4 Leukocytic Disorders

Leukocytes

Protection from non-self-cells and from altered self-cells

Two broad groups:

o Phagocytes granulocytes, monocytes
o Immunocytes lymphocytes, plasma cells

Formation of Neutrophil and Monocyte Phagocytes

Eosinophils and basophils are also formed in the marrow in a process similar to that for neutrophils.
Granulopoiesis
Proliferative/mitotic production:
progenitor cells, myeloblasts,
promyelocytes, myelocytes
Post-mitotic maturation
compartment:
metamyelocytes, bands,
segmenters
Reserve/storage pool
In bloodstream, two pools:
1) circulating; 2) marginating
Kinetics:
6-10 hours in circulating pool
4-5 days in tissue
6-10 days bone marrow

Neutrophil Kinetics
CSF, colony-stimulating factor.
G, granulocyte.
IL, interleukin.
M, monocyte.
SCF, stem cell factor.

White cells: Normal blood counts

TOTAL LEUCOCYTES
9
Adults
4.0 11.o X 10 /L
9
Neonates
10.0 25.0 X 10 /L
9
1 year
6.0 18.0 X 10 /L
9
4 7 years
6.0 15.0 X 10 /L
9
8 12 years
4.5 13.5 X 10 /L
Reference Ranges for the Differential Leukocyte Count in Adults
Cell
Proportional Count Absolute Count
n
9
(%)
(X10 /L)
Neutrophils
37-80
Adults: 1.8 7.0
Pedia: 1.0 8.5
Lymphocytes
10-50
Adults: 1.5 4.0
Pedia: 1.5 8.8
Monocytes
0 - 12
.03 - .9
Eosinophils
0 9.5
0.0 0.67
Basophils
0 2.5
0.0 0.20

Factors influencing neutrophil count:

Rate of inflow of cells from the marrow

(mitosis/proliferation, maturation/storage release)

Proportion of neutrophils between the marginal (cells

adhering to vessels walls) granulocytic pool and the
circulating (non-adhering cells) granulocytic pool

Rate of outflow of neutrophils from the blood

(migration from and through vessels into tissues, both
randomly and at sites of inflammation, infection, etc.)
Host factors that can modify degree of neutrophil response:

Age: children respond more intensely than adults

Virulence of infecting agent

Hematinic deficiency &/or marrow failure

rainwater@mymelody.com || 1st semester, AY 2011-2012

Leucocyte Count
9

NV: 4-11 x 10 /L
Calculation of absolute values for each leucocyte class

is encouraged
Absolute vs. relative leucocytosis

Use of absolute values has made the definition of

normal range more precise and provides best value
for determining abnormality
Leucocytosis

Increase in WBC count above upper limit of normal

for age and sex

Specify: neutrophilia, lymphocytosis, monocytosis,

eosinophilia, basophilia
Leucopenia

Decrease in total WBC count below the lower limit of

normal for age and sex

Neutropenia, lymphocytopenia
NB: Increase in any cell type maybe clinically important
but decrease is usually significant only for neutrophils.
Neutrophilic Leucocytosis
9

Absolute count >7.5 X 10 /L

bands & neutrophils

Pathophysiologic mechanisms:
1. Increased cell production
2. Accelerated release of cells from marrow into blood
3. Shift from marginal to circulating pool
4. Reduced egress of neutrophils from blood to tissues
5. Combination
Causes of Neutrophilia

Increased production:
chronic disorders - infections, tumors, inflammation,
endocrinopathies, myeloproliferative disorders

Increased production and peripheral cell survival:

CML

Accelerated release from the marrow:

stress, intoxication, infections, inflammation,
corticosteroids, endotoxins

Increased shift from marginal pool to circulating pool:

stress, intoxication, hypoxia, infections, exercise,
adrenalin

Decreased egress from circulating pool:

corticosteroids

Shift to the left: increase in immature peripheral

blood granulocytes, usually seen in acute infection
Leukemoid reaction: reactive and excessive
leucocytosis usually characterized by release of
immature cells(myeloblasts, promyelocytes,
myelocytes)
9
WBC >50 x 10 /L with shift to the left
Conditions: severe and chronic infection,
severe hemolysis , metastatic CA
High leucocyte alkaline phosphatase (LAP)
score

