CH6 - White Blood Cell Disorders Flashcards
What does hematopoetic CD34+ stem cells produce?
Both
Myeloid Stem Cells
and
Lymphoid Stem Cells
What do myeloid stem cells produce?
Erythroblast
Myeloblast
Monoblast
Megakaryoblast
What does erythroblast produce?
RBCs
What does myeloblast produce?
Neutrophils
Basophils
Eosinophils
What does monoblast produce?
Monocytes
What does megakaryoblast produce?
Megakaryocytes->
Platelets
What does lymphoid stem cells produce?
B lymphoblast
and
T Lymphoblast
What does B lymphoblast produce?
Naïve Bcells
What do Naïve B cells produce?
Plasma cells
What does T lymphoblast produce?
Naïve Tcells
What does Naïve T cells produce?
CD8+
and
CD4+
T cells
How does hematopoiesis occur?
via
stepwise differentiation
of
CD34+ HSCs
in Bone Marrow
What happens to hematopoetic stem cells?
Cells mature and are released from the bone marrow into blood
What is the normal white blood cell (WBC) count?
it is approximately 5-10 K/mL³
What is a low WBC count? What is it called?
< 5 K
called
Leukopenia
What is a high WBC count? What is it called?
> 10 K
called
leukocytosis
What is a low or high WBC count usually due to?
↓ or ↑
in
ONE
particular cell lineage
What is neutropenia?
↓ circulating neutrophils
What are some of the causes of neutropenia?
1) Drug toxicity
(chemo drugs interfere with rapidly dividing cells like Neutrophils)
2) severe infection ->
Neutrophils go to tissue site of infection
How can drug toxicity lead to neutropenia?
e.g., chemotherapy with alkylating agents, interfere with rapidly dividing tumor cells
BUT ALSO
Hematopoietic progenitor cells in bone marrow ->
↓ production of WBCs, especially neutrophils = b/c they are the most abundant
Chemo patients are commonly Neutropenic
so treat ith GM-CSF/G-CSF
How does severe infection lead to neutropenia?
e.g., gram-negative sepsis leads to increased movement of neutrophils into tissues resulting in decreased circulating neutrophils.
What is GM-CSF or G-CSF?
granulocyte monocyte stimulating factor
and
granulocyte stimulating factor
used to boost neutrophil count -> ↓ the risk of infection
What is lymphopenia?
Low number of circulating lymphocytes (B & T cells)
What are the some of the causes of lymphopenia?
1) Immunodeficiency
2) High Cortisol state
3) Aautoimmune destruction
4) Whole body Radiation
What are some examples of immunodeficiency that lead to lymphopenia?
DiGeorge syndrome (Failure to form 3rd and 4th Pharyngeal pouch)-> No Thymus -> T cells don’t develop properly
or
HIV -> Destruction of CD4 TH cells
How does a High Cortisol state lead to lymphopenia?
induce apoptosis in lymphocytes
Exogenous corticosteroids or Cushing syndrome
What is an example of autoimmune destruction leading to lymphopenia?
SLE (Systemic lupus erythematosus) -> Can produce Ab’s against any blood cell line
How can whole body radiation lead to lymphopenia?
Lymphocytes are most sensitive cell to radiation
lymphopenia is the earliest change to emerge after whole body radiation
What are the different types of leukocytosis?
1) neutrophilic leukocytosis
2) monocytosis
3) Eosinophilia
4) Basophilia
5) Lymphocytic leukocytosis
What does neutrophilic leukocytosis refer to?
High number of circulating neutrophils
What are the causes of neutrophilic leukocytosis?
2 Primary Forces driving Acute Inflammation
1) Bacterial infection
2) tissue necrosis
+
3) High cortisol state
How does Bacterial infection or tissue necrosis lead to neutrophilic leukocytosis?
Induces bone marrow to produce and release as many granulocytes/neutrophils as possible, including immature forms (left shift = ↓ Fc Receptors (CD16) -> decreased ability to bind Abs that have opsonized bacteria)
+
release marginated pool
(also happens with cortisol surge)
When immature neutrophils are released into the blood, how are they characterized?
by decreased Fc receptors (CD16)
What is the marker for the decreased Fc receptor?
CD16
Why are Fc receptors important?
They help the neutrophil to recognize immunoglobulin which is going to act as an opsonin for phagocytosis
How does high cortisol state lead to neutrophilic leukocytosis?
impairs leukocyte adhesion ->
release of marginated pool of neutrophils
What does monocytosis refer to?
increased circulating monocytes
What are the causes of monocytosis?
