White Blood Cell Disorders

1. Benign Quantitative WBC Disorders

A. Absolute neutrophilic leukocytosis
i. Mechanism:
1. Increased marrow production and release from marrow
(infection, necrosis)
2. Decreased adhesion to endothelium (corticosteroids) .
B. Leukemoid reaction
i. WBC > 50,000 cells/L
ii. Can involve PMNs, lymphocytes, or eosinophils
iii. No nucleated RBCs; no blasts; bone marrow does not reveal a
leukemia.
iv. Usually secondary to severe infections
C. Leukoerythroblastic reaction
i. Left shifted smear (Increased bands, metamyelocytes, etc.) +
nucleated RBCs
ii. Causes: marrow Infiltration by tumor (breast cancer), myelofibrosis
D. Absolute neutropenia
i. Mechanisms:
1. Reduced granulopoiesis (aplastic anemia).
2. Increased adhesion to vessel endothelium (endotoxic shock)
3. Increased destruction (autoimmune neutropenia-- Felty's syndrome
in rheumatoid arthritis)
ii. Predisposes a patient to infection because the number of leukocytes is
insufficient to combat infection.
iii. Poor wound healing
E. Absolute lymphocytosis
i. Mechanisms:
1. Increased production (viral infections).
2. Increased release from LNs due to decreased adhesion in
efferent lymphatics (pertussis).
ii. Children normally have 60% lymphocytes in the total differential,
while adults normally have 60% neutrophils
F. Atypical lymphocytosis
i. Atypical lymphocytes are antigenically stimulated lymphocytes
resulting in nucleoli in the nucleus and abundant blue staining cytoplasm
from synthesis of proteins on ribosomes.
ii. Causes: infectious mononucleosis, mono syndromes (CMV.
toxoplasmosis), drug effect (phenytoin), viral hepatitis
G. Absolute lymphopenia
i. Mechanisms:
1. Decreased production (combined B and T immunodeficiency)
2. Increased destruction (SLE autoimmune destruction, AIDS)
3. Decreased release from nodes due to increased adhesion to
efferent lymphatics (corticosteroids).
H. Eosinophilia
i. Causes:
1. Type I hypersensitivity reactions: hay fever,, bronchial asthma.
2. Invasive helminthic infections (hookworm, Strongyloides, not
pinworms)
3. Hodgkin's disease
4. Addison's disease (increased cortisol destroys eosinophils, while
decreased cortisol results in eosinophilia)
5. Polyarteritis nodosa
I. Eosinopenia
1. Causes: corticosteroids, Cushing's

J.

