectious process
• Absence of clonal markers

Bone marrow examination distinguishes primary from secondary causes: In ET, bone marrow shows large mature megakaryocytes with deeply lobulated nuclei dispersed throughout sections, without significant trilineage proliferation or dysplastic features. 3

Clinical Significance and Thrombotic Risk

Thrombotic complications occur significantly more frequently in primary thrombocytosis (both arterial and venous) compared to secondary thrombocytosis (venous only, and only with additional risk factors). 2, 8

Increased platelet turnover (measured by reticulated platelet percentage >10-15%) correlates strongly with thrombotic events in both primary and secondary thrombocytosis. Patients with thrombocytosis and thrombosis have reticulated platelet percentages of 11-15% versus 3-5% in asymptomatic patients. 8

Specific thrombotic considerations:

• Primary thrombocytosis patients with thrombosis have absolute reticulated platelet counts of 90-102 × 10⁹/L versus 26-35 × 10⁹/L in asymptomatic patients 8

• Secondary thrombocytosis alone (without additional risk factors like immobility, malignancy, or surgery) does not significantly increase thrombotic risk 7, 2

• Chronic inflammation, malignancy-associated, and high-altitude thrombocytosis may benefit from antiplatelet therapy based on individual risk assessment 5

Diagnostic Algorithm

Step 1: Confirm true thrombocytosis by examining peripheral blood smear to exclude pseudothrombocytosis from platelet clumping or cellular fragments. 4, 6, 5

Step 2: Obtain complete blood count with differential to identify isolated thrombocytosis versus other cytopenias or polycythemia. 4

Step 3: Assess for obvious secondary causes through targeted history: recent surgery/trauma, active infection, known malignancy, iron deficiency, inflammatory conditions, or splenectomy. 3, 4, 1

Step 4: If no clear secondary cause identified or platelet count >1000 × 10⁹/L, obtain molecular testing for JAK2V617F, CALR, and MPL mutations. 3, 1

Step 5: If molecular markers positive or clinical suspicion high for MPN, proceed to bone marrow biopsy to confirm diagnosis and exclude other myeloid neoplasms. 3

Step 6: If molecular markers negative and secondary causes excluded, measure acute phase reactants (CRP, fibrinogen, ESR) to support reactive etiology versus occult primary disorder. 7

Critical pitfall: The presence of a condition associated with reactive thrombocytosis (infection, inflammation, malignancy) does not exclude concurrent ET if diagnostic criteria are otherwise met—both can coexist. 3