Leukopenia

(1)

Departments of Internal Medicine & Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Leukopenia is an abnormally low number of circulating leukocytes or white blood cells. The cutoff for normal leukocyte count varies between labs but usually ranges between 3500 and 4000 cells/μL.

It is the most common hematologic abnormality seen with psychotropic medications. The majority of drug-induced reductions in leukocytes cause neutropenia, a reduction in neutrophils.

Neutropenia is usually defined as an absolute neutrophil count (ANC) <1500 cells/μL. ANC is the product of the white blood cell (WBC) count and the percentage of neutrophils and is reported along with the automated cell counts in almost all laboratories.

Neutropenia is classified according to severity as shown in the table.

Classification of neutropenia

Neutropenia	ANC (cells/μL)
Mild	>1000<1500
Moderate	>500<1000
Severe	<500

Agranulocytosis is defined as the complete absence of circulating neutrophils but is sometimes applied to profound neutropenia with ANC < 500.

Pathology

Neutrophils are produced by myeloid precursor cells in the bone marrow and migrate to the circulation and other tissues. In addition to decreased production and increased destruction, shift of neutrophils from circulation to tissues can result in a reduced neutrophil count.

Etiology

Major causes of neutropenia are benign ethic neutropenia and drug-induced states. The following table lists these and other causes of neutropenia.

Causes of neutropenia

Benign chronic (blacks, certain Arab, Jewish and West Indian groups)

Drug induced (commonly chemotherapy; also antibiotics and psychotropics)

Postinfectious (bacterial, viral, or parasitic)

Immune mediated (collagen vascular disorders)

Nutritional deficiencies (commonly folate, Vitamin B12)

Bone marrow disorders (Myelodysplasia)

Congenital neutropenia syndromes (usually diagnosed in childhood); Cyclic neutropenia is one type but usually benign

Benign ethnic neutropenia

Prevalence: As high as 10%; more common in African descent

Degree: Usually ANC>1000<1500

Mechanism: Not clearly understood. Generally these people have a preserved bone marrow neutrophil reserve and are not at increased risk of infections

Clinical presentation: Often encountered when performing lab tests for routine screening. It may be detected for the first time in a psychiatric setting

Diagnosis: Based on history and chronic low ANC with no other identified etiology

Management: Generally, these people do not need referral to a hematologist as long as the ANC remains stable. There is no threshold for referral for a bone marrow evaluation but may be considered if ANC < 1000 or it trends down

Psychotropic Medications and Neutropenia

Almost all major classes of psychotropic medications have been associated with neutropenia. The mechanism of drug-induced neutropenia is either decreased production in bone marrow due to direct toxic effect or sensitization of neutrophils to peripheral destruction. The effect is usually seen within 1–2 weeks of treatment. Withdrawing medication usually leads to resolution in 3–4 weeks [1].

Agranulocytosis is a rare side effect but is associated with up to 10% mortality when it occurs. It occurs later in treatment, about 3–4 weeks after exposure, and also resolves within 3–4 weeks of stopping the medication [1].

When the mechanism is bone marrow suppression, drug-induced neutropenia may be dose related and predictable whereas when the mechanism is immune-mediated destruction, it is idiosyncratic. However, with most medications, the mechanism is not clearly defined and they may both suppress bone marrow production and initiate peripheral destruction. Agranulocytosis is thought to be more commonly an idiosyncratic reaction unrelated to dose. But neutropenia can be a precursor for the more serious agranulocytosis . Unfortunately, there is no reliable way to predict which patients with neutropenia will progress to agranulocytosis . Agranulocytosis may also occur without antecedent neutropenia . Risk for neutropenia is higher at younger ages while risk for agranulocytosis is higher in the elderly.

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