Exam 13 - Heme18 - Disorders Of Wbc's

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Clarification of terms:

Leukocytes = white blood cells = “WBCs”

-...: “ability to ingest things”
*Granulocytes
Neutrophils
Eosinophils
Basophils

*Monocytes/... (circulating vs. in tissues)


Lymphocytes
(lymphocytes to be covered later, with immune deficiencies)

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Phagocytes
macrophages

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General Function of Phagocytes:

Granulocytes: Exert effects via ... substances
-...- Cell killing
-...- Release of inflammatory mediators
-...- General role in allergic response


Monocytes/macrophages: Dual roles in cell killing and ... presentation

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granule
Neutrophils
Basophils
Eosinophils
antigen

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Granulocytes: Types of granules:

Primary granules (...) :
-Like lysosomes, released intracellularly
-Contain ... which react with peroxide/ halide to produce hypochlorous acid


Secondary granules:
-Smaller, released intra or ...
-May contain ligand-binding proteins (apolactoferrin, cobalamin-binding protein)
-Secondary granules can also release their contents into the extracellular space.

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azurophilic
myeloperoxidases
extracellularly

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Aspects of granulocyte function:

Mobilization /Chemotaxis – Chemoattractants (e.g. cytokines, complement, phospholipids) via concentration gradients

Migration into the ...– Circulating WBCs marginate, adhering to vessel endothelium, then “crawl” between endothelial cell junctions into the periphery

Recognition – Surface receptors for ... and complement trigger ingestion of opsonized microbes

Degranulation – Granule contents ... into a phagocytic vesicle or the external environment

Peroxidation – NADPH oxidase produces superoxide anion (...) --> H2O2, hypochlorous acid, hydroxyl radicals, and reactive aldehydes

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tissues
IgG
released
respiratory burst

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Life of a neutrophil:

Marrow (about 12 days)
-... compartment (myeloblast --> myelocyte)
-... compartment (myelocyte --> band form)
-... compartment (band form --> neutrophil)

Circulation (only several ...)
-Circulating pool
-Marginating pool

Tissue compartment (several ...)

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Mitotic
Maturation
Storage
hours
days

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Life of a Neutrophil: Growth Factors:

...: Lineage-restricted to granulocytes and their precursors, promotes superoxide production, ADCC and phagocytosis


...: Stimulates proliferation and differentiation of a broad range of progenitors, including cells with stem cell properties


...: Known mediator of stem cell renewal and proliferation; it also promotes commitment of stem cells to a broad range of colony types

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G-CSF
GM-CSF
IL-3

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Beware the Angry Neutrophil!

Changes in neutrophil appearance reflective of a hypermetabolic state:
-... – Prominence of azurophilic granules containing bacteriocidal enzymes
-... – Aggregations of rough endoplasmic reticulum
-Cytoplasmic vacuoles –Phagocytosis
-“... shift” - Release of immature neutrophils from the marrow compartment

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Toxic granulation
Döhle bodies
Left

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Life of a Monocyte/Macrophage:

Marrow: Monoblasts --> monocytes --> bloodstream

Bloodstream (average 8 hours) --> tissues

Monocytes in tissues = ...
-May live in tissues for months
-Function in antigen recognition, presentation and signaling
-Activate in response to local factors

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macrophages

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Monocytes/Macrophages: Multiple roles in immunity:

Major role in ... presentation
-Located at the interface of the body with the environment
-Presence in the skin, lungs, liver, gut and spleen maximizes ... recognition
-Role in delayed-type hypersensitivity and granuloma formation

Recognize and ... tumor cells

Scavenge and clear debris

Immune signaling
-Cytokines and inflammatory mediators

Some microbicidal functions
-Particularly Legionella, Listeria and Toxoplasma, which ... efficiently killed by neutrophils

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antigen
immune
destroy
are not

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Functional Classification of the Major Granulocyte Disorders:

Disorders of granulocyte function
-Disorders of oxidative metabolism
*Chronic ... disease (CGD)
* ... deficiency

-Disorders of ...– Chediak-Higashi syndrome

-Disorders of ... – Leukocyte adhesion deficiency

-Disorders of ... – Hyper IgE syndrome

Disorders of granulocyte production/maturation
-Congenital ...