Basophilia
1. Causes: CMPDs (PCV, CGL, etc.)
K. Monocytosis
i. Causes:
1. Chronic infection (TB)
2. Autoimmune disease (SLE, rheumatoid arthritis)
3. Malignancy
2. Benign Qualitative WBC disorders
A. The oxygen dependent myeloperoxidase system (MPO system) is the most
potent of all the bactericidal mechanisms (also discussed in inflammation
notes) -- see diagram.
i. Opsonized bacteria coated by IgG and C3b are easily phagocytized
by neutrophils and monocytes, which contain receptors for IgG and
C3b on their cell membrane.
ii. Bacteria are enclosed within a phagosome (vacuole in the cytoplasm)
iii. Lysosomes empty their enzymes (MPO and others) into the
phagosomes, which is now called a phagolysosome
iv. After phagocytosis has occurred, NADPH oxidase, located in the leukocyte
cell membrane, converts molecular oxygen from the surrounding
tissue into singlet oxygen, which is a free radical that generates the
energy referred to as the respiratory burst
v. Singlet oxygen Is converted Into hydrogen peroxide by superoxide
dismutase (SOD)
vi. In the presence of MPO, a lysosomal enzyme present within the
phagolysosome, peroxide plus chloride ions are converted into HOCI
(bleach), which ultimately destroys the bacteria.
vii. The excess peroxide is either neutralized by
viii. Catalase derived from peroxisomes in the cell or by glutathione
(GSH) in the HMS
B. Types of tests
i. Peroxidase stains of leukocytes are used to demonstrate whether
MPO is present in the leukocyte granules. MPO is in the primary, or
azurophilic granules commonly seen with regular Wright- Giemsa stained
peripheral smears.
ii. The respiratory burst mechanism in the oxygen dependent MPO
system is evaluated with the nitroblue tetrazolium (NBT) dye test
(colorless dye converted to colored dye in PMNs if system is working) or the
chemiluminescence assay (detects energy given off from free radical
formation).
C. Qualitative disorders
i. Primary or acquired MPO deficiencies are common (neonates) and
result in susceptibility to infections.
ii. Chediak Higashi syndrome is an autosomal recessive disease with a
primary defect in the polymerization of microtubules in leukocytes,
which interferes with their emigration through tissue in response to
chemotactic agents
1. In addition, the leukocytes contain giant lysosomes in their
cytoplasm that are unable to properly release their lysosomal
enzymes into the phagosomes, thus impairing bactericidal function as
well.
iii. Chronic granulomatous disease (CGD) is a sex- linked recessive
disease characterized by the absence of NADPH oxidase
1. The respiratory burst mechanism is impaired, so peroxide is
unavailable for the reaction with chloride ions to generate
HOCl

2. Patients are unable to utilize the oxygen-dependent MPO system

unless the bacterial pathogen supplies the peroxide during it's
own metabolism
3. Both the NBT and the chemiluminescence assays are negative,
indicating absence of the respiratory burst
4. Staphylococcus aureus is catalase-positive, so endogenouslyderived peroxide generated during its metabolism is quickly
destroyed by its own catalase, thus evading destruction within
the phagolysosome
5. Streptococci, however, are catalase-negative, when peroxide is
formed, the missing ingredient is now available to form HOCl,
and the organisms are destroyed.
iv. Acquired chemotactic problems are noted in newborns and leukemic
neutrophils, and diabetics
3. Benign White Blood Cell Disorders
A. Infectious mononucleosis (IM)
i. EBV infects B cells, since all B cells have EBV receptors.
1. Atypical lymphocytes in IM are T cells reacting against infected
B cells.
ii. Clinical
1. Exudative tonsillitis is common and is due to EBV and/or group
A streptococcus; petechia are commonly present on the soft
palate
2. Tender anterior and posterior cervical adenopathy
3. Anicteric hepatitis (jaundice is rare in IM) with tender
hepatomegaly
4. Splenomegaly (splenic rupture is rare unless the patient is involved in
contact sports or an accident).
5. Extreme malaise
6. Develop a rash within 24 hours of taking ampicillin (so do CMV
patients); it is not an allergic rash, so ampicillin can be given in the
future for another disease
7. CMV and toxoplasmosis also produce a mono- syndrome, but
there is no posterior cervical adenopathy or exudative
tonsillitis
iii. Laboratory:
1. Monospot (heterophile antibody) is positive; heterophile antibody
is an antibody against an antigen in a different species
2. Initial leukopenia followed by atypical lymphocytosis
3. If the heterophile test negative, order anti VCA. IgM (viral
capsid antigen), which is increased
4. Increased transaminases (hepatitis), increased ALP, but total
bilirubin normal (anicteric hepatitis)
5. Cold AIHA due to anti-I antibodies.
B. Myeloproliferative disorders: general comments
i. Myeloproliferative diseases are due to unregulated stem cell proliferation.
1. Polycythemia rubra vera (PRV) has an increase in RBCs, WBCs and
platelets
2. Chronic granulocytic leukemia has a primary increase in WBCs and
platelets to a lesser extent
3. Agnogenic myeloid metaplasia has an increase in marrow fibrosis
due to secretion of platelet, derived growth factor by megakaryocytes
4. Essential thrombocythemia has a primary increase in platelets and
WBCs to a lesser extent.
ii. They infrequently develop acute leukemia except for chronic
granulocytic leukemia