Chronic Inflammatory states
(e.g., autoimmune and infections)
and
Malignancy
What does eosinophilia refer to?
increased circulating eosinophils
What are the causes of eosinophilia?
1) allergic reactions (type I hypersensitivity)
2) parasitic infections
and
3) Hodgkin lymphoma (due to ↑ IL-5)
What is eosinophilia driven by?
↑ eosinophil chemotactic factor (IL-5)
What does basophilia refer to?
↑ circulating basophils
What is basophilia classically seen in?
CML (Chronic Myeloid Leukemia)
What does lymphocytic leukocytosis refer to?
↑ circulating lymphocytes
What are the causes of lymphocytic leukocytosis?
1) Viral infection
2) Bordetella pertussis
How does viral infections lead to lymphocytic leukocytosis?
b/c CD8+ T Cells handle viral infections and are called to the site of infection
How does Bordetella pertussis infection lead to lymphocytic leukocytosis?
This bacteria is an exception b/c it
produces Lymphocytosis-Promoting Factor->
blocks circulating lymphocytes from leaving the blood to enter the lymph node
Normally, lymphocytes made in BM-> blood-> enter lymph node to make Ab’s or to be stimulated to fight infection.
If they can’t enter lymph node, they are stuck in blood
What is infectious mononucleosis?
most commonly due to
EBV infection -> lymphocytic leukocytosis comprised of reactive CD8+ T cells (normal response to viral infection)
CMV is less common cause
How is EBV transmitted?
by saliva (kissing disease)
classically affects teenagers
What does EBV primarily infect?
- Oropharynx-> pharyngitis
- Liver-> hepatitis with hepatomegaly and elevated liver enzymes
- B cells
CD8+ T-cell response to EBV infection leads to what?
1) Generalized LAD (Lymphadenopathy) because of CD8+ Tcells hyperplasia/expansion in the paracortex of lymph nodes
2) Splenomegaly because Tcells in PALS (Periarterial lymphatic sheath) of white pulp undergo hyperplasia/expansion
3) High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood
How does the CD8+ T cell response lead to generalized lymphadenopathy (LAD)?
It is due to T-cell hyperplasia in the lymph node paracortex
How does CD8+ T cell response lead to splenomegaly?
It is due to T-cell hyperplasia in the periarterial lymphatic sheath (PALS) of the Spleen’s white pulp
What are the major components of the spleen?
Red pulp (blood) - looks red
and
White pulp (Lymphocytes) - looks blue
Tcells grow and expand around Arteries of white pulp
(called PALS - (periarterial lymphatic sheaths)
What are the Atypical Lymphocytes in Mononucleosis?
They are just reactive CD8+ Tcells
which have a massive nucleus (much bigger than normal = size of RBC)
Abundant blue cytoplasm (more than normal)
Originally were thought to be monocytes-> hence the name mononucelosis
What is used for screening of IM?
The monospot test
What does the monospot test do?
Detects IgM antibodies that cross-react with horse or sheep red blood cells (heterophile antibodies)
hetero = other (animals RBCs)
Phile - like (these IgM Ab’s react against them)
When would the monospot test turn positive?
Usually turns positive within 1 week after infection
What would a negative monospot test suggest?
CMV as a possible cause of Infectious Mononucleosis
How is a definitive diagnosis for Infectious Mononucleosis made?
serologic testing for the EBV viral capsid antigen
What are the complications of EBV?
1) increased risk for splenic rupture b/c splenomegaly can cause the capsule of spleen to rupture (advise avoiding contact sports for 1 year)
2) Rash if exposed to Penicillin
3) Dormancy of virus in the B cells it attacks->
recurrence of infectious mononucleosis and potentially developing B cell lymphoma (especially if immunodeficiency develops e.g. HIV)
What are patients told who have an increased risk for splenic rupture?
patients are generally advised to avoid contact sports for one year.
When might a rash develop as a complication of EBV?
if exposed to ampicillin
With EBV complications, why is there a risk of recurrence and B cell lymphoma?
Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops.
What is acute leukemia?
Neoplastic proliferation of blasts
Accumulation of >20% blasts in BM
(Normal: 1-2%)
What is the acute presentation for acute leukemia?