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granulomatous
Myeloperoxidase
degranulation
adhesion
chemotaxis
neutropenias

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...:

Defect:
-Inability to produce superoxide radicals (respiratory burst)
-Impaired defense against microbes producing catalase – (Staphylococcus aureus, E. coli, Klebsiella, Serratia, Salmonella, Pseudomonas)

Clinical presentation:
-Recurrent infections with ... (+) bacteria
-Usually inherited as X-linked recessive
-... left as residua of infections

Diagnosis:
-History of recurrent or unusual infections,
*Especially Serratia or hepatic abscesses
-NBT test: specific stain for oxidative activity

Treatment:
-Chronic antibiotic prophylaxis,
-Possibly BMT if HLA-matched sibling, g-interferon

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Chronic granulomatous disease (CGD)
catalase
Granulomas

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... deficiency:

Defect:
-Abnormal ... (mutation of post-translational processing)
-Bacterial killing delayed, but eventually normal
-Impaired killing of fungal pathogens (Candida, Aspergillus)

Clinical presentation:
-Usually clinically mild
-Some increased risk for disseminated fungal disease (usually in conjuction with diabetes mellitus)
-Autosomal recessive, variable expression

Diagnosis:
-Specific deficiency of neutrophil/monocyte peroxidase by histochemical analysis, with normal eosinophil peroxidase noted

Treatment:
-Usually none needed, guided by frequency/severity

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Myeloperoxidase
myeloperoxidase

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... syndrome:

Defect:
-Aberrant vesicle sorting/transport leads to abnormal granule formation (gene involved has been identified)
-Granules progressively fuse to form oversized, dysmorphic granules which are functionally inefficient
*Degranulation delayed in response to infection
*Chemotaxis also impaired
-Defect is systemic, affecting all granule-containing cells (including melanocytes, Schwann cells, platelets)

Clinical presentation:
-Oculocutaneous ... - as melanosomes can’t disperse
-Additional problems in this disorder:
*Frequent bacterial infections, chronic periodontitis/gingivitis
*Mild bleeding tendency (due to platelet granule defect)
*Peripheral neuropathies
-Autosomal recessive

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Chediak Higashi
albinism

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Chediak Higashi syndrome:

Diagnosis:
-Phenotype and history of recurrent infections
-Characteristic “...” granules visible on blood smear in neutrophils and eosinophils, much more so in the ...

Clinical course:
-Leukemic-like phase of the disease (“accelerated phase”) kills most patients prior to age 20
*Thought to be related to defects in NK cell function
*Diffuse extensive lymphohistiocytic infiltration with hepatosplenomegaly
*Profound pancytopenia, secondary infection and bleeding
*... infection is the trigger for many patients
*No real effective therapy unless BMT is an option

Treatment:
-Chronic antibiotic prophylaxis, vitamin ...
-BMT if HLA-matched sibling

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giant
marrow
EBV
C

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Hyperimmunoglobulinemia E syndrome (“Job’s syndrome”):

Defect:
-Impaired generation of ...
*Problems with neutrophil ...
*Secondary elevation in IgE levels (very high)

Clinical presentation:
-Symptoms of ... and hypersensitivity at the same time
*Chronic eczematous dermatitis
*Recurrent skin, sinus and pulmonary infections (Staph a particular problem)
*Mucocutaneous candidiasis
*Skeletal and dental abnormalities (fractures, retained primary teeth)
-Autosomal dominant with incomplete penetrance

Diagnosis:
-Markedly ... IgE measurements, CBC with eosinophilia
-Clinical presentation overlaps several other immunodefiencies

Treatment:
- Supportive (treat the symptoms)
- Prophylactic antibiotics, g-IFN has been tried, may be helpful

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gamma-interferon
chemotaxis
immunodeficiency
elevated

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Neutropenia:

Absolute neutrophil count (ANC)
-Multiply the total WBC count by the percentage of neutrophils

Neutropenia = less than ... neutrophils/microliter

Needs to be taken in context of the patient

Risk of infection
-ANC 1000-1500 NONE
-ANC 500 –1000 MINIMAL
-ANC 200 - 500 MODERATE TO SEVERE (skin, mucous membranes)
ANC <... SEVERE (sepsis, hepatic abscesses, pneumonitis)

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1500
200

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Congenital Neutropenias: Reticular dysgenesis:

Defect:
-Selective failure of myeloid/lymphoid ... cells

Clinical presentation:
– Overwhelming ... defect, death in infancy
-Some genetic factors (not classic Mendelian)

Diagnosis:
-Marrow shows absence of myeloid & lymphoid elements

Treatment:
-... is the only option

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stem
immune
BMT

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Congenital Neutropenias:
Kostmann syndrome:

Defect:
-Neutrophil elastase gene mutation --> maturation arrest at ...-myelocyte stage

Clinical presentation:
-Early onset recurrent, life-threatening bacterial infections
-ANC < ...
-10% of patients progress to MDS/AML

Diagnosis:
-Marrow reveals characteristic maturation arrest
-Clinical presentation as above (not subtle)

Treatment:
-Most respond well to ... (90%)
*Prior to G-CSF most Kostmann’s patients died in early childhood
-For severe cases, BMT may be an option
-10% eventually develop MDS/AML

