What are the causes of thrombocytosis and leukocytosis?

Causes of Elevated Platelets and WBC

Primary (Clonal) Causes

The most critical distinction is between primary clonal disorders and reactive causes, as primary thrombocytosis carries significantly higher thrombotic risk and requires different management. 1, 2

Myeloproliferative Neoplasms

• Essential thrombocythemia presents with sustained platelet count ≥450 × 10⁹/L with megakaryocytic proliferation, JAK2 V617F mutation in 50-60% of cases, and CALR or MPL mutations in JAK2-negative patients. 3, 4

• Polycythemia vera demonstrates JAK2 V617F mutation in >90% of cases with trilineage proliferation (elevated hemoglobin, platelets, and WBC), hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women, and subnormal erythropoietin levels. 1, 3

• Primary myelofibrosis shows megakaryocyte proliferation with atypia, often with JAK2 V617F or MPL mutations, and bone marrow fibrosis on silver staining. 1

• Chronic myelogenous leukemia (CML) is characterized by BCR-ABL1 fusion gene and can present with both thrombocytosis and leukocytosis. 1

Acute Leukemias

• Acute myeloid leukemia can present with hyperleukocytosis (WBC >100,000/μL), constituting a medical emergency due to risk of leukostasis, hemorrhage, and tumor lysis syndrome. 1, 5

• Chronic lymphocytic leukemia presents with progressive lymphocytosis, with increases >50% over 2 months or lymphocyte doubling time <6 months. 1

Reactive (Secondary) Causes

Secondary thrombocytosis accounts for 66-88% of extreme thrombocytosis cases and rarely causes thrombotic complications unless additional risk factors are present. 6, 2

Inflammatory and Autoimmune Conditions

• Adult-Onset Still's Disease commonly presents with marked neutrophilic leukocytosis (50% with WBC >15,000/μL, 37% exceeding 20,000/μL) and reactive thrombocytosis due to chronic inflammatory cytokine cascade and bone marrow granulocyte hyperplasia. 7, 1

• Connective tissue diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease cause persistent leukocytosis and thrombocytosis through ongoing inflammation. 1, 8

Infectious Causes

• Chronic infections (tuberculosis, endocarditis, parasitic infections) commonly cause both monocytosis and reactive thrombocytosis. 8

• Acute infections account for 24% of secondary thrombocytosis cases and can produce marked leukocytosis with left shift. 5, 2

Tissue Damage and Malignancy

• Tissue damage (surgery, trauma, burns) represents 42% of secondary thrombocytosis cases. 2

• Solid malignancies account for 13% of secondary thrombocytosis and can produce reactive leukocytosis. 8, 2

• Metastatic cancer and lymphoproliferative disorders cause reactive leukocytosis through bone marrow stimulation. 1

Other Reactive Causes

• Iron deficiency causes reactive thrombocytosis and can mask polycythemia vera by normalizing hemoglobin levels. 1, 3

• Splenectomy triggers reactive thrombocytosis and monocytosis due to loss of splenic sequestration. 1, 8

• Medications including corticosteroids, lithium, and beta agonists commonly cause leukocytosis. 5

• Physical or emotional stress (seizures, anesthesia, overexertion) elevates white blood cell counts. 5

Diagnostic Algorithm

Red Flags for Primary (Clonal) Disorders

• Platelet count >1,000 × 10⁹/L increases likelihood of essential thrombocythemia (93.8% of clonal thrombocytosis cases are myeloproliferative disorders). 6

• WBC >100,000/μL represents a medical emergency requiring immediate aggressive hydration and cytoreduction with hydroxyurea due to risk of brain infarction and hemorrhage. 1, 5

• Concurrent cytopenias or abnormalities in multiple cell lines suggest primary bone marrow disorder. 1, 5

• Constitutional symptoms (weight loss, night sweats, fatigue), splenomegaly, hepatomegaly, or lymphadenopathy increase suspicion for malignancy. 1, 5

Essential Testing

• Peripheral blood smear to assess for dysplasia, left shift, immature cells, and blast forms. 1, 8

• JAK2 V617F mutation testing should be performed in all patients with suspected myeloproliferative neoplasm (present in >90% of polycythemia vera, 50-60% of essential thrombocythemia). 3, 9

• CALR and MPL mutation testing in JAK2-negative patients with suspected essential thrombocythemia. 3

• BCR-ABL1 testing to exclude chronic myelogenous leukemia. 1, 8

• Bone marrow biopsy is indicated for persistent unexplained elevations, absolute monocyte count ≥1 × 10⁹/L, concurrent cytopenias, constitutional symptoms, or dysplastic features on peripheral smear. 1, 8

Distinguishing Features

• Primary thrombocytosis is associated with significantly higher platelet counts (mean difference significant), increased arterial and venous thrombotic complications (17.1% vs 7.9% in secondary), and presence of clonal markers. 2

• Secondary thrombocytosis shows elevated ESR, elevated fibrinogen, and thrombotic events restricted to venous system only when additional risk factors present. 7, 2

• Leukocytosis at diagnosis in polycythemia vera and essential thrombocythemia is associated with higher risk of thrombosis and major hemorrhage, particularly in patients aged <60 years. 7

Critical Pitfalls

• Failing to calculate absolute counts (relying on percentages alone) can miss significant elevations or lead to unnecessary workup. 8

• Attributing elevations solely to inflammation without excluding clonal disorders delays diagnosis of treatable malignancies. 8, 9

• Missing iron deficiency in polycythemia vera patients, as iron replacement can unmask the diagnosis when hemoglobin is borderline. 3

• Underestimating thrombotic risk in extreme thrombocytosis (≥1,000 × 10⁹/L), which paradoxically can cause acquired von Willebrand disease and hemorrhagic complications. 7, 6