(F) L3.1 Non-malignnt WBC disorders Flashcards
causes of non-malignant WBC disorders
genetic or acquired
causes: Infection, trauma, injury, or inflammatory
responses.
● Types of Anomalies:
○ Quantitative
■ Absolute increase or decrease in
specific white blood cells in response to
stress or infection.
■ Disorder on the number of circulating cells
○ Qualitative
■ Morphological changes in white blood
cells during infections
■ Changes in the normal morphology of
circulating cells
❖ Normal morphology but abnormal
function
● These abnormalities are typically reversible once the
stressful event subsides.
STRESS/REACTIVE DISORDER
Causes: Genetic mutations leading to abnormal
appearance of white blood cells.
● Types of Changes:
○ Quantitative: Changes in the number of
leukocytes.
○ Functional: Changes in the function of
leukocytes.
○ Morphologic: Structural changes in leukocytes.
● Reversibility: These abnormalities are non-reversible.
● Severity: The severity can range from mild to severe.
GENETIC DISORDERS
types of WBC disorders
a. neutrophil
b. monocytes / macrophages
c. eosinophils
d. basophils
e. lymphocytes
f. leukopenia
- Increase during acute bacterial infections
- Increase during chronic
infections. - Decrease in WBC count.
- Increase during viral infections to help achieve lifetime immunity
- Increase during parasitic infections or larval invasions.
- Increase in certain immune responses and
allergic reactions
- A
- B
- F
4.E - C
- D
Increase in neutrophils above 7.0 × 109
/L in adults and
8.5 × 109
/L in children
● Normal Relative Count: Approximately 50% to 70%
NEUTROPHILIA
By adding the number of segmented and band neutrophils (may include metamyelocytes and
myelocytes).
Used to evaluate neutrophelia
ANC Calculation
If there is neutrophilia, there is always
a shift to the (left/right)
left
leukemoid reaction
a. parasitic infection
b. treponemal infection
a
neutropenia
associations of leukemoid reaction
infections
medications
other conditions (intoxications, hemorrhage, hemolysis, and splenectomy)
Metabolic disease and inflammation
neutropenia
what is the indicator of leukemoid reactions
toxic vacuoles in neutrophils
neutropenia
Presence of immature neutrophils nucleated red blood
cells (RBCs), and teardrop RBCs in a peripheral blood
smear.
INDICATORS
● Immature Neutrophils and Nucleated RBCs: Key
features of LER.
● Teardrop RBCs: Suggest extramedullary
hematopoiesis and myelofibrosis, especially primary
myelofibrosis.
● Neutrophilia: Often accompanies LER.
ASSOCIATIONS
● Cancers: Space-occupying metastasis, lymphoma,
leukemia, and primary myelofibrosis.
● Other Conditions: Hemolytic disorders, infections,
hemorrhage, and other conditions.
BONE MARROW INVOLVEMENT
● Space-Occupying Lesions: Metastatic tumors,
fibrosis, lymphoma, leukemia, or a marked increase in
one of the normal marrow cells.
LEUKOERYTHROBLASTIC REACTION
a. neutropenia
b. severe neutropenia
c. agranulocytosis
Decrease in the Absolute Neutrophil Count (ANC) to
less than 1.5 × 109
/L
Neutrophil count less than 0.1 ×
109
/L.
ANC less than 0.5 × 109
/L,
significantly increasing the risk of opportunistic
infections.
ACB
CAUSES OF NEUTROPENIA
- (increased / decreased) rate of removal / destruction
- (increased/decreased) production / ineffective hematopoiesis
- circulating vs marginal pool ratio
- Combination of above factors
increased
decreased
neutropenia
Caused by antibody binding to neutrophil antigens
IMMUNE-MEDIATED NEUTROPENIA
neutropenia
Cause: Maternal IgG crosses the placenta and binds to
neutrophil-specific antigens inherited from the father
(e.g., FcgRIIIb, NB1, HLA).
● Incidence: Approximately 1 in 2000 births.
● Neutrophil Count: Increases or returns to normal after
a few months as maternal antibodies decline and
disappear from the baby’s circulation.
ALLOIMMUNE NEONATAL NEUTROPENIA
neutropenia
Primarily Affects: Children.
● Cause: Development of antibodies to HNA-1.
● Severity: Moderate to severe neutropenia.
● Nature: Self-limiting
AUTOIMMUNE NEUTROPENIA
neutropenia
Associated Conditions: Autoimmune disorders such
as rheumatoid arthritis (RA), Felty syndrome, systemic
lupus erythematosus (SLE), and Sjogren syndrome.