C. Myeloproliferative: Polycythemia rubra vera (PRV)

i. MC In females 40-50 years of age
ii. Clinical
1. Mnemonic: 4 H's
a. Hypervolemia due to an increased plasma volume; only
polycythemia with an increase in plasma volume
b. Hyperviscosity due to an increased RBC mass;
predisposes the patient to thrombotic episodes (AMI,
stroke), which are the MCC of death or bleeding episodes
from rupture of vessels and/or qualitative platelet
defects (do not: work properly)
c. Hyperuricemia due to increased breakdown of nucleated
cells with an increase in purine metabolism leading to
hyperuricemia
d. Histaminemia due to increased release of , histamine
from mast cells/basophils, which are increased in all
myeloproliferative diseases; increased histamine
produces vasodilatation, which contributes to the
plethoric face; also responsible for pruritus after warm
baths, which stimulates the release of histamine from
mast cells/basophils.
e. Splenomegaly (common in all myeloproliferative
diseases)
iii. Laboratory
1. Increased RBC mass and increased plasma volume (only
polycythemia with both increased)
2. Normal arterial oxygen saturation
3. Thrombocytosis
4. Neutrophilic leukocytosis with increased basophils
5. Increased LAP score (neutrophils stained for presence of alkaline
phosphatase; 100 cell count and scoring of intensity of stain;
summation individual scores = LAP score)
6. Increased serum B12 (WBCs carry B 12)
7. Packed marrow with panmyelosis (everything increased)
8. Iron deficiency present (low MCV) if phlebotomized or bleeding
9. Low EPO (increased RBC mass suppresses erythropoietin).
10.Hyperuricemia (increased purine metabolism).
iv. Treatment
1. Phlebotomy alone is the treatment of choice: reduces RBC mass and
make patient iron deficient, so less RBC production
2. Phlebotomy plus chemotherapy, or phlebotomy plus
radioactive P32 (danger of acute leukemia)
v. Differential with other causes of polycythemia
1. Polycythemia can be absolute (increased RBC mass) or relative
(normal ROC mass but decreased plasma volume;
hemoconcentrated)
2. Polycythemia can be appropriate (stimulus of hypoxemia) or
inappropriate (no hypoxemic stimulus; PRY and ectopic
erythropoietin syndromes)
3. First step in work-up of polycythemia is an arterial blood gas
to see if it is an appropriate or inappropriate polycythemia
4. RBC mass, plasma volume, and erythropoietin levels are also
useful in working up the polycythemias
5. Classification of polycythemia
a. Absolute polycythemia: Appropriate (Hypoxemia or tissue
hypoxia present; increased RBC mass; increased erythropoietin)

i. Chronic obstructive pulmonary disease

ii. High altitude resident
iii. Cyanotic congenital heart disease (right to left shunt)
b. Absolute polycythemia: Inappropriate (no hypoxia or hypoxemic
stimulus; increased RBC mass; low erythropoietin)
i. Polycythemia rubra vera
c. Absolute polycythemia: Inappropriate (no hypoxia or hypoxemic
stimulus; increased ROC mass; increased erythropoietin) .
i. Renal disorders (adenocarcinoma, cysts, Wilm's tumor)
ii. Endocrine disorders (Cushing's--cortisol stimulates
erythropoiesis)
iii. Miscellaneous (leiomyoma, cerebellar hemangioblastoma,
hepatocellular carcinoma)
d. Relative polycythemia (normal ROC mass; decreased plasma
volume; normal erythropoietin)
i. Dehydration :
ii. Stress polycythemia (obese, hypertensive males)
e. Summary chart (N = normal; SaO2 = oxygen saturation in
arterial blood gas)
Condition
RBC mass
Plasma volume
SaQ2
EPO
PRV

