Zaporizhzhia State Medical University

Pathophysiology Department

WBC pathology
Lecturer:
Associate Professor T. A. Grekova
 Lecture Plan
1. Stages of leukopoiesis, leukocytic formula
2. Leukopenia, pathogenesis, clinics
3. Leukocytosis, pathogenesis, clinics
4. Types of neutrophils nuclear shift
5. Pathogenesis of leukemoid reaction
6. General pathogenesis of leukemia
7. Blood count and clinical manifestation of
AML, ALL, ALL, CLL
LEUKOPOIESIS
Granulocytes Agranulocytes

The reference range of total leukocytes

for adults (males and females) is
4.00-9.00 x 109/L
 Leukogram - WBC differential count
% correlation between different forms of WBC
Neutrophils
Eosino Baso Lymph Mono
phils phils myelo juvenil segme ocytes cytes
band
cyte e nted
2-5 0-1 0 0 2-5 50-70 20-40 3-10

               

% of WBC type * total WBC count

Absolute value =
100
 Pathological forms of leukocytes
Regenerative forms of leukocytes -
normally found only in the bone marrow
Degenerative forms of leukocytes -
Neutrophils with Leukocytes with
hypersegmented Döhle bodies
nucleus
• infections
•  level of
glucocorticoids • poisoning

• B12 deficiency • burns

Gumprecht’s
Leukocytes with shadows
toxic
smudge cells
granulation
• cell’s partial
• severe
breakdown
inflammation
during
• tumor necrosis preparation of a
smear (CLL)
Functional defects in leukocytes
 Leukopenia - WBC < 4*109 /L
Leucopenia pathogenesis
 impairment and/or depression of leukopoiesis (genetic defect,
disturbances of its neurohumoral regulation, deficiency of
proteins, vitamin В12, folic acid, etc., prolonged administration
of medicinal preparations);
 excessive destruction of leukocytes in the vessels or
hemopoietic organs (ionizing radiation, antileukocyte
antibodies, toxic factors, overactive spleen);
 redistribution of leukocytes in the blood flow (shock, prolonged
muscular work, massive destruction of leukocytes in tissues -
peritonitis, pleuritis, mechanic lesion);
 increased loss of leukocytes (chronic blood loss, plasmo- and
lymphorrhea – burns; chronic purulent processes –
osteomyelitis, peritonitis);
In expressed leucopenia the anti-tumor and anti-infection
resistance decreases, septic process generalization, infections
and neoplasms may develop.
 Classification of leucopenia
 Absolute - decreasing of an absolute count of some types of
leukocytes;
 Relative - a decrease in the percentage of some types of
leukocytes at the expense of an increase of some other their
types)
By origin:
 Physiologic leucopenia - is the redistribution leucopenia
occurring in transferring of a considerable part of leukocytes to
some parts of the blood flow
 Pathologic leucopenia - a decrease in the absolute number of
certain types of white blood cells
• primary (congenital or hereditary) - Chediak-Higashi, chronic granulomatous
disease
• secondary (acquired) - Ionizing radiation, chemicals (insecticides),
medicines: non-steroidal anti-inflammatory drugs, sulfonamides, barbiturates;
autoimmune diseases: systemic lupus erythematosis; cachexia
 According to the percentage of certain types of white blood
cells in peripheral blood (in the leukocyte count) – neutropenia,
eosinopenia, monocytopenia, lymphopenia, bazopenia
 Leukopenia types
Eosinopenia
 after anaphylactic attacks (histaminase)
 severe stress
  glucocorticoids level, glucocorticoid therapy
Lymphopenia
 primary immunodeficiency (Louis-Bar, Wiskott-Aldrich syndrome, Di Giorgi)
 immunosuppressive status (stress, hypercorticism, long-term steroid and
radiation therapy)
 characteristic of various diseases and immunodeficiency syndromes :
measles, poliomyelitis, lymphoma (Hodgkin's disease), AIDS (destruction of
lymphocytes), systemic lupus erythematosus
Monocytopenia
 not a distinct disorder
 excess of glucocorticoids, bone marrow damage (leukemia, aplastic anemia,
Addison-Biermer anemia, radiation disease, cancer metastasis,
chemotherapy). Reduction in blood monocytes can be observed on a
background of the height of acute infection (in conjunction with neutropenia),
exacerbation of TB process, rheumatic heart disease (in combination with
lymphocytosis).
The term Basopenia do not use as normally basophils may be
absent in the peripheral blood.
Neutropenia - neutrophils <1,5 *109/L
Agranulocytosis – total WBC 1-3*109/L
granulocytes < 0.75*109/L
Clinically -  resistance to infection
 Fever

