Two Main Types of Leukocytosis
Leukocytosis is fundamentally divided into two categories: reactive (secondary) leukocytosis and primary (clonal/malignant) leukocytosis, with the distinction being critical as it determines whether the patient requires supportive care versus urgent hematologic evaluation and treatment. 1, 2
Type 1: Reactive (Secondary) Leukocytosis
Reactive leukocytosis represents the bone marrow's normal physiologic response to external stimuli and is the most common cause of elevated white blood cell counts. 1, 3
Common Causes of Reactive Leukocytosis:
Infectious Causes:
- Bacterial infections are the most frequent trigger, producing neutrophilic leukocytosis with a "left shift" (increased immature neutrophils) 1
- Viral infections can cause lymphocytosis 4
Inflammatory and Autoimmune Conditions:
- Adult-Onset Still's Disease commonly presents with marked neutrophilic leukocytosis, with 50% of patients having WBC >15,000/μL and 37% exceeding 20,000/μL 5
- Chronic inflammatory conditions cause persistent leukocytosis through ongoing bone marrow granulocyte hyperplasia 5
- Connective tissue diseases and autoimmune disorders 6, 5
Medication-Induced:
- Corticosteroids are among the most common pharmacologic causes 1
- Lithium and beta-agonists frequently elevate white blood cell counts 1
Physical and Emotional Stress:
- Seizures, anesthesia, or overexertion can trigger leukocytosis 1
- Emotional stress elevates WBC counts through catecholamine release 1
Other Reactive Causes:
- Iron deficiency, splenectomy, surgery 6
- Metastatic cancer and lymphoproliferative disorders (as reactive phenomena) 6
Type 2: Primary (Clonal/Malignant) Leukocytosis
Primary leukocytosis results from intrinsic bone marrow disorders where abnormal clonal proliferation of hematopoietic cells occurs. 1, 2
Common Causes of Primary Leukocytosis:
Acute Leukemias:
- Acute myeloid leukemia (AML) can present with hyperleukocytosis (WBC >100,000/μL), constituting a medical emergency due to risk of hemorrhagic events, tumor lysis syndrome, and leukostasis 5
- Acute lymphoblastic leukemia presents with immature lymphoblasts 2
- These patients are typically acutely ill at presentation 1
Chronic Leukemias:
- Chronic lymphocytic leukemia (CLL) presents with progressive lymphocytosis, with increases >50% over 2 months or lymphocyte doubling time <6 months 5
- Chronic myelogenous leukemia (CML) is characterized by BCR-ABL1 fusion gene 6
- These patients are often diagnosed incidentally and present with less severe symptoms than acute leukemias 1, 3
Myeloproliferative Neoplasms:
- Polycythemia vera demonstrates JAK2 V617F mutation in >90% of cases, with trilineage proliferation 6
- Essential thrombocythemia shows sustained platelet count ≥450 × 10⁹/L with megakaryocytic proliferation 6
- Primary myelofibrosis presents with megakaryocyte proliferation and atypia, often with JAK2 V617F or MPL mutations 6
Critical Distinguishing Features
Red Flags for Primary (Malignant) Leukocytosis:
- Extremely elevated WBC counts (>100,000/μL represents a medical emergency) 1
- Concurrent abnormalities in red blood cell or platelet counts 1
- Constitutional symptoms: weight loss, night sweats, fever 1
- Hepatosplenomegaly or lymphadenopathy 1
- Abnormal peripheral blood smear showing blasts, dysplasia, or monomorphic lymphocyte population 2
- Presence of clonal markers (JAK2 V617F, BCR-ABL1, MPL mutations) 6
Features Favoring Reactive Leukocytosis:
- Pleomorphic (varied) lymphocyte morphology rather than monomorphic population 2
- Activated neutrophil changes on peripheral smear 2
- Clinical context of infection, inflammation, or medication use 1
- Resolution with treatment of underlying condition 1
Critical Management Pitfall
The most dangerous error is failing to recognize hyperleukocytosis (WBC >100,000/μL) as a medical emergency requiring immediate aggressive hydration (2.5-3 liters/m²/day) and consideration of cytoreduction with hydroxyurea (50-60 mg/kg/day) to prevent brain infarction, hemorrhage, and tumor lysis syndrome. 5, 7, 1