Hypoxemia (COPD)

Ectopic erythropoietin

N
N

Stress polycythemia
N

N
N
Dehydration
N

N
N
D. D. Myeloproliferative: Chronic granulocytic! myelogenous leukemia (CGL or
CML)
i. 1. 30% of all leukemias between 30-50 years old; male dominant
cancer.
ii. 2. causes: radiation, benzene
iii. 3. clinical:
1. a. in~ 3 years, progress into an acute blast crisis with
myeloblasts (majority) or lymphoblasts (20-30%---do marker
studies)
2. b. massive hepatosplenomegaly; infarcts common
3. c. soft tissue collections of leukemic cells called chloromas
iv. 4. laboratory
1. a. WBC counts 50,000 to 200,000 cells/L
2. b. peripheral blood with mature and immature WBCs
(myelocyte most abundant cell); increased basophils and
eosinophils; myeloblasts < 10% blasts; pseudo- Pelger Duet
cells
3. c. bone marrow: hypercellular fibrotic with < 10% blasts.
4. d. Ph chr positive (#22---95 % cases); t 9;22 translocation of cabl oncogene from 9 to 22 with fusion near the break cluster
region (bcr) of chr 22
5. e. positive bcr study In almost all cases
6. f. low leukocyte alkaline phosphatase score (LAP score; see
PRV discussion).
7. g. thrombocytosis (only leukemia with thrombocytosis).
8. h. anemia (marrow infiltration by leukemic cells).
v. 5. treatment: alkylating agents; Philadelphia chromosome is not lost with
treatment.
E. E. Myeloproliferative: Agnogenic myeloid metaplasia
i. 1. age: over 50 years old

ii. 2. primary stem cell disorder originating in the spleen with reactive
marrow fibrosis from megakaryocytes secreting platelet derived
growth factor, which stimulates marrow fibrosis
1. a. extramedullary hematopoiesis in spleen, liver and other
sites
iii. 3. clinical:
1. a. massive splenomegaly (extramedullary: hematopoiesis) with LUQ
pain due to Infarctions and size of spleen.
iv. 4. laboratory:
1. a. WBC count 10,000 to 50,000 cells/L.
2. b. leukoerythroblastic smear; tear drop RBCs (damaged when
getting out of fibrosed sinusoids); pseudo-Pelger Duet cells;
basophilia
3. c. thrombocytosis
4. d. bone marrow: fibrosed; numerous megakaryocytes; "dry
tap"--cannot aspirate marrow because it is fibrosed
5. e. LAP score increased
v. 5. no specific treatment; can progress to acute leukemia as terminal
event; usually die in 5 years.
F. F. Myeloproliferative: Essential thrombocythemia
i. 1. age: over 50 years old
ii. 2. clinical:
1. a. rule out other causes of thrombocytosis (iron deficiency,
malignancy, etc.).
2. b. commonly causes bleeding (patients do not function properly--qualitative defects), which leads to Iron deficiency
iii. 3. laboratory
1. a. platelet count> 600,000 cells/L
2. b. bone marrow with increased dysplastic megakaryocytes
3. c. absolute neutrophilic leukocytosis
iv. 4. treat with alkylating agents; compatible with long life.
G. G. Myelodysplastic syndrome (MDS)
i. 1 . stem cell disorder predominantly in the elderly (over 60) with an
increased risk for developing acute leukemia
ii. 2. laboratory:
1. a. chromosome abnormalities common: 50% have a 5q anomaly
2. b. dimorphic RBC population (microcytic and macrocytic);
siderocytes (iron in RBCs) in peripheral blood (sometimes
called Pappenheimer bodies--best visualized with Prussian
blue stain)
3. c. pancytopenia common
4. d. bone marrow commonly has ringed sideroblasts
(sideroblastic anemia) and increased myeloblasts
4. Malignant White Blood Cell Disorders: Leukemia
A. A. Leukemia: Overview
i. 1. leukemias are malignant neoplasms of hematopoietic stem cells
within the bone marrow which ultimately replace the marrow and spill
over into tile peripheral blood in the majority of cases
ii. 2. predisposing factors for leukemia include:
1. a. chromosomal abnormalities: trisomy 21 in Down's syndrome
2. b. RNA oncogenic viruses: HTLV-l in T cell leukemia
3. c. chromosomal instability syndromes (increased mutations):
ataxia telangiectasia, Bloom's syndrome
4. d. ionizing radiation: atomic bomb; acute leukemia is the MC
malignancy associated with irradiation
5. e. drugs/chemicals: benzene; alkylating agents