 Necrotic angina

 Inflammation of the mouth, nose and eyes

 Furunculosis

 Pneumonia

 Septicemia, urosepsis
Pathogenetic forms of agranulocytosis
 Primary (inherited) - Kostmann syndrome
 Secondary (acquired):
 Myelotoxic (drugs - cytostatic preparations; alimentary

factors; ionizing radiation; infections - mononucleosis,

hepatitis, HIV, rubella, staphylococci, tuberculosis; bone
marrow metaplasia
 Autoimmune - unusual sensitivity of the organism to some

drugs (sulphanylamides, amidopyrine) that is accompanied

by anti-leukocyte antibodies formation (IgG, IgM). Fixing on
the surface of leukocytes they destroy them with the
participation of activated components of the complement
system. As a rule, in immune agranulocytosis only the
content of leukocytes decreases. Other blood cells are not
affected: no anemia, thrombocytopenia, relative
lymphocytosis is observed.
 Leukocytosis - WBC > 9 *109/L
Causal factors:
Physical factors - ionizing radiation;
Chemical - alcohol, deficiency of oxygen in the
inspired air; drugs stimulating the cells proliferation;
Biological factors - waste products of the living and
dead components of viruses, bacteria, Rickettsia,
immune complexes (antigen-antibody); histamine,
cell degradation products
Absolute leukocytosis –infection, inflammation,
marrow neoplasia
 activation of leukopoiesis