● Other Factors: Immune complex deposition,
granulopoiesis-inhibiting cytokines, and splenomegaly
can also induce neutropenia.
SECONDARY AUTOIMMUNE NEUTROPENIA
neutropenia
● Nature: Most often an acquired condition.
● Causes: Numerous, including drug-induced
neutropenia and neonatal alloimmune neutropenia.
ACQUIRED NEUTROPENIA
neutropenia
Source: Most cases of acquired neutropenia.
● Mechanism: Due to myeloid suppression or
immunologic response.
DRUG-INDUCED NEUTROPENIA
neutropenia
2 types of acquired neutropenia
drug induced
neonatal alloimmune neutropenia
neutropenia
Mechanism: Maternal immunoglobulin G (IgG) crosses
the placenta and binds to paternal human neutrophil
antigens (HNA) on fetal leukocytes.
● Effect: Antibody-coated neutrophils are removed from
circulation, resulting in an ANC of less than 0.5 × 109
/L,
often within 1 week of birth
● Common HNAs: HNA-1 and HNA-3 (most often
implicated), HNA-2 (historically common).
● Incidence: 0.9% in the U.S. (2021).
● Infections: Usually not life-threatening.
● Recovery: ANC generally normalizes within 6 months
as maternal IgG is cleared from circulation.
NEONATAL ALLOIMMUNE NEUTROPENIA (NAN
neutropenia
NC below the age-specific reference interval and
presence of IgG autoantibodies against one or more
human neutrophil antigens (HNA).
Incidence: Approximately 1 per 100,000 children under
10 years.
● Onset: Typically manifests around 7 to 9 months.
● Symptoms: Mild infections, usually manageable with
conservative approaches.
● Treatment: Routine antibiotic prophylaxis is not
commonly used.
● Prognosis: Self-limiting, with most patients recovering
spontaneously by 4 to 5 years.
AUTOIMMUNE NEUTROPENIA (AIN)
neutropenia
Common in Adults: Associated with various conditions
and factors.
● Associated Conditions:
○ Connective tissue disorders.
○ Felty syndrome.
○ Hematopoietic neoplasms.
○ Solid tumors.
○ Primary immunodeficiencies.
○ Bacterial and viral infections.
○ Transplant.
○ Idiosyncratic reactions to medications.
● Immunologic Mechanisms:
○ Formation of immune complexes.
○ Haptens.
○ Drug-induced formation of neutrophil
autoantibodies.
○ T-lymphocyte toxicity.
AUTOIMMUNE NEUTROPENIA (AIN
causes cyclic neutropenia
ELANE mutations
Neutropenia
- Less severe than Severe Congenital Neutropenia
(SCN1), which also involves ELANE mutations - Episodes of severe neutropenia (less than 0.2 × 109
/L)
occur in approximately 21-day cycles, each lasting 3 to
5 or more days - Accompanied by absolute monocytosis
causes cyclic neutropenia
all but one is a symptom of neutropenia episodes
Mouth ulcers
● Sore throat
● Gingivitis
● Rash
● lesions
● Fatigue
● Fever
● Cervical lymphadenopathy
lesions
Cyclic neutropenia has (high / no / lower) risk of life threatening infections compared to SCN1
lower
Adult predominantly affects women 18 to 35 y.o.,
generally shows more immature neutrophils than
mature neutrophil
CHRONIC IDIOPATHIC NEUTROPENIA
EOSINOPHILIA
Increase in circulating eosinophils with an absolute
count above 0.4 × 109
/L
○ Nonmalignant causes of eosinophilia
○ Cytokine stimulation, especially from
interleukin-3 and interleukin-5 (IL3 and IL5)
EOSINOPHILIA
EOSINOPHILIA
(>1.5 × 109
/L) lasting more than 6 months without an
identifiable cause, the diagnosis is most likely;
considered myeloproliferative neoplasm
HYPEREOSINOPHILIC SYNDROME (HES)
An absolute count of basophils greater than 0.15 × 109
/L
○ The presence of a malignant myeloproliferative
neoplasm such as chronic myelogenous
leukemia
BASOPHILIA
- Absolute monocyte count greater than 1.0 × 109
/L in adults and greater than 3.5 × 109/L in neonates - First sign of recovery from acute overwhelming
infection or severe neutropenia - Most commonly after cancer chemotherapy
positive sign of recovery
MONOCYTOSIS
Absolute monocyte count of less than 0.2 × 109
/L
○ Very rare in conditions which do not also involve
cytopenias of other lineage(s) such as aplastic
anemia or chemotherapy-induced cytopenia
MONOCYTOPENIA
monocytopenia
matching type
a. aplastic anemia
b. myelosuppressive therapies
c. steroid therapy
d. hemodialysis
e. sepsis
f. viral infections
- Often with other cytopenias.
