Abnoramilities of white blood cells may involve changes in their blood counts, in the normal

content of young and mature forms, or emergence of the immature precursors in the
peripheral blood. Abnoramilties may also concern the function of leukocyte.
Disorders of white blood cells may be classified into two broad categories: proliferative
disorders and leukopenias. Proliferation of white cells may be reactive and neoplastic.
The number of leukocytes, or white blood cells, in the peripheral circulation normally
ranges from 4000 to 8,000/ L of blood.
Increase in the white blood cell counts that exceeds the upper limit is called leukocytosis; the
opposite shift beyond the lower limit is designated as leukopenia. The specific types of
leukopenia are called neutropenia, lymphopenia, monopenia, eosinopenia etc,
depending on the type of cells involved. Respectively, the specific types of
leukocytosis

are

neutrophilia,

lymphocytosis,

monocytosis,

eosinophilia,

or

basophilia.
Leukocytosis and leukopenia are not discrete nozological entities, and they are often used as
indices of the extent and course of various pathologic processes.
LEUKOPENIA
The term leukopenia describes an absolute decrease in white blood cell numbers. The
disorder may affect any of the specific types of white blood cells, but most often it affects the
neutrophils, which are the predominant type of granulocyte.
Neutropenia
The obligation of the neutrophil in phagocytic defense of the host is generally met if the
neutrophil count is above 1000 cells/L. If the neutrophil count below 500 cells/uL,
the incidence of serious, recurrent, and difficult-to-treat infections rises markedly.
When there are less than 200 cells/uL, (Agranulocytosis) the inflammatory process is
absent.
Acquired Neutropenia
Abnormalities in the marrow compartment: Bone marrow defects account for the majority of
neutropenias in clinical practice. Failure of the marrow compartment can occur as a
result of direct injury, in which case the marrow usually contains fewer than normal
hematopoietic cells, or from maturation defects of hematopoietic cells, characterized
principally by normal or increased numbers of morphologically abnormal
hematopoietic cells.
1

Drug-induced injury is most common. These drug-induced reactions can result from direct
drug-mediated cytotoxicity or from an immune mechanism in which neutrophils are destroyed in
extramedullary sites or the marrow compartment is injured. Neutrophils have human leukocyte
antigens (HLA) and other antigens specific to a given leukocyte line. Antibodies to these specific
antigens have been identified in some cases of drug-induced neutropenia.
Radiation may result in acute self-limited and chronic marrow injury. Chronic radiation-induced
injury can also result in the later development of myelodysplasia and nonlymphocytic
leukemia, both of which often present with neutropenia. Immune-mediated bone
marrow failure can be mediated by autoantibodies or by T lymphocytes that inhibit the
growth of the bone marrow precursor cells.
In splenomegaly, neutrophils may be trapped in the spleen along with other blood cells. In
Feltys syndrome, a variant of rheumatoid arthritis, there is increased destruction of neutrophils
in the spleen.
Hereditary or congenital hematologic diseases include idiopathic cyclic neutropenia, ChediakHigashi syndrome, aplastic anemia. Bone marrow invasion by abnormal cells can
result in neutropenia. Carcinoma of the lung, breast, prostate, and stomach, as well as
malignant hematopoietic disorders, can occupy enough of the medullary space to
cause global marrow failure.
Congenital Neutropenia
A decreased production of granulocytes are hereditary hematologic disorders, including
cyclic neutropenia and Kostmanns syndrome. Periodic or cyclic neutropenia is an autosomal
dominant disorder with variable expression that begins in infancy and persists for decades. It is
characterized by periodic neutropenia that develops every 21 to 30 days and lasts approximately
3 to 6 days.
Although the cause is undetermined, it is thought to result from impaired feedback
regulation of granulocyte production and release. Kostmanns syndrome, which occurs
sporadically or as an autosomal recessive disorder, causes severe neutropenia while preserving
the erythroid and megakaryocyte cell lineages that result in red blood cell and platelet
production. The total white blood cell count may be within normal limits, but the neutrophil
count is less than 200/ L. Monocyte and eosinophil levels may be elevated.
A transient neutropenia may occur in neonates whose mothers have hypertension. It
usually lasts from 1 to 60 hours but can persist for 3 to 30 days. This type of neutropenia, which
is associated with increased risk of nosocomial infection, is thought to result from transiently
reduced neutrophil production.
2