 release of WBC from bone marrow storage pools

Relative leukocytosis - redistribution of leukocytes

in the vessels.
 Etiology of leukocytosis
Physiological leukocytosis - sign of the physiological state of the body usually
neutrophilic
Relative - short-term leukocytosis is redistributive in nature and linked to the mobilization
of the reserve into the blood stream of mature white blood cells from the organs depot:
 Alimentary - in 1-3 hours after a meal
 Myogenic - physical overload
 Emotional - mental excitement
 Acclimatization - flight over the time zones
Absolute - is due to activation of leukocytes formation processes in the bone marrow:
 newborns - within the first week of life and having protective value.
 pregnant women – from the 2nd half of pregnancy.
 after delivery - on the 2nd week.
Pathological - disease symptom
 Infection - pneumonia, meningitis, scarlet fever and other;
 Inflammation - especially in purulent inflammation;
 Toxogenic - exogenous (benzene, aniline) and endogenous (uremia, diabetic coma);
 Posthemorrhagic - after acute blood loss;
 New formation - the decay of tumors;
 Leukemia - acute and chronic leukemia.
 Centrogenic - when shock conditions, epilepsy, agony, postoperative - is
redistributive.
Mechanisms of leukocytosis development
1. Reactive leukocytosis - increased normal leukopoiesis due to
increase in the activity of humoral leukopoiesis stimulants (growth
factors). The result is an increase in the number of proliferating
cells, combined with their differentiation into mature leukocytes
(inflammatory reactions, allergic processes). It is referred to
absolute leukocytosis.
2. Redistributive leukocytosis - redistribution of WBCs in the
bloodstream. Accumulation of mature leukocytes in some organs
(lungs, liver, intestine wall), the absence of leukopoietic tissue
hyperplasia, total WBC count within the normal range (after
physical exertion - myogenic leukocytosis, traumatic, blood
transfusion, anaphylactic shock). There is no increase in the
number of young forms of leukocytes. It is relative leukocytosis.
3. Leukocytes hyperproduction in tumor lesions of hematopoietic
tissue (leukemia). The total number of WBCs is increased due to
leukemic cells proliferation. It is absolute leukocytosis.
4. Hemoconcentration leukocytosis due to organism hypohydration
with the development of hypovolemia (repeated vomiting, diarrhea,
polyuria). The total number of normal WBCs count per unit volume
of blood as well as the number of other blood cells are increased. It
is relative leukocytosis.
 Types of leukocytosis
Eosinophilia Basophilia
>5% >1%
anaphylactic and reaginic allergic reactions
as a reaction to foreign proteins, associated with anti-toxic, anti-histamine (via
histaminase of eosinophil granules), phagocytic (phagocytosis of immune
complexes) functions
chronic myeloid leukemia, polycythemia vera
infection diseases (scarlet fever, syphilis, tuberculosis)
endocrinopathy (pituitary cachexia, myxedema, type 1 diabetes mellitus,
thyroiditis)
parasites’ invasions vaccination
skin diseases (psoriasis, eczema) hemolytic anemia
collagenoses (rheumatism, hemophilia
dermatomyositis, rheumatoid arthritis,
lupus erythematosus)
 Lymphocytosis > 45% in the leukogram
Physiological lymphocytosis
in children from the 4-5th day of life up to 4-5th years;
Absolute pathological lymphocytosis (>40%):
 Formation of anti-infective immunity:
 Acute viral infections: Epstein-Barr virus,
cytomegalovirus, hepatitis;
 Acute and chronic infections: tuberculosis, brucellosis
typhoid, syphilis, malaria;
 Allergic bronchial asthma
 Lymphoid malignancies
 Malnutrition
 Some endocrine disorders (myxedema, acromegaly)
 Relative lymphocytosis
 Total WBC count normal or lower
 Leukocytic formula – WBC 4 *109/L
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segment ytes cytes
juvenile band
cyte ed
2 0  0 0  0 29 60 10
Mechanisms:
 neutrophils migration in the sites of inflammation
 connective tissue diseases;
 thyrotoxicosis
 increased granulocytes destruction
 splenomegaly (splenic sequestration of granulocytes);
 in patients with neutropenia (decreased granulocyte count causes
leukopenia and most remaining cells are lymphocytes, but the
absolute number of lymphocytes remains normal
 Monocytosis
 >10%
 bacterial infections (tuberculosis, syphilis, bacterial
endocarditis);
 viral infections;
 protozoal and rickettsial infections (amoebiasis,
leishmaniais, toxoplasmosis, malaria, typhus);
 convalescence from acute infection;
 hematopoietic disorders (leukemia, myeloma);
 non-infectious causes (unspecific ulcerative colitis,
chronic granulomatous colitis);
 autoimmune disorders (thyroiditis);
 cancer (breast and ovarian);
 after splenectomy
 Neutrophilia
Aseptic (not-infectious) neutrophilia
 burns, myocardial infarction, intestinal

impassability, immunocomplex diseases;

 uremia, diabetic ketoacidosis,

thyreotoxocosis,  histamine synthesis

Infectious neutrophilia
acute infections, caused by pyogenic bacteria
(Pneumococcus, Streptococcus,
Staphylococcus and others);
Bone marrow tumors (chronic myelogenic
leukemia, polycytemia vera).
 Neutrophils nuclear shift (NNS)
Shift right – often combined with the signs of WBCs
degeneration and a decrease in the band neutrophils
content
Shift left – an increase in the young forms of neutrophils

Leukocytosis without nuclear shift – the total number of

leukocytes is slightly increased to 10-11 x 109/l due to
segmented neutrophils.
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segmente ytes cytes
juvenile band
cyte d
0 0  0 0  5  70 20  9
It indicates process purity:
 some physiological leukocytosis
 some forms of pulmonary infectious diseases
 lung hemorrhages
 Neutrophils nuclear shift (NNS)
Hyporegenerative NNS to the left –  of band neutrophils %
(easy current of infection/inflammation)
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segmente ytes cytes
juvenile band
cyte d
1 0  0 0  8  69 20  9
It occurs in infectious and parasitic diseases, catarrhal appendicitis,
moderate blood loss
Regenerative NNS to the left –  of band neutrophils %,
appearance of juvenile cells (moderate infection/inflammation and
more sufficient resistance of the organism)
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segmente ytes cytes
juvenile band
cyte d
1 0  0 2  8  57 20  9