- Especially Epstein-Barr virus (EBV).
- Associated with monocytopenia
- Linked to monocytopenia.
- Common cause.
- Patients may experience it.
- A
- F
- E
- C
- B
- D
MONOCYTOPENIA association type
profound monocytopenia
a. Hairy Cell Leukemia
b. Myeloid Neoplasms with Germline GATA2
Mutations
both
Absolute lymphocytes count greater than 10.0 × 109
/L
(young children)
● Absolute lymphocytes count greater than 4.5 × 109
/L
(adult)
LYMPHOCYTOSIS
LYMPHOCYTOSIS
a. relative
b. absolute
- percentage of lymphocytes is
increased but the absolute lymphocyte count is
within the normal range - exceeds the upper limit of norma
AB
Absolute lymphocyte count below 2.0 × 109
/L (young
children)
● Absolute lymphocyte count below 1.0 × 109
/L
LYMPHOCYTOPENIA
A. newborn infants
B. children older than 2 weeks, younger than 8-10 years
- normally
have higher absolute lymphocyte counts than adults - have lymphocyte counts very similar to those of
adults
BA
Quantitative disorders
Sex-linked recessive, autosomal dominant or autosomal
recessively inherited disorders with a heterogeneous
presentation causing premature cell aging, primarily
affecting skin, nails, and bone marrow
DYSKERATOSIS CONGENITA (DC)
CAUSES
● Gene mutations impacting telomere maintenance
(e.g., DKC1, TERT)
FEATURES
● Skin: hyperpigmentation, nail dystrophy, oral
leukoplakia
● Bone: marrow failure (cytopenias) and increased
cancer risk
DIAGNOSIS
● Genetic testing and telomere analysis
TREATMENT
● Hematopoietic stem cell transplantation (HSCT) for
bone marrow failure
● Supportive care: cancer monitoring and symptom
management
DYSKERATOSIS CONGENITA (DC)
CLASSIFICATION
● Rare genetic disorder affecting bone marrow,
pancreas, and bones
CAUSES
● Mutation in the SBDS gene (autosomal recessive)
SYMPTOMS
● Blood: Neutropenia, anemia, thrombocytopenia
● Pancreas: Digestive issues, poor growth,
malabsorption, steatorrhea
● Bones: Delayed growth, skeletal abnormalities
● Other: Developmental delays, severe infections, failure
to thrive
DIAGNOSIS
● Genetic testing (DNA sequencing)
● Blood counts
● Pancreatic enzyme tests
TREATMENT
● G-CSF: For neutropenia and severe infections
● Enzyme replacement: For digestive issues
● Bone marrow transplant: For severe cases, especially
with bone marrow failure, MDS, or AML
SHWACHMAN-DIAMOND SYNDROME (SDS)
● Rare inherited disorder (autosomal recessive or Xlinked) causing bone marrow failure, cytopenias, and
increased cancer risk
● Cause: FA gene mutations (e.g., FANCA, FANCC)
disrupt DNA repair, leading to genetic instability
● Features
○ Hematologic: anemia, leukopenia,
thrombocytopenia
○ Physical: short stature, skin pigmentation
changes, skeletal anomalies
○ Cancer: increased risk of leukemia, MDS, and
other cancers
● Diagnosis: chromosome breakage and genetic test
● Treatment:
○ HSCT for bone marrow failure
○ Androgens and growth factors for blood counts
○ Regular cancer monitoring
● Prognosis: improved with HSCT and surveillance
FANCONI ANEMIA (FA
a. fanconi anemia
b. fanconi syndrome
- a kidney disorder impacting electrolyte and nutrient reabsorption in the renal tubules
- primarily affects the bone marrow and leads to cancerrisk
BA
Morphologic abnormalities with and without functional
defects
● Normal morphology with functional abnormalities
● Monocyte/macrophage lysosomal storage diseases
● Genetic B and T lymphocyte abnormalities
QUALITATIVE DISORDERS OF LEUKOCYTES
● Variants, transformed, or atypical lymphocytes
● Variant lymphocytes indicate stimulation by a virus,
particularly EBV, which causes IM
REACTIVE LYMPHOCYTES
NEUTROPHILS – REATIVE MORPHOLOGIC
●Prominent dark purple-black granules in the
cytoplasm of neutrophils, unevenly distributed
● Composition: primary granules
● Causes: bacterial infection and sepsis and
administration of G-CSF
TOXIC GRANULATION
NEUTROPHILS – REATIVE MORPHOLOGIC
● Appearance: Pale, blue-gray cytoplasmic inclusions.