Increased demand for neutrophils in the extravascular compartment can lead to transient
neutropenia, especially in patients with severe acute infections. In such cases, the
marrow storage pool is used up before it can be restored by increased proliferative
activity of granulocyte progenitor cells. In patients with autoimmune neutropenia and
hypersplenism loss of neutrophils can outstrip marrow production.
Perturbations of the peripheral blood compartment result from shifts in the circulating pool.
In pseudoneutropenia, neutrophil production and utilization are normal, but the size
of the marginated pool is increased and the circulating pool is decreased. Because
these marginated cells, while hidden from the counting machine, maintain their
capacity to migrate to sites of infection, patients with pseudoneutropenia are not at
increased risk of infection unless a neutrophil function abnormality coexists. Acquired
pseudoneutropenia often occurs as an acute or subacute response to systemic
infections.
The clinical features of neutropenia usually depend on the severity of neutropenia and the
cause of the disorder. Because the neutrophil is essential to the cellular phase of inflammation,
infections are common in persons with neutropenia, These infections commonly are caused by
organisms that normally colonize the skin, vagina, and the gastrointestinal tract.
The signs and symptoms of neutropenia include malaise, chills, and fever, followed by
extreme weakness and fatigue. The white blood cell count often is reduced to 1000/L and, in
certain cases, may fall to 200 to 300/L. The most frequent site of serious infection is the
respiratory tract, a result of bacteria, fungi, and protozoa that frequently colonize the airways.
Ulcerative necrotizing lesions of the mouth are common in neutropenia.
Ulcerations of the skin, vagina, and gastrointestinal tract, risk for development of
potentially fatal septicemia may occur.
Lymphopenia is less common, and in addition to the congenital immunodeficiency diseases, it is
most commonly observed in case of human immunodeficiency virus (HIV) infection,
after therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders,
malnutrition, and certain acute viral infection.
Lymphopenia may represent a physiologic response to a variety of stressful events, including
bacterial infections and trauma. These responses are likely mediated by high levels of
endogenous glucocorticoids that induce rapid decline in circulating levels of B and T
lymphocytes. Lymphocyte values generally return to normal within 24 to 48 hours. In
some patients lymphocytopenia results from antilymphocyte antibodies.

Eosinopenia and basophilopenia are more common than monocytopenia in clinical practice
and most often represent redistributional mechanisms resulting from stress, including
acute infections, widespread neoplasms, and severe injury (e.g., burns). A variety of
humoral factors, including glucocorticoids, prostaglandins, and epinephrine, are
released in such settings and are known to induce eosinopenia.
Leukocytosis
The leukocytosis may be physiological - newborns and pregnant, and pathological - (infections,
traumas, toxins: metabolic (uremia), drugs, chemicals, tissue destruction or necrosis: infarction,
burns, neoplasia, etc. Hemorrhage, especially into a body cavity, rapid hemolysis, hematologic
disorders: leukemias, myeloproliferative disorders, and endocrine infringements).
Leukocytosis is a common reaction in a variety of inflammatory states. The peripheral blood
leukocyte count is influenced by several factors, including: 1) the size of the myeloid
and lymphoid precursor and storage cell pools; 2) the rate of release of cells from the
storage pool into the circulation; 3) the proportion of cells that are marginating at any
one time (marginating pool); 4) the rate of extravasation of cells from the peripheral
blood into tissues.
Neutrophilia results from the following:
1) increased neutrophil production,
2) increased marrow release, or
3) defective margination.
Increased production is also associated with chronic inflammation and certain myeloproliferative
disaeses.
Increased production of leukocytes is usually accompanied by shifts in the differential white cell
counts in the peripheral blood toward the increase in the young forms. The relative
increase in the young cells compared to the mature ones is called "shift to the left".
The relative increase in the segmented forms compared to the band forms is called
"shift to the right".
Hyperregenerative shift to the left attests to the extensive proliferation of the myeloid precursor
cells. It is characterized by a pronounced increase in the band neutrophils, and
emergence of significant amounts of metamyelocytes. Myelocytes can also be found.
The leukocyte counts reach 20,000 to 25,000 cells/uL, but may be normal, or even