It occurs in severe forms of acute infectious and parasitic diseases -

diphtheria, scarlet fever, dysentery, lobar pneumonia, suppurative
appendicitis, peritonitis, retropharyngeal abscess.
 Neutrophils nuclear shift
Hyperregenerative NNS to the left - a large
percentage of young neutrophils and myelocytes
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segmente ytes cytes
juvenile band
cyte d
0 0  2 7  16  51 18  4
It occurs in myelogenous type of leukemoid reaction, severe infectious
and parasitic diseases, pneumonia with abscess, phlegmonous
appendicitis, peritonitis, sepsis
Regenerative- degenerative NNS –the absolute
numbers of band or immature neutrophils are greater
than the absolute numbers of segmented neutrophils
Neutrophils
Eosino Baso Lymphoc Mono
phils phils myelo segmente ytes cytes
juvenile band
cyte d
4 0 2 7  16 42 20  9
It occurs in severe course of infectious diseases, endogenous
intoxications
 Leukemoid reactions
 WBC count (> 30*109 / L)
immature WBC in peripheral blood, similar to leukemia
 of WBC is always reversible and does not transform
into leukemia
Types:
myelogenous, eosinophilic, lymphocytic, monocytic
Mechanisms:
 output of immature cells
  production of WBC
Causes
 the same as in leukocytosis
 Leukemia
is a systemic clonal neoplastic disease, when a
mutant tumor clone originates from progenitor
hemopoietic cells, it occurs primarily in the
bone marrow; is manifested by uncontrolled
proliferation and rejuvenation of hemopoietic
elements without their maturation and
metaplasia of the hemopoietic tissue.
Features of leukemia:
 abnormal proliferation of leukemic cells;
 organs infiltrations by leukemic cells;
  apoptosis of leukemic cells;
 suppression of normal hemopoiesis
 Etiology of leukemia
 environmental factors:
 natural or artificial ionizing radiation;
 certain kinds of chemicals (benzene and other
aromatic hydrocarbons);
 some viruses:
 human T-lymphotrophic virus;
 Epstein-Barr virus
 genetic
predisposition
 immunologic deficiency
 Pathogenesis of leukemia
1) Initiation stage - mutation of normal hemopoetic cells;
2) Promotion stage - monoclonal proliferation - development
of primary leukemia of some hemopoetic cells;
3) Tumor progression stage –polyclonal proliferation - tumor

becomes malignant
 Leukemia types
Acute leukemia
 growth of immature poorly differentiated cells
 "hiatus leukemicus" - a lack of cell stages of
maturation between blasts and mature cells in
leukocytic formula
 occur in children and young adults
 rapid progression and spread of the malignant cells to
the organs of the body
Chronic leukemia
 growth of abnormal mature cells
 slower rate of tumor progression
 mostly occurs in older people, but can theoretically
occur in any age group
 Leukemia classification

 leukopenic form - WBC count lower than

4*109/L
 aleukemic form – WBC count lower than
10*109/L.
 subleukemic form – 10-50 *109/L, a few
blasts in peripheral blood.
 leukemic form – more than 50 *109/L,
blasts prevalence in peripheral blood.
 Leukemia classification (ICD-10)
Acute leukemias:
 Acute Undifferentiated Leukemia (pluripotent
stem cell is affected - AUL )
 Acute Myeloblastic Leukemia (AML)
 Acute Lymphoblastic Leukemia (ALL)

Chronic Leukemias:
 Chronic Lymphocytic Leukemia (CLL)
 Chronic Myeloid Leukemia (CML)
 Acute myeloid leukemia
a cancer of the myeloid line of WBC
 the most common acute leukemia affecting adults
 increased number of malignant WBC displace
normal hemopoiesis
 decreased count of RBC, platelets, and normal
WBC

Myeloblasts

Peripheral blood Bone marrow

 Clinical manifestations of Acute
myeloid leukemia
 Common symptoms are fever, weight loss, loss
of appetite;
 the patient has persistent or frequent infections;
 metaplastic anemia - can cause fatigue,
paleness, and shortness of breath in exertion;
 lack of platelets can lead to easy bruising or
bleeding in minor injuries;
 bone pain and joint pain and;
 enlargement of the spleen and lymph node
swelling is not significant
 Acute myeloid leukemia
 myeloblasts in a peripheral blood and their prevalence
in marrow;
 hiatus leukemicus – the lack of cell stages of
maturation between myeloblasts and mature
neutrophils;