6. f. immunodeficiencies: Wiskott Aldrich syndrome; Bruton's

agammaglobulinemia
iii. 3. acute leukemias
1. a. characterized by the presence of blasts in the peripheral blood
and bone marrow (> 30%)
2. b. abrupt onset with progressive downhill course
3. c. block in the differentiation of leukemic stem cells with a
prolongation in the cell cycle and accumulation of leukemic
cells.
4. d. leukemic cells eventually crowd out other hematopoietic
cells, thus creating anemia and thrombocytopenia
5. e. more common than chronic leukemia
iv. 4. chronic leukemias
1. a. mixture of mature and immature cells (small number of blasts) in
the peripheral blood and bone marrow (< 30% blasts)
2. b. insidious onset and a relatively indolent clinical course
v. 5. variants of leukemia are lymphocytic and myelogenous
1. a. frequency of leukemia related to age brackets is as follows:
2. children: acute lymphoblastic leukemia
3. 15 to 39: acute myelogenous leukemia
4. 40 to 59: acute myelogenous leukemia
5. and chronic myelogenous leukemia;
6. 60+: chronic lymphocytic leukemia:
vi. 6. clinical findings associated with leukemia
1. a. cytopenias: infection, bleeding, fatigue
2. b. hepatosplenomegaly and lymphadenopathy (leukemic
infiltration)
3. c. DIC
vii. 7. laboratory features of leukemia include:
1. a. WBC count is less than 10,000 cells/L in 50 % (aleukemic
leukemia) or greater than 100,000 cells/L in 20 %.
2. b. normocytic normochromic anemia
3. c. thrombocytopenia
4. d. bone marrow: usually hypercellular in acute and chronic
leukemias
5. e. peroxidase, Sudan black B, and specific esterase stains are
positive in acute myelogenous leukemia
6. f. non-specific esterase stains not Inhibited by fluoride are
markers for monocytic leukemias
7. g. the PAS stain reveals blocks of PAS + material in the
cytoplasm of lymphoblasts
8. h. the neoplastic B cells of hairy cell leukemia are positive for
tartrate resistant acid phosphatase (TRAP)
9. i. immunophenotyping is useful in identifying n and T cell
lineage in acute and chronic lymphocytic leukemias
viii. 8. if left untreated, leukemia is ultimately fatal due to:
1. a. thrombocytopenia and/or qualitative platelet defects leading
to hemorrhage (e.g. CNS bleed)
2. b. leukocyte dysfunction leading to infection
B. B. Acute lymphocytic leukemia (ALL)
i. 1. MC leukemia and overall type of cancer in children (usually < 15
years old)
ii. 2. classification:
1. Common ALL (60%; CAI.JI.JA positive; MC)
2. CALLA negative
3. Pre B ALL

