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White Blood Cell Disorders

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LEUKOPENIA AND LEUKOCYTOSIS
1. BASIC PRINCIPLES
A. Hematopoiesis occurs via a stepwise maturation ofCD34+ hematopoietic stem cells
(Fig. 6.1).
B. Cells mature and are released from the bone marrow into the blood.
C. A normal white blood cell (WBC) count is approximately 5-10 K/~tL.
1. A low WBC count(< 5 K) is called leukopenia.
2. A high WBC count (> 10 K) is called leukocytosis.
3. A low or high WBC count is usually due to a decrease or increase in one
particular cell lineage.

II. LEUKOPENIA
A. Neutropenia refers to a decreased number of circulating neutrophils. Causes include
1. Drug toxicity (e.g., chemotherapy with alkylating agents)-Damage to stem cells
results in decreased production ofWBCs, especially neutrophils.
2. Severe infection (e.g., gram-negative sepsis)- Increased movement of neutrophils
into tissues results in decreased circulating neutrophils.
3. GM-CSF or G-CSF may be used pharmacologically to boost granulocyte
production, thereby decreasing risk of infection.
B. Lymphopenia refers to a decreased number of circulating lymphocytes. Causes
include
1. Immunodeficiency (e.g., DiGeorge syndrome or HIV)
2. High cortisol state (e.g., exogenous corticosteroids or Cushing syndrome)-
induces apoptosis of lymphocytes
3. Autoimmune destruction (e.g., systemic lupus erythematosus)
4. Whole body radiation-Lymphocytes are highly sensitive to radiation;
lymphopenia is the earliest change to emerge after whole body radiation.

III. LEUKOCYTOSIS
A. Neutrophilic leukocytosis refers to increased circulating neutrophils. Causes include
1. Bacterial infection or tissue necrosis- induces release of marginated pool and
bone marrow neutrophils, including immature forms (left shift); immature cells
are characterized by decreased Fe receptors (CD16).

2. High cortisol state-impairs leukocyte adhesion, leading to release of
marginated pool of neutrophils
B. Monocytosis refers to increased circulating monocytes. Causes include chronic
inflammatory states (e.g., autoimmune and infectious) and malignancy.
C. Eosinophilia refers to increased circulating eosinophils. Causes include allergic
reactions (type I hypersensitivity), parasitic infections, and Hodgkin lymphoma.
Eosinophilia is driven by increased eosinophil chemotactic factor.
0. Basophilia refers to increased circulating basophils; classically seen in chronic
myeloid leukemia
E. Lymphocytic leukocytosis refers to increased circulating lymphocytes. Causes
include
1. Viral infections- I lymphocytes undergo hyperplasia in response to virally
infected cells.
2. Bordetella pertussis infection-Bacteria produce lymphocytosis-promoting
fac tor, which blocks circulating lymphocytes from leaving the blood to enter the
lymph node.

IV. INFECTIOUS MONONUCLEOSIS (IM)
A. EBV infection that results in a lymphocytic leukocytosis comprised of reactive CDs+
T cells; CMV is a less common cause.
l. EBV is transmitted by saliva (“kissing disease”); classically affects teenagers
B. EBV primarily infects
1. Oropharynx, resulting in pharyngitis
2. Liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes
3. B cells
C. Cos+ T-cell response leads to
l. Generalized lymphadenopathy (LA D) due to T-cell hyperplasia in the lymph
node paracortex
2. Splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath
(PALS)
3. High WBC count with atypical lymphocytes (reactive c os+ T cells) in the blood
(Fig. 6.2)
D. The monospot test is used for screening.
1. Detects IgM antibodies that cross-react with horse or sheep red blood cells
(heterophile antibodies)
2. Usually turns positive within 1 week after infection
3. A negative monospot test suggests CMV as a possible cause of IM.
4. Definitive diagnosis is made by serologic testing for the EBV viral capsid
antigen.