Causes of Neutrophilic Leukocytosis

Bacterial infections (especially pyogenic bacterial,

localized or generalized)

Inflammation and tissue necrosis (e.g., myositis,

vasculitis, cardiac infarct, trauma)

Metabolic disorders
(e.g., uremia, eclampsia, gout, acidosis)
Neoplasms of all types
(carcinoma, lymphoma, melanoma)
Acute hemorrhage or hemolysis
Drugs (e.g., corticosteroids, lithium, tetracycline)
Chronic myelogenous leukemia, myeloproliferative
diseases such as polycythemia vera, myelofibrosis,
essential thrombocytosis
Treatment with myeloid factors (e.g., G-CSF, GM-CSF)
Rare inherited disorders
Asplenia
9

Neutropenia: ANC<1.5 x 10 /L
Degree of Neutropenia and ANC
9
Normal:
> 1.5 x 10 /L
9
Mild:
ANC 1.0-1.5 x 10 /L
9
Moderate: ANC .5-1.0 x 10 /L (some increased risk for infection)
9
Severe:
ANC < .5 x 10 /L (significant risk of infection)
Mechanisms for Production of Neutropenia
Decreased flow of neutrophils from the marrow due

to lack of production or ineffective production (i.e.,

proliferation or production defect)

Increased removal of neutrophils from the blood

(survival defect)

Altered distribution between circulating and marginal

granulocytic pools
Combination of factors

Neutropenia and the risk of infection

9

ANC <1.5 x 10 /L

Risk of infection depends on 3 factors

1. Absolute neutrophil count (ANC)
2. Neutrophil reserve in the bone marrow
3. Duration

Neutrophil reserve: normal if with the ff:

No prior cytotoxic therapy

Appropriate ANC increases in response to

infections or stress

Normal bone marrow biopsy

Duration of neutropenia

Periodic or episodic (e.g. post chemo)

Chronic

Causes of Neutropenia

Bone marrow failure

Aplastic anemia; leukemia; myelodysplasia;

myelofibrosis; marrow infiltrations;
megaloblastic anemia

Splenomegaly
Infections

Immune-related

Drug-induced
Some Drugs Associated with Neutropenia

Anti-inflammatory: Aminopyrine, phenylbutazone

Antibacterial: Chloramphenicol, sulfas, penicillins,

cephalosporins, antivirals vs AIDS

Anticonvulsants: Phenytoin, phenobarbital

Antithyroids: Carbimazone

Phenothiazines: Chlorpromazine, promethazine

Cardiac meds: antiarrhythmics, digoxin, diuretics, ACEI

Chemotherapy

Tolbutamide, phenidione, H2 antagonists

rainwater@mymelody.com || 1st semester, AY 2011-2012

Lymphocytosis

Absolute count: >4.0 X 109/L

Maybe categorized as either

monoclonal or polyclonal

Review of peripheral smear important:

reactive lymphocytes seen in viral infections
large granular lymphocytes in large granular
lymphocytic leukemia
smudge cells seen in CLL
blasts of acute leukemia
Causes of Lymphocytosis

Monoclonal lymphocytosis: due to underlying

lymphoproliferative disorders - lymphocytes are
increased due to an intrinsic defect in the expanded
lymphocyte population
Ex: Lymphoproliferative disorders

Polyclonal lymphocytosis: secondary to stimulation

or reaction to factors extrinsic to the lymphocyte.
(Inflammation and/or infections)
Acute infections: Rubella, pertussis, mumps,

infectious mononucleosis, acute infectious

lymphocytosis
Chronic infections: Tuberculosis, brucellosis,
infective hepatitis, syphilis
Immune mediated: drug sensitivity, vasculitis, graft
rejection, Graves, Sjogrens
Stress acute, transient

Lymphocytopenia

Absolute count:

Adults < 1.0 X 10 /L

9
Children < 2.0 X 10 /L

Causes of Lymphocytopenia
Destruction radiation, chemotherapy,

corticosteroids

Debilitative starvation, aplastic anemia, terminal

cancer, collagen vascular disease
Infectious- viral hepatitis, influenza, typhoid fever, TB