decreased. The latter may be seen after a long period of stimulated hematopoiesis, and
reflects the exhaustion of the bone marrow.
A variety of physiologic stresses can release neutrophils from the storage pool into the
circulating pool. Also, peripheral neutrophils normally segregate into two equal pools:
the circulating pool and the marginated pool. Neutrophilia can result rapidly from a
shift of neutrophils from the marginated to the circulating pool - "demargination". This
response can be elicited by injections of epinephrine. In patients with acute
inflammatory illnesses, storage pool release and demargination usually occur together.
Monocytosis
Monocytosis is defined as absolute peripheral blood monocyte counts of 500 cells/uL in adults.
Monocytosis often occurs in patients with tuberculosis, syphilis, fungal infections,
ulcerative and granulomatous colitis, and sarcoidosis. High levels of monocytes in the
blood are most often encountered in patients with hematopoietic malignancies,
including acute and chronic myelomonocytic leukemia, acute monocytic leukemia,
and chronic myelogenous leukemia of the juvenile type.
Eosinophylia
Eosinophilic leukocytosis (eosinophilia) exists when the eosinophil count in the peripheral blood
exceeds 400 cells/uL. Eosinophils not only function as phagocytes but also play an
essential role in modulating the potentially toxic effects of mast cell degranulation in
hypersensitivity reactions. Because eosinophils have a unique capacity to release
substances toxic to vascular endothelial cells, very high levels of eosinophils in the
circulation can result in vascular, pulmonary, and cardiac injury.
Lymphocytosis
Lymphocytosis is defined as any lymphocyte count in excess of 5000 cells/uL. Mild to moderate
lymphocytosis is most commonly caused by viral infections, including infectious
mononucleosis and infectious hepatitis. Acute bacterial infections rarely cause
lymphocytosis.
LEUKEMOID REACTION
Leukemoid reaction resembles the picture of leukemia in the peripheral blood. This change
consists of increase in the young, or emergence of the immature cells, sometimes blast
forms. As in leukemia, leukemoid reaction is usually accompanied by increase in the
total cell number. But sometimes cell counts are normal, or even decreased.
5

Leukemoid reaction occurs in massive infection, allergic diseases, in response to

extensive tissue damage, hemolysis, or as a result of tumor destruction.
The pathophysiology of leukemoid reaction includes focal reactive proliferation of the bone
marrow with increased production of precursors, belonging to various hematopoeitic
lineages. The concomitant increase in permeability of the blood-marrow barrie, leads
to leakage of the immature forms into the peripheral blood.
Based on the cell type, leukemoid reactions are classified as myelocytic, monocytic,
lymphocytic, or mixed, lymphomonocytic, or myelomonocytic. Depending on the
total cell counts leukemoid reactions can be leukopenic, leukocytic (from 10,000 to
80,000 leukocytes/uL), or normocytic.
Leukemoid reaction appears to be adaptive since it is accompanied by accumulation of
functionally active mature leukocytes in the peripheral blood.
Leukemias
The leukemias are malignant neoplasms of cells originally derived from hematopoietic
stem cells. They are characterized by diffuse replacement of bone marrow with unregulated,
proliferating, immature neoplastic cells. The leukemic cells spill out into the blood, where they
are seen in large numbers.
Classification
The leukemias are classified into four types: acute lymphocytic (lymphoblastic) leukemia,
chronic lymphocytic leukemia, acute myelogenous (myeloblastic) leukemia, and chronic
myelogenous leukemia.
The lymphocytic leukemias involve immature lymphocytes and their progenitors that
originate in the bone marrow, and infiltrate the spleen, lymph nodes, CNS, and other tissues.
The myeloid leukemias, which involve the pluripotent myeloid stem cells in bone marrow,
interfere with the maturation of all blood cells, including the granulocytes, erythrocytes, and
thrombocytes.
auses of hematopoietic cell malignancies
*Inherited genetic factors (Fanconi anemia, ataxia-telangiectasia, Down syndrome).
*Chemical agents (benzene, smoking, petroleum products, herbicides, pesticides).
*Viruses (human T-lymphocyte leukemia virus I (HTLV-I), Epstein-Barr virus, human
herpesvirus 8).
*Physical factors (ionizing radiation).
6