○ Composition: Aggregates of denatured
ribosomal RNA or remnants of rough
endoplasmic reticulum.
○ Location: Typically found near the cell
membrane.
○ Size and Shape: Vary between 1 and 5 μm in
diameter, often indistinct
DOHLE BODIES
In ____________, similar inclusions (Dohle bodies) can be found in eosinophils, basophils, and monocytes.
May-Hegglin Anomaly (MHA),
Reactive (Toxic) Morphology in neutrophils
appearance
a. toxic granulation
b. Dohle bodies
c. Cytoplasmic vacuoles
- Small to large
circular clear areas in
cytoplasm; rarely
may contain
organism - Dark, blue-black
Cytoplasmic
granules - Intracytoplasmic,
pale blue round or
elongated bodies
between 1 and 5 μm
in diameter, usually
adjacent to cellular
membranes; can be
indistinct
CAB
Reactive (Toxic) Morphology in neutrophils
Associated with
a. toxic granulation
b. Dohle bodies
c. Cytoplasmic vacuoles
- inflammation, infection,
pregnancy, G-CSF
administration - Bacterial infection,
autophagy secondary
to drug ingestion, acute
alcoholism, or storage
artifact
AB and C
Unstained circular area within the cytoplasm
● Causes: bacterial or fungal infection, poisoning, burns,
chemotherapy, artifact
VACUOLES
NEUTROPHIL VACUOLATION
Occurrence: Less common than toxic granulation
(TGs) and Döhle bodies.
● Appearance: Found in neutrophils with toxic
granulation and/or Döhle bodies.
● Indication: General sign of phagocytic activity.
● Association: More closely linked to infections than TGs
or Döhle bodies alone.
● Characteristics:
○ Variable size (up to 6 μm in diameter).
○ Irregular distribution within the cell.
○ May rarely contain microorganisms.
○ Can coalesce and distort cellular morphology.
TOXIC VACUOLES
Process: Cellular degradation involved in neutrophil
biology and pathophysiology.
● Formation: Small vacuoles (~2 μm in diameter) with
wider cytoplasmic distribution than toxic vacuoles.
● Association: Not linked with toxic granulation or Döhle
bodies.
● Occurrence: During cell death, hypoxia, starvation,
chemical exposure (including alcohol poisoning), toxic
radiation levels, and VEXAS syndrome.
● VEXAS Syndrome: Vacuoles present in other
hematopoietic cells.
AUTOPHAGIC VACUOLATION
Six or more lobes in granulocyte nucleus
● Causes: megaloblastic anemias, chronic infection,
myelodysplastic syndrome, rarely inherited
HYPERSEGMENTATION
Degeneration of a cell in which the nucleus shrinks
in size and the chromatin condenses to a solid,
structureless mass or masses (part of apoptosis, or is
indicative of the effects of chemotherapy
PYKNOSIS
Indication: Imminent cell death.
● Appearance:
○ Water loss in the nucleus.
○ Dense, dark chromatin.
○ Visible chromatin or filaments between nuclear
lobes of segmented neutrophils.
PYKNOTIC NUCLEI
Found In: Dead neutrophils.
● Appearance:
○ Rounded, dense nuclear fragments.
○ No visible filaments or chromatin pattern.
○ Presence of granules (key difference from
nucleated RBCs, which are agranular).
● Common Confusion: Sometimes mistaken for
nucleated RBCs.
● Associated With: Excessive delay between specimen
collection and blood film preparation, similar to
autophagic vacuoles.
APOPTOTIC NUCLEI
Bluish-green or mostly green amorphous, refractile,
shiny bodies of irregular shape, size, and number.
● Location: Found in the cytoplasm of neutrophils and
occasionally in monocytes.
● Composition: Thought to contain lipofuscin from
necrotic liver parenchymal cells.
Significance: Often a
sign of impending
death in critically ill patients.