E. Complications
l. Increased risk for splenic rupture (Fig. 6.3); patients are generally advised to
avoid contact sports for one year.
2. Rash if exposed to ampicillin
3. Dormancy of virus in B cells leads to increased risk for both recurrence and
B-celllymphoma, especially if immunodeficiency (e.g., HIV) develops.

ACUTE LEUKEMIA
I. BASIC PRINCIPLES
A. Neoplastic proliferation of blasts; defined as the accumulation of> 20% blasts in the
bone marrow.
B. Increased blasts “crowd-out” normal hematopoiesis, resulting in an “acute”
presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropen ia
(i nfection).
C. Blasts usually enter the blood stream, resulting in a high W BC count.
1. Blasts are large, immature cells, often with punched out nucleoli (Fig. 6.4).
D. Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute
myelogenous leukemia (AML) based on the phenotype of the blasts.

II. ACUTE LYMPHOBLASTIC LEUKEMIA
A. Neoplastic accumulation oflymphoblasts (> 20%) in the bone marrow
1. Lymphoblasts are characterized by positive nuclear staining for TdT, a DNA
polymerase.
2. TdT is absent in myeloid blasts and mature lymphocytes.
B. Most commonly arises in children; associated with Down syndrome (usually arises
after the age of 5 years)
C. Subclassified into B-ALL and T-ALL based on surface markers
D. B-ALL is the most common type of ALL.
1. Usually characterized by lymphoblasts (TdT+) that express CDlO, CD19, and
CD20.
2. Excellent response to chemotherapy; requires prophylaxis to scrotum and CSF
(Fig. 6.5)
3. Prognosis is based on cytogenetic abnormalities.
i. t(l2;21) has a good prognosis; more commonly seen in children
ii. t(9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+
ALL)
E. T-ALL is characterized by lymphoblasts (TdT+) that express markers ranging from
CD2 to CDS (e.g., CD3, CD4, CD7). The blasts do not express COlO.

1. Usually presents in teenagers as a mediastinal (thymic) mass (called acute
lymphoblastic lymphoma because the malignant cells form a mass)

III. ACUTE MYELOID LEUKEMIA
A. Neoplastic accumulation of myeloblasts (> 20%) in the bone marrow
B. Myeloblasts are usually characterized by positive cytoplasmic staining for
myeloperoxidase (MPO).
1. Crystal aggregates of MPO may be seen as Auer rods (Fig. 6.6).
C. Most commonly arises in older adults (average age is 50-60 years)
D. Subclassified based on cytogenetic abnormalities, lineage of myeloblasts, and surface
markers. High-yield subtypes include
l. Acute promyelocytic leukemia (APL)
i. Characterized by t(l5;17), which involves translocation of the retinoic acid
receptor (RAR) on chromosome 17 to chromosome 15; RAR disruption
blocks maturation and promyelocytes (blasts) accumulate.
ii. Abnormal promyelocytes contain numerous primary granules that increase
the risk for DIC.
iii. Treatment is with all-trans-retinoic acid (ATRA, a vitamin A derivative),
which binds the altered receptor and causes the blasts to mature (and
eventually die).
2. Acute monocytic leukemia
i. Proliferation of monoblasts; usually lack MPO
ii. Blasts characteristically infiltrate gums (Fig. 6.7).
3. Acute megakaryoblastic leukemia
i. Proliferation of megakaryoblasts; lack MPO
ii. Associated with Down syndrome (usually arises before the age of 5)
E. AML may also arise from pre-existing dysplasia (myelodysplastic syndromes),
especially with prior exposure to alkylati ng agents or radiotherapy.
1. Myelodysplastic syndromes usually present with cytopen ias, hypercellular bone
marrow, abnormal maturation of cells, and increased blasts(< 20%).
2. Most patients die from infection or bleeding, though some progress to acute
leukemia.

CHRONIC LEUKEMIA
I. BASIC PRINCIPLES
A. Neoplastic proliferation of mature circulaling lymphocytes; characterized by a high
WBCcount
B. Usually insidious in onset and seen in older adults

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