*Iatrogenic factors (radiotherapy, certain forms of chemotherapy). *Chromosomal translocations

and oncogenes.
General characteristics of leukemia:
*Atypism.
*Coexistence of 2 lines of hematopoietic cells of the same type: normal and malignant.
*The malignant line is characterized by impairment of differentiation and is presented by blasts
and immature precursors.
*The normal population of cells is crowded out.
*Leukemic reaction in the peripheral blood.
Classification of leukemic reaction in the peripheral blood based on leukocyte counts and
presence of the blast forms:
1. Leukemic leukemia - leukocyte counts exceed 50,000 or 80,000 cells/ul; great amount of
blasts.
2. Subleukemic leukemia - leukocyte counts are less than 50,000 cells/ul; great amount of blasts.
3. Leukopenic leukemia - leukocyte counts are below the normal value; blast cells can be found.
4. Aleukemic leukemia - normal picture of the peripheral blood; malignant cells can be found
only in the bone marrow.
Leukemic reaction of the peripheral blood includes:
*Leukocytosis (typically).
*Significant increase in the young cells and emergence of immature precursors including blasts
(shift to the left).
*Hiatus leukaemicus (acute myeloid leukemia).
*Eosinophilic-basophilic association (chronic myeloid leukemia).
*Anemia.
*Thrombocytopenia.
7

General characteristics of acute lymphoblastic leukemia/lymphoma:

*includes a group of neoplasms composed of immature, precursor B (pre-B) or T (pre-T)
lymphocytes referred to as lymphoblasts
*the majority (~85%) of ALL are pre-B tumors that typically manifest as childhood acute
leukemias
*the less common pre-T cell ALLs tend to present in adolescent males as lymphomas, often with
thymic involvement
*the marrow contains > 30% of lymphoblasts; similar number of blasts in the peripheral blood
also makes the diagnosis.
General characteristics of chronic lympholastic leukemia/lymphoma.
*the most common is a B-cell form, which presents with asymptomatic lymphocytosis in
patients with a median age 60;
*the minimum lymphocytosis to make the diagnosis of CLL is 5*109/L;
*the incidence is over 10 per 100,000 per year for persons over 70 but less than 1/100,000 for
those under 50
*more common in males and in whites;
*the peripheral blood contains fragile lymphocytes which are frequently disrupted in the process
of making the smear, producing the so-called smudge cells.
Classification of myeloid neoplasms:
1. Acute myeloid leukemias (AML) (immature progenitor cells accumulate in the bone marrow).
2. Myelodisplastic syndromes (MDS) (ineffective hematopoiesis and resultant peripheral blood
cytopenia).
3. Chronic myeloproliferative disorder (MPD) (increased production of one or more terminal
differentiated myeloid elements that usually leads to elevated peripheral blood
counts).

General characteristics of acute myeloid leukemias (AML):

*AMLs affects primarily adults, peaking in incidence between ages of 15 and 39 years
*in AML normal marrow elements are replaced by relatively undifferentiated blasts
*the replication rate of malignant blasts is lower than that of normal myeloid progenitors, and the
malignant blasts fail to differentiate
*myeloid precursor cells accumulate in the marrow and suppress remaining normal
hematopoietic progenitor cells
*failure of normal hematopoiesis results in anemia, neutropenia, and thrombocytopenia.
General characteristics of chronic myeloid leukemia (CML):
*refers to chronic myeloproliferative disorder;
*CML affects primarily adults, peaking in incidence between ages of 30 and 40 years;
*the diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem
cell possessing a reciprocal translocation between chromosome 9 and 22;
*the disease is characterized by the inevitable transition from a chronic phase to an accelerated
phase and on to blast crisis.