What are the common causes of a leukemoid reaction in a patient with thalassemia?

Leukemoid Reaction in Thalassemia: Causes and Mechanisms

Primary Cause: Extramedullary Hematopoiesis and Marrow Stress

The leukemoid reaction in thalassemia is primarily driven by chronic hemolysis and compensatory extramedullary hematopoiesis, not by infection or malignancy as seen in other populations. 1, 2

The pathophysiology in thalassemia patients differs fundamentally from typical leukemoid reactions:

• Chronic hemolytic stress creates persistent bone marrow stimulation, leading to marked granulocyte expansion and release of immature forms into peripheral blood 1
• Ineffective erythropoiesis in thalassemia causes marrow hyperplasia that extends beyond the erythroid lineage, affecting myeloid production 3
• The bone marrow becomes infiltrated with erythroid precursors attempting to compensate for chronic anemia, which paradoxically stimulates myeloid proliferation 1

Secondary Causes Requiring Immediate Evaluation

Infection (Most Common Acute Trigger)

In thalassemia patients with acute leukemoid reaction, severe infection must be excluded first, as this represents the most common cause requiring urgent intervention in the general population with leukemoid reactions 2, 4:

• Bacterial infections (particularly Clostridium difficile, tuberculosis, severe bacterial sepsis) account for 56% of true leukemoid reactions 2
• Asplenic thalassemia patients have increased susceptibility to encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) 3
• Obtain blood cultures, assess for fever, and examine for localizing signs of infection before attributing leukocytosis to thalassemia alone 5

Iron Overload Complications

Cardiac complications from iron overload can trigger stress-related leukocytosis in thalassemia patients 3:

• Arrhythmias (both atrial fibrillation and ventricular arrhythmias) occur with myocardial iron deposition and may precipitate acute stress responses 3
• Heart failure from iron cardiomyopathy creates a systemic inflammatory state that can elevate white blood cell counts 3
• Evaluate cardiac function with echocardiography and T2* MRI if available when leukocytosis appears acutely 3

Paraneoplastic Leukemoid Reaction

While less common in thalassemia specifically, solid tumors can produce granulocyte colony-stimulating factors leading to marked leukocytosis 2, 6:

• Paraneoplastic leukemoid reactions accounted for 16% of cases in modern cohorts and carry poor prognosis 2
• Tumors drive myelopoiesis through cytokine production (G-CSF, GM-CSF, IL-6) 6
• Consider age-appropriate cancer screening if leukocytosis is persistent and unexplained 2, 6

Critical Diagnostic Pitfall to Avoid

Do not assume leukocytosis in thalassemia is benign without excluding chronic myelogenous leukemia (CML) 7, 1:

• Peripheral blood FISH using dual probes for BCR and ABL genes should be performed to exclude CML in any thalassemia patient with persistent leukocytosis >50,000/μL 7
• Manual peripheral blood smear examination is essential to evaluate for dysplasia, blast cells, and basophilia that would suggest myeloid malignancy rather than reactive process 5, 8
• The presence of marked basophilia, absolute monocytosis, or any circulating blasts mandates bone marrow examination 7, 8

Practical Diagnostic Algorithm

When encountering leukocytosis in a thalassemia patient:

1. Confirm the white blood cell count with manual differential and peripheral smear review to assess for immature forms, dysplasia, and blast percentage 5, 8

2. Assess for acute infection with blood cultures, inflammatory markers, and clinical examination for fever or localizing symptoms 5, 2

3. Exclude CML with BCR-ABL testing if WBC >50,000/μL or if basophilia/left shift is prominent 7, 1

4. Evaluate cardiac status if acute presentation, checking for arrhythmias or heart failure that may represent iron overload complications 3

5. Consider malignancy screening if leukocytosis persists without clear cause, particularly in older patients 2, 6

Prognosis and Clinical Significance

Leukemoid reactions carry significant mortality risk regardless of etiology, with death rates differing significantly between infectious and malignant causes 2:

• Lower hemoglobin, older age, and increased segmented neutrophil count independently predict mortality 2
• Both infectious and paraneoplastic leukemoid reactions have poor prognosis with high mortality rates 2
• This is not merely a benign paraneoplastic phenomenon but represents serious underlying pathology requiring aggressive investigation 6