Anemia (fatigue)
Thrombocytopenia (bleeding)
Neutropenia (infection)
What is the reason for the acute presentation of acute leukemia?
Increased blasts crowd-out normal hematopoiesis
In acute leukemia, why is there a high WBC count?
Neoplastic blasts enter bloodstream ->
High WBC count
Describe blasts
Large - bigger than RBC’s
Immature cells: Very little cytoplasm
often Punched out nucleoli
What is acute leukemia subdivided into?
Acute Lymphoblastic Leukemia (ALL)
or
Acute Myelogenous Leukemia (AML)
The subdivision of acute leukemia is based on what?
phenotype of the blasts (Markers)
b/c histology inconclusive
What is acute lymphoblastic leukemia?
Neoplastic accumulation of lymphoblasts (> 20%) in BM
Why is TdT useful in characterizing lymphoblasts?
B/c TdT is a DNA polymerase
EXPRESSED in the Nucleus of Lymphoblasts
and
ABSENT in myeloid blasts and mature lymphocytes
TdT is a DNA Polymerase that adds N-nucleotides to the V, D, and J exons of the TCR and BCR genes during antibody gene recombination, enabling the phenomenon of junctional diversity
Why is MPO useful in characterizing lymphoblasts?
How is it detected?
Myeloperoxidase is only expressed in Myeloblasts
Detected by:
1) Chemical study to determine MPO is in cell cytoplasm
2) view AUER RODS under microscope b/c MPO can crystalize inside of cells in the form of Auer rods
AML (Acute Myeloid Leukemia)
*It is an enzyme that produces hypochlorous acid (HOCl) bleach from hydrogen peroxide (H2O2) and chloride anion (Cl−) during neutrophil’s respiratory burst
Neutrophil verdoperoxidase has green heme pigment giving secretions rich in neutrophils, such as pus and some forms of mucus a greenish color
Acute lymphoblastic leukemia most commonly arises in whom?
children
What syndrome is associated with ALL?
At what age does ALL arise?
Down syndrome
(usually after 5 y.o.)
Acute lymphoblastic leukemia is subclassified into?
What is basis of classification?
B-ALL
and
T-ALL
based on surface markers
*B/c Lymphoblast differentiates into
1) B-Lymphoblast -> B-cell
and
2) T-Lymphoblast -> T-cell
so neoplastic proliferation of either one -> ALL
both express TdT in nucleus but their surface markers will be different
What is the most common type of ALL?
B-ALL
What is B-ALL usually characterized by?
lymphoblasts (TdT+) that express
CD10
CD19
CD20
What is the treatment for B-ALL?
Excellent response to chemotherapy
requires prophylaxis (i.e. direct injection) into scrotum and CSF
b/c chemo can’t cross BBB or Blood Testicle Barrier
What is the prognosis B-ALL
and how is it determined?
Generally good
based on cytogenetic abnormalities
Which B-ALL has a good prognosis and is more commonly seen in children?
t(12;21)
Most common, and commonly seen in kids
Which B-ALL has a poor prognosis and in what population is it seen?
t(9;22)
Philadelphia chromosome (Ph+ ALL)
poor prognosis; more commonly seen in adults
This translocation is much more common with CML but B-ALL also possible
What is T-ALL characterized by?
lymphoblasts (TdT+) that express markers from
CD2 - CD8
Blasts do not express CD10
How does T-ALL usually present?
T is the menmonic
mediastinal (Thymic) mass
Usually in Teenagers
called Acute Lymphoblastic Lymphoma because the malignant cells form a mass
and not just lymphoblasts floating in blood
What is acute myeloid leukemia?
Neoplastic accumulation of myeloblasts (> 20%) in BM
How are myeloblasts usually characterized?
by positive cytoplasmic staining for myeloperoxidase (MPO)
via
1) Chemical stain
or
2) visually see as Auer Rods
So Auer Rods in blasts = AML
What may be seen in the characterization of myeloblasts?
Crystal aggregates of MPO = Auer rods
In whom does acute myeloid leukemia most commonly arise?
older adults (average age is 50-60 years)
What is the subclassification of AML based on?
From highest to lowest priority
1) Cytogenetic abnormalities
2) Lineage of myeloblasts
3) Surface markers
What are the high-yield subtypes?
Acute Promyelocytic Leukemia
Acute Monocytic Leukemia
Acute Megakaryoblastic Leukemia
What is acute promyelocytic leukemia characterized by?
t(15;17)
Translocation of the retinoic acid receptor (RAR) on chromosome 17 to chromosome 15
What is the effect of RAR disruption in Acute Promyelocytic Anemia?