Abnormal lymphatic circulation intestinal

lymphangiectasia, obstruction, thoracic duct
drainage/rupture, CHF
Monocytosis
9

Absolute count >0.8 X 10 /L

Causes:
>50% due to hematologic disorders
(e.g, AML, MDS, lymphomas)
10%
inflammatory and immune disorders
8%
malignant diseases

Eosinophilia

Mild:
Moderate:

Severe:

<1500 cells/uL
1500-5000 cells/ uL
>5000 cells/uL

Causes of Eosinophilia

Allergic diseases especially hypersensitivity of the

atopic type (e.g., bronchial asthma, hay fever,
urticarial and food sensitivity)

Parasitic diseases (e.g., amoebiasis, hookworm,

ascariasis, tapeworm infection, filariasis,
schistosomiasis, trichinosis)

Recovery from acute infection

Certain skin diseases (e.g., psoriasis, pemphigus and

dermatitis herpetiformis, urticarial and angioedema,

atopic dermatitis)
Inflammatory-eosinophilic fasciitis, Churg-Strauss

syndrome, polyarteritis nodosa, vasculitis, serum

sickness

Non-parasitic infections systemic fungal, scarlet

fever, chlamydial pneumonia of infancy
Respiratory pulmonary eosinophilic syndromes

(Ioefflers, tropical pulmonary eosinophilia), ChurgStrauss syndrome

Neoplastic CML, Hodgkins lymphoma, T-cell

lymphoma

Idiopathic hypereosinophilic syndromes

Others certain drugs, hematologic and visceral

malignancies, GI inflammatory diseases, sarcoidosis,

Wiskott-Aldrich

Primary hypereosinophilic syndrome

Criteria: >1500 eosinophils/uL for more than 6
months
Absence of an underlying cause of
eosinophilia despite extensive evaluation
Presence of end-organ damage or
dysfunction related to eosinophilia: skin,
heart, nervous system
Basophilia
9

Absolute count >0.2 X 10 /L

Causes:
Myeloproliferative diaseases

Allergic food, drugs, foreign proteins

Infectious variola, varicella

Chronic hemolytic anemia

Especially post-splenectomy

Inflammatory collagen vascular diseases,

ulcerative colitis

Causes of Monocytosis

Infectious tuberculosis, subacute bacterial

endocarditis, syphilis, protozoan, rickettsial

Recovery from neutropenia

Hematologic leukemias, myeloproliferative

disorders, lymphomas, multiple myeloma

Inflammatory collagen vascular diseases, chronic

ulcerative colitis, sprue, myositis, polyarteritis,
temporal arteritis

Others solid tumors, immune thrombocytopenic

purpura, sarcoidosis

rainwater@mymelody.com || 1st semester, AY 2011-2012

Acute Leukemia

Characterized by accumulation of malignant white

cells (blasts) in the blood and bone marrow
Defined by presence of >20% blasts in the blood and

bone marrow
Laboratory features

1. Anemia
2. Thrombocytopenia
3. Leukocyte count
May be high, low, normal
<5000/uL in half of patients
Note for absolute lymphocytosis
High WBC count with high lymphocyte %
Can present with pancytopenia

Myelogenous vs. lymphocytic

May be difficult to differentiate based on clinical

manifestations and simple morphology

Other tests
o
Cytochemical stains
o
Immunophenotyping

Flow cytometry
Chronic Myelogenous Leukemia
Laboratory features

A complete spectrum of myeloid cells in the

peripheral blood (WBCs in all stages of maturation).
The levels of neutrophils and myelocytes exceed
those of blasts and promyelocytes.

Increased basophils
Normochromic, normocytic anemias

Platelet count frequently increased but may be

normal or decreased

Leucocyte alkaline phosphatase is low

Bone marrow is hypercellular with myeloid

hyperplasia

Ph chromosome on cytogenetic analysis

(conventional or FISH)

Serum uric acid is usually elevated

Chronic Lymphocytic Leukemia
Laboratory Evaluation

Absolute lymphocytosis

Absolute neutrophil count is variable

Anemia or thrombocytopenia
o
30% of patients
15% Hgb less than 11mg/dL or platelets less
o
than 100,000

rainwater@mymelody.com || 1st semester, AY 2011-2012