(F) L3.1 Non-malignnt WBC disorders Flashcards by Nathalie Grace Castillo

causes of non-malignant WBC disorders

genetic or acquired

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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

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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

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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

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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

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By adding the number of segmented and band neutrophils (may include metamyelocytes and
myelocytes).

Used to evaluate neutrophelia

ANC Calculation

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If there is neutrophilia, there is always
a shift to the (left/right)

left

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leukemoid reaction
a. parasitic infection
b. treponemal infection

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neutropenia

associations of leukemoid reaction

infections
medications
other conditions (intoxications, hemorrhage, hemolysis, and splenectomy)
Metabolic disease and inflammation

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neutropenia

what is the indicator of leukemoid reactions

toxic vacuoles in neutrophils

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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

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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

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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

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neutropenia

Caused by antibody binding to neutrophil antigens

IMMUNE-MEDIATED NEUTROPENIA

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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

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neutropenia

Primarily Affects: Children.
● Cause: Development of antibodies to HNA-1.
● Severity: Moderate to severe neutropenia.
● Nature: Self-limiting

AUTOIMMUNE NEUTROPENIA

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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

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neutropenia

● Nature: Most often an acquired condition.
● Causes: Numerous, including drug-induced
neutropenia and neonatal alloimmune neutropenia.

ACQUIRED NEUTROPENIA

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neutropenia

Source: Most cases of acquired neutropenia.
● Mechanism: Due to myeloid suppression or
immunologic response.

DRUG-INDUCED NEUTROPENIA

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neutropenia

2 types of acquired neutropenia

drug induced
neonatal alloimmune neutropenia

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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

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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)

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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

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causes cyclic neutropenia

ELANE mutations

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# 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 1. Often with other cytopenias. 2. Especially Epstein-Barr virus (EBV). 3. Associated with monocytopenia 4. Linked to monocytopenia. 5. Common cause. 6. Patients may experience it.

1. A 2. F 3. E 4. C 5. B 6. 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 1. percentage of lymphocytes is increased but the absolute lymphocyte count is within the normal range 2. exceeds the upper limit of norma

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 1. normally have higher absolute lymphocyte counts than adults 2. have lymphocyte counts very similar to those of adults

# 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 1. a kidney disorder impacting electrolyte and nutrient reabsorption in the renal tubules 2. primarily affects the bone marrow and leads to cancerrisk

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 1. Small to large circular clear areas in cytoplasm; rarely may contain organism 2. Dark, blue-black Cytoplasmic granules 3. 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 1. inflammation, infection, pregnancy, G-CSF administration 2. 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 1. severe form, very rare. Nearly all neutrophils have a round or oval nucleus (100%) 2. mild form, most common. Neutrophils have bilobed nucleus (55 to 93%)

● 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 1. delayed bacterial killing 2. shows large, fused granules

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