Leukopenia refers to an abnormal decrease in the number of leukocytes. This may be secondary to a deficiency of any or all of the WBCs but it is most commonly caused by a depression of neutrophils (neutropenia). Granulocytopenia, often used as a synonym for neutropenia, technically refers to decreased eosinophils and basophils as well as neutrophils.

Neutropenia is defined as less than 1.5 x 10⁹ /L neutrophils in the perpherial blood. Fewer than 1.0 x 10 /L neutrophils compromises the ability to fight infection.

Agranulocytosis refers to extremely low levels of neutrophils (< 0.5 x 10⁹ /L).

The causes of leukopenia may be marrow failure, peripheral destruction or shift into the storage or marginated compartments.\

---

Causes of decreased marrow production:

1) drug induction - ie. cytolytic; metabolic; idiosyncratic
2) aplastic anemia - hypoplasia of bone marrow
3) myelofibrosis - metastatic cancer; granulomas; fibrosis
4) ineffective hematopoiesis - ie. megaloblastic anemia

Decreased survival of neutrophils (increased utilization or increased destruction):

This differs from marrow failure because of normal numbers of erythroid and megakaryocytic elements. There will often be myeloid hyperplasia, but without maturing metamyelocyte, band, and polylobed forms.

1) acute infection - transient increased utilization
2) drug induced - immunologic
3) neutrophil aggregation - complement induced
4) hypersplenism - decreased survival
5) leukopheresis

Causes of increased margination or storage (typically transient neutropenia with normal total number of neutrophils and neutrophil kinetics):

1) hemodynamic changes
2) viremia
3) hypersensitivity
4) hemolysis

Several minor causes of neutropenia need to be mentioned in the category of "you can't diagnose what you don't know exists".

Cyclic neutropenia is an autosomal dominant disorder of unknown etiology in which 3-6 days of neutropenia occur every 21-30 days in a periodic pattern. During the periods of neutropenia the patient may develop fever and infections such as stomatitis, cellulitis, and vaginitis. There appears to be some abnormality of feedback mechanisms.

Chronic idiopathic neutropenia is a disorder in which the neutrophil count is less than 1.0 x 10⁹/L, but results in few infections.

A 35-year-old woman, with a history of depression x1 month was treated with phenothiazine by Dr. Lucy van Pelt. She now presents with a 10 day history of fever, chills, and malaise. In the past 3 days she noted increased weakness and fatigability. The chest X-ray shows evidence of early pneumonia. There is no splenomegaly. Laboratory values are shown at right. The PB smear showed normocytic/ normochromic RBCs.

Your second patient is a 27-year-old man in for an insurance physical exam. He is pale and gave a history of bleeding gums and several recent episodes of epitaxis. Upon further questioning you find that he comes home from work and goes almost immediately to bed. The CBC results you ordered returned later that day and are shown at right. The PB smear showed normocytic/hypochromic RBCs.

Some drugs induce cytolysis causing general marrow depression and resulting in aplastic anemia. Examples include alkylating agents, inhibitors of mitosis, DNA depolymerizors, and ionizing radiation.

DNA synthesis may be impaired by some drugs - phenothazines, chloramphenicol, and purine and pyrimidine antagonists (methotrexate, hydroxyurea, azothioprine, cytosine arabinoside, and 6-mercaptopurine).

Ideiosyncratic reactions are seen with other compounds (chloramphenicol, gold salts, phenylbutazone, thiazides, sulfonamides, quinine, procanamide, etc.).

In immunologic neutropenia, the drug and neutrophil surface protein form an antigenic complex. Antibody is produced against against this complex and remains inactive in the plasma. When this drug is given it interacts with neutrophil surface protein and complexes antibody. This causes leukoagglutiation or activation of complement.

The neutrophils are destroyed by complement or the clumps of neutrophils (at right) are removed from the circulation or sequestered in the lungs, spleen, etc. (seen with aminopyrine, thiouracil and some sulfonamides)

Clinical features of neutropenia:

Fever may be secondary to the release of leukokines during peripheral destruction of neutrophils.

The initial symptoms of neutropenia begin after 1-3 days with malaise, chills, sore throat, fever. Later easy fatigability and weakness are seen.

Infection is the most serious consequence of neutropenia. Neutropenia less than 1.0 x 10 ⁹/L seriously compromises the ability to fight infection. Agranulocytosis (< 0.5 x 10 ⁹ /L) may lead to death within days due to overwhelming infection.

Other forms of leukopenia:

Eosinopenia*( < 0.04 x10 ⁹ /L ) may be seen in acute stress (glucocorticoid or epinephrine stimulation), acute inflammation (interleukin-5), Cushing's syndrome or corticosteroid administration.

Basopenia*( < 0.01 x10 ⁹ /L ) may be seen with corticosteroid administration, stress, acute inflammation, and hyperthyroidism.

Monocytopenia ( < 0.2 x10 ⁹ /L ) may be seen in the first few hours after giving predisone, but by 12 hours returns to normal.

Lymphocytopenia ( < 1.5 x10 ⁹ /L for adults; < 3.0 x10 ⁹ /L for children ) may be seen with corticosteroid Rx, chemoRx, irradiation, Hodgkin's disease, HIV**infection, and chronic diseases ie. sarcoid, TB, lupus.

*Note: Both eosinophils and basophils, like neutrophils, exhibit diurnal variation, being lowest in the morning and highest in the evening.

**Note: In HIV infection the lymphopenia is largely due to a loss of CD4 positive T-helper lymphocytes.