4. B ALL (worst prognosis)

5. T ALL (intermediate prognosis; mediastinal involvement)
iii. 3. clinical:
1. a. fever without infection
2. b. bone pain and tenderness over bones
3. c. hepatosplenomegaly (leukemic Infiltration)
4. d. generalized lymphadenopathy (leukemic Infiltration)
5. e. ecchymoses (thrombocytopenia)
6. f. CNS or testicular Involvement (leukemic infiltration).
iv. 4. laboratory
1. a. anemia, thrombocytopenia, absolute neutropenia
2. b. normal to elevated lymphocyte count with Lymphoblasts in
peripheral blood
3. c. bone marrow packed with Lymphoblasts
4. d. lymphocyte markers: CALLA positive (common ALL antigen)
is the MC variant; majority are B cell origin
v. 5. treatment:
1. a. remission-induction therapy, followed by consolidation
therapy, followed by maintenance therapy.
2. b. relapses MC occur in the bone marrow but are also common
in the CNS (reason for intrathecal methotrexate or irradiation
of neuraxis) and testes (MC extramedullary site)
vi. 6. prognosis:
1. a. children < 2 years old or> 10 years have worst prognosis
2. b. 60% overall 5 year survival
C. C. Chronic lymphocytic leukemia
i. 1. MC leukemia in patients over 60; B cell leukemia
ii. 2. clinical
1. a. generalized lymphadenopathy
2. b. hepatosplenomegaly.
3. c. increased incidence of AIHA and thrombocytopenia,
hypogammaglobulinemia (infection), and second malignancies.
iii. 3. laboratory
1. a. anemia (50%), thrombocytopenia, neutropenia.
2. b. absolute Lymphocytosis (15,000-200,000 cells/L) with
smudge cells (fragile lymphocytes); cells look mature; almost
100% of cells are lymphocytes In a 100 cell count
3. c. bone marrow: packed with lymphocytes
4. d. 50% die of infection; median survival 4-6 years; blast crisis
is rare.
D. D. Adult T cell leukemia
i. 1. associated with HTLV-l retrovirus; MC in Japan; sporadic in USA;
majority are men
ii. 2. clinical
1. a. lymphadenopathy and hepatosplenomegaly
iii. 3. laboratory
1. a. malignant T cells in peripheral blood, nodes and marrow
2. b. hypercalcemia is characteristic (not a feature of other
leukemias): lymphoblasts secrete osteoclast activating factor; lytic
areas in bone
iv. 4. poor prognosis
E. E. Hairy cell leukemia
i. 1. chronic progressive B cell malignancy MC seen In middle-aged
men
ii. 2. clinical
1. a. splenomegaly common

2. b. autoimmune syndromes (vasculitis, arthritis)

3. c. lytic bone lesions
4. d. increased incidence Mycobacterium avium intracellulare
iii. 3. laboratory
1. a. pancytopenia.
2. b. immature cells with hairy projections.
3. c. bone marrow: always packed.
4. d. positive tartrate resistant acid phosphatase stain (TRAP)
iv. 4. treatment:
1. a. splenectomy is mainstay of treatment (favorite site of
malignant cell proliferation in red pulp, an unusual site for
leukemias)
2. 5. prognosis: 50% 5 year survival.
F. F. Acute non-lymphocytic leukemias
i. 1 . general comments
1. a. MC leukemia 15-39 years; tied with CGL for 40-59 age bracket
2. b. FAB (French-American-British) classification (M1 through M7)
ii. 2. acute granulocytic leukemia (M1 and M2):
1. a. auer rods present In M2 (MC overall type)
iii. 3. acute progranulocytic leukemia (M3)
1. a. auer rods present
2. b. high association with DIC
3. c. hypergranular and hypogranular types
iv. 4. acute myelomonocytic leukemia (M4)
1. a. positive non-specific esterase stain
v. 5. acute monocytic leukemia (M5)
1. a. positive non-specific esterase stain
2. b. gum infiltration
vi. 6. Diguglielmo's (M6)
1. a. bizarre PAS positive erythroblasts (erythroblasts are
normally negative for PAS)
2. b. increased myeloblasts
vii. 7. acute megakaryocytic leukemia (M7)
viii. 8. overall long term survival 0-15%