Disruption of RAR disrupts ability of Promyelocytes to mature ->
Accumulation of Promyelocytes (blasts) accumulate
How does acute promyelocytic leukemia lead to ↑ risk for DIC?
The accumulating promyelocytes contain many Auer rods ->
which can activate coag cascade ->
↑ risk of DIC
BECAUSE of DIC,
Acute Promyelocytic Anemia
is a MEDICAL EMERGENCY
What is the treatment for acute promyelocytic leukemia?
with all-trans retinoic acid (ATRA, a vitamin A derivative)
How does ATRA work?
It binds the altered receptor and causes the promyeolcytes (blasts) to mature (and eventually die)
What is acute monocytic leukemia?
Proliferation of monoblasts;
usually lack MPO
b/c Monoblasts are typically MPO-negative and promonocytes are MPO variable . MPO is expressed later in differentiation into Macrophage
* has no distinctive cytogenetic abnormality, so classification based on lineage (monoblast)
In acute monocytic leukemia what do blasts characteristically do?
infiltrate gums
What is acute megakaryoblastic leukemia?
Proliferation of megakaryoblasts;
lack MPO, because platelets obviously not involved in oxygen-dependent killing
What is acute megakaryoblastic leukemia associated with?
Down syndrome
usually arises before the age of 5
by contrast Down syndrome associated with ALL
AFTER age of 5
How else can Acute Myeloid Leukemia arise?
From pre-existing dysplasia = myelodysplastic syndromes
especially with prior exposure to alkylating agents or radiotherapy
What do myelodysplastic syndromes usually present with?
cytopenias b/c the blasts are dysplastic they have abnormal maturation
and
therefore get stuck in bone marrow = hypercellular bone marrow
BM Biopsy will show increased blasts < 20%. If number were to increase to >20% it would then be classified as Acute Myeloid Leukemia NOT Dysplastic syndrome
With myelodysplastic syndromes resulting in acute myeloid dysplastic syndrome what do most patients die from?
Most patients die from infection or bleeding because of cytopenias, though some progress to acute myeloid leukemia.
What is chronic leukemia?
Neoplastic proliferation of
MATURE circulating lymphocytes
(B-cells or T-cells)
What is chronic leukemia characterized by?
High WBC count
Describe the onset of chronic leukemia?
Insidious onset
Often Asymptomatic
Can live a long time with this disease
Usually seen in older adults
What is chronic lymphocytic leukemia?
Neoplastic proliferation of naive B cells
Co-express
CD5
(abnormally expressed; normally on T-cells)
and
CD20
What is the prototypic/classic Chronic Leukemia?
CLL
Chronic Lymphocytic Leukemia
It is a proliferation of Naive Bcells that just left BM
Co-express CD5 (normally expressed on T-cell) and CD20
What is the most common leukemia overall?
Chronic lymphocytic leukemia (CLL)
NOT SURE THIS IS TRUE
In CLL what is seen on the blood smear?
↑ lymphocytes
and
↑ smudge cells (big cells that look like someone smashed a normal lymphocyte with their finger)
Small Lymphocytic Lymphoma
When Chronic Lymphocytic Leukemia (CLL) spreads to lymph nodes-> generalized lymphadenopathy
Because now a mass in the lymph node, Called Lymphoma NOT Leukemia
What are the complications of CLL?
1) Hypogammaglobulinemia - these neoplastic Bcells never develop into Ig producing Plasma Cells. As they take over as the dominant Bcell, normal infection response with maturation to Ig producing Plasma cell happens less and less -> death from infection
2) autoimmune hemolytic anemia b/c if these neoplastic B-cells actually make Ig, it is not against an infectious agent, but against patient’s own RBC’s
3) Richter transformation - Transformation from small lymphocytic lymphoma to diffuse large B-cell Lymphoma
What is the most common of death in CLL?
infection
What is Richter transformation?
transformation of small lymphocytic lymphoma ->
diffuse large B-cell lymphoma
b/c
one of the neoplastic B-cells of CLL (now residing in a lymph node or spleen) acquires more mutations, transforming into a rapidly growing aggressive tumor->
instead of just general lymphadenopathy patient presents with a single
enlarging lymph node or spleen as aggressive neoplastic cell proliferates at unprecedented rate