MONOCYTES
Associated With:
○ Infections, including COVID-19
○ Recovery from myelosuppression
○ Administration of GM-CSF
● Morphological Features:
○ More immature chromatin patterns
○ Small nucleoli
○ Increased nucleus-to-cytoplasm (N:C) ratio
○ Deepened cytoplasmic basophilia
○ Increased vacuoles
○ Distinct
granulation
REACTIVE MONOCYTES
T or F
Ruptured eosinophils are not counted wih intact eosinophils in microscopic WBC differentials
F (should be counted)
Overlooking damaged eosinophils or
classifying them as smudge cells can lead to falsely
(increased / decreased) eosinophil counts.
decreased
Affected basophils may show only a
residual pinkish tinge in or around the cell, which might
be the only clue that these cells are not neutrophils
HYPOGRANULAR BASOPHILS
A rare, inherited autosomal dominant conditions
characterized by abnormal nuclear morphology of
neutrophils
● Mutations in the lamin b-receptor gene
○ Inner nuclear membrane protein
● Morphology: hyposegmentation, bilobed (“pince-nez”
or “dumbbell-shaped”) nuclei
○ Nuclear chromatin is densely clumped
PELGER-HUET ANOMALY (PHA)
types of PELGER-HUET ANOMALY (PHA
a. heterozygous PHA
b. homozygous PHA
- severe form, very rare. Nearly all neutrophils have a round or oval nucleus (100%)
- mild form, most common.
Neutrophils have bilobed nucleus (55 to 93%)
BA
● Hematologic malignancies such as myelodysplastic
syndrome (MDS)
● Acute myeloid infection
● Chronic myeloproliferative neoplasms
NEUTROPHILS WITH PHA MORPHOLOGY
PSEUDO PELGER HUET ANOMALY
● HIV infection
● Tuberculosis
● Mycoplasma pneumoniae
● Severe bacteria infection
PSEUDO-PHA NEUTROPHILS
DRUGS KNOWN TO INDUCE PSEUDO-PHA INCLUDE EXCEPT:
● Mycophenolate mofetil
● Valproate
● Sulfisoxazole
● Ganciclovir
● Ibuprofen
● Azithromycin
● Chemotherapies such as paclitaxel and docetaxel
azithromycin
Laboratory Issue in Pleger-Huet Anomaly
(True/Congenital and
Pseudo/Acquired)
- number of cells affected : 63-93%
- WBC lineages : All lineages
potentially affected
– nuclear shape and
chromatin structure - PBS: Neutrophils exhibit
normal granulation
TRUE PHA
Laboratory Issue in Pleger-Huet Anomaly
(True/Congenital and
Pseudo/Acquired)
- number of cells affected :<38%
- WBC lineages : Seen only in
neutrophils except –
cases of N-MDS-M,
E, B-exhibit PHA
morphology - PBS: Hypogranular N –
common findings –
MDS related pseudo
PHA
TRUE PHA
Nature: Rare, autosomal dominant disorder.
● Affected Cells: Neutrophils, eosinophils, basophils, and
monocytes.
● Morphology:
○ Variable thrombocytopenia.
○ Giant platelets.
○ Large Döhle body-like inclusions.
MAY-HEGGLIN ANOMALY
Mutations in the MYH9 gene on chromosome
22q12-13
MAY-HEGGLIN ANOMALY
- Classification: Rare, fatal hereditary autosomal
recessive disorder categorized as familial
hemophagocytic lymphohistiocytosis syndrome with
hypopigmentation. - Giant, dysfunctional lysosomal granules in neutrophils,
monocytes, lymphocytes (Peroxidase-positive deposits)
CHEDIAK-HIGASHI SYNDROME
Mutation in the LYST gene on chromosome
1q42.3
CHEDIAK-HIGASHI SYNDROME
CHEDIAK-HIGASHI SYNDROME has a high risk of developing which disease
- its is characterized to b a life-threatening syndrome of excessive immune action
- without treatment most children with CHS succumb to the disease before 7 years
hemophagocytic lymphohistiocytosis
all are clinical manifestations of Chediak-higashi disease except one
- partial albinism
- present in adolescence
- severe recurrent life-threatening bacterial infections
- mild bleeding
- easy bruising
- progressive neurologic development
present in infancy not adolesence
laboratory findings Chediak-Higashi disease
a. PBS
b. neutrophil function test
- delayed bacterial killing
- shows large, fused granules
BA
Resemble CHS granules and are often seen in
acute myeloid leukemia (AML), chronic myeloid
leukemia, myelodysplastic neoplasms (MDSs),
and rarely in acute lymphoblastic leukemia
Pseudo–Chédiak-Higash (PCH)
Nature: Rare, autosomal recessive disorder.
● Affected Cells: Granulocytes, monocytes, and
lymphocytes.
● Morphology:
○ Large, dark-staining metachromatic cytoplasmic
granules (Reilly bodies).
ALDER-REILLY ANOMALY
- Large, dark purple-red (metachromatic)
granules in neutrophils, eosinophils, and
basophils. - Sometimes found in monocytes and
lymphocytes. - composed of partially digested
mucopolysaccharides.
Alder-Reilly Inclusions / Reilly Bodies