Neutrophils
Eosino Basophi Lymph Mono
phils ls pro ocytes cytes
myelo myelo segmen
myelo juvenile band
blasts cytes ted
cytes

0 0 62 0 0 0 3 23 11 1

 absence of eosinophils and basophils in the leukocytic

formula;
 anemia and thrombocytopenia; they indicate leukemia
severity;
 Acute lymphoblastic leukemia

 children of 2-4 years old

 affection of lymphatic nodes and spleen
 enlarged mediastinal nodes there are dry cough,
shortness of breath;
 enlarged mesoperitoneal nodes can cause
stomachaches
 Pains in bones (more often in shins)
 Other clinical signs: fatigue, pallor, infection, and
easy bruising and bleeding
 Acute
lymphoblastic
leukemia
Lymphoblasts
in the peripheral
blood smear

Neutrophils Lymphocytes
Bas
Eosino Mono
ophil
phils cytes
s
mye big
juve lympho prolymph mediu small
locy band segm. lympho
nile blasts ocytes m L. L.
tes cytes

0 0 0 0 1 16 61 0 0 0 19 3
 Undifferentiated leukemia

Acute undifferentiated
leukemia affects
pluripotent blood
stem cell.
This is one of the most
malignant forms of
acute leukemia (fast
progress, severe
course).
 Chronic myeloid leukemia
 abnormal proliferation of myeloid cells
 characteristic chromosomal translocation
called the Philadelphia chromosome
 Symptoms: malaise, fever, increased
susceptibility to infections, anemia, and
thrombocytopenia
 enlargement of spleen and liver (due to
leukemic infiltration)
 fat marrow of long bones is replaced with
myeloid tissue
 Chronic myeloid leukemia

 detectingthe Philadelphia chromosome

 absence of hiatus leukemicus
 eosinophil-basophil association

Neutrophils
Eosino Basoph Lymph Mono
phils ils pro ocytes cytes
myelo myelo segmen
myelo juvenile band
blasts cytes ted
cytes

8 4 6 10 16 15 13 12 10 6
 Chronic myeloid leukemia

bone marrow

peripheral blood
Clinical manifestation of Chronic
myeloid leukemia
 Chronic phase: mild symptoms of fatigue
or abdominal fullness
 Accelerated phase: further increase in
granulocytes count, decrease of RBC and
platelets, increasing splenomegaly
 Blast crisis; behaves like an acute
leukemia, >20% myeloblasts in peripheral
blood
 Chronic lymphocytic leukemia
 lymphoid hyperplasia of hemopoetic organs
(lymphatic nodes, spleen, marrow)
 accompanied by lymphoid infiltration of other
organs and tissues.
 suppression of myelopoesis (anaemia,
granulocytopenia and trombocytopenia.
 CLL is formed mostly by mature lymphocytes
 Chronic lymphocytic leukemia

 CLL is considered to be benign, non-

malignant tumour
 B-population of lymphocytes is mainly
affected
 severe violations of immunity
 predominance of mature lymphocytes
 presence of all lymphocytes maturation
forms
 Gumprekht’s shadows
 Chronic lymphocytic leukemia

lymphocytes

Neutrophils Lymphocytes
Bas
Eosino Mono
ophil
phils cytes
s mye
juve lympho prolymph
big
mediu small
locy band segm. lympho
nile blasts ocytes m L. L.
tes cytes

0 0 0 0 2 36 5 9 11 14 19 3
 Manifestations of leukemia
Supression of hemopoiesis:
 metaplastic anemia
 secondary immunodeficiency syndrome
 easy bruising and bleeding
Leukemic infiltration
 splenomegaly, hepatomegaly
 lymphadenopathy
 bone and joint pain
Stages of leukemic infiltration

Liver Bones,
Bone marrow Thymus nervous system,
Lymphoid tissue kidneys
Neutrophils’ “Left shift”
Common causes of leukocytosis
 Drugs intake (low doses of corticosteroids,
lithium and beta blockers).
 Splenectomy –  of WBC destruction
 Hemolytic anemia - leukocytosis occur in
association with increased RBC production.
 Malignancy - tumor nonspecifically stimulates
bone marrow to produce WBC
 In most cases - inflammation or infection.
Acute myelogenous leukemia

Myeloblasts

Peripheral blood Bone marrow