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promyelocyte
200
G-CSF

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Congenital Neutropenias: ... syndrome:

Defect:
-Defect affecting at least neutrophil chemotaxis -- but effects of mutation more global (candidate gene has been identified)

Clinical presentation:
-Poor growth, short stature, pancreatic insufficiency
-Variable neutropenia, anemia, thrombocytopenia
-Autosomal recessive
-Preleukemic syndrome (15-30% develop MDS)

Diagnosis:
-Clinical history as above
-Exclusion of cystic fibrosis and related diseases
-Hypocellular bone marrow

Treatment:
-Close monitoring (annual marrow with cytogenetics)
-Pancreatic enzyme supplementation if needed
- Role of G-CSF not yet defined for this condition

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Shwachman Diamond

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Congenital Neutropenias:
... neutropenia:

Defect:
-Mutations in neutrophil elastase gene (different than Kostmann’s) – not a preleukemic state. Thought to affect maturation and chemotaxis

Clinical presentation
-Oscillatory neutropenia with 21-day periodicity
*Monocytes, platelets, reticulocytes and lymphocytes cycle at same frequency
– Autosomal dominant in 50% of cases

Diagnosis:
-Demonstration of periodicity with regular (e.g. twice-weekly) ...
-Confirmed by marrow findings of myeloid maturation arrest/hypoplasia

Treatment:
-Increased risk of opportunistic infections at the neutrophil nadirs.
-... helpful for symptomatic patients
*Appears to both raise the nadir and decrease the periodicity of neutropenia
-Careful attention to symptoms of infection

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Cyclic
CBCs
G-CSF

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Congenital Neutropenias:
Benign congenital neutropenia:

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Acquired Neutropenias:

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Basophilia:

... (and allergic) reactions:
-Drug, food reactions; urticaria

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Hypersensitivity

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Monocytosis:

Infections:
-Examples: EBV, tuberculosis

Hematologic causes
-Chronic ..., leukemia/lymphoma, marrow recovery

Other causes:
-Systemic ... disease
-Post-...

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neutropenia
inflammatory
splenectomy

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Who to work up for a WBC disorder:

General guidelines: If within past year:
-More than ... systemic bacterial infections (sepsis, meningitis, osteomyelitis)
-... or more serious respiratory infections (cellulitis, draining otitis media, lymphadenitis)
-Infection at an unusual site (hepatic or brain abscess)
-Unusual pathogens (Aspergillus, Nocardia)
-Infections of unusual severity

Staged workup:
-Start with complete blood count (CBC), ....
-If normal, evaluate complement levels, QUIGS
-If normal, --> evaluation(s) of granulocyte/lymphocyte function

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two
Three
smear

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Hereditary/morphologic abnormalities of neutrophils:

... anomaly
-Dumb-bell, peanut or spectacle-shaped nuclei in neutrophils, may be congenital or acquired

... neutrophils
-Seen in vitamin B12 and folate deficiency

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Pelger Huet
Hypersegmented

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Infection and Leukocytosis:

Acute bacterial infections
-Disseminated or localized
-... infections - neutrophil response
-After several days “bandemia” may resolve while neutrophilia remains

Acute viral infections
-... often predominant cell type, varies with infection/patient
-Marked leukocytosis associated with adenovirus, EBV, pertussis

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Pyogenic
Lymphocytes

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Clarifying terms:

...
-Elevated total WBC count

...
-Elevation in neutrophils (absolute not relative)

“...”
-Immature forms of neutrophils in the circulation (bands, metamyelocytes, myelocytes)
-Can occur without elevation of WBC count

... reaction
-Profound response of marrow to stress
-Includes “emptying out” of stored neutrophils plus immature forms of neutrophils

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Leukocytosis
Neutrophilia
Left shift
Leukemoid

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Steroid-induced Neutrophilia:

Down-regulation of adherence proteins
-Decreased adherence to endothelium
-Decreased tissue egress

... release from marrow into the circulation

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Increased

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...-Induced Neutrophilia:

Basically anything that causes release of endogenous epinephrine will trigger a stress-associated neutrophilia via demargination:
-Vigorous exercise
-Anxiety
-Seizures
-Vomiting

Not normally associated with left shift, toxic granulation, Döhle bodies or neutrophilic vacuoles (unless accompanied by injury)

Physiologic neutrophilia of the newborn

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Stress

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...:

Defined as a total WBC count > 30-50K; immature forms present on the smear

When are they seen?
-Severe infections or metabolic stress
-More prominent in infants/neonates

How do you know it isn’t leukemia?
-Reason present for marrow response?
-Recovery from severe insult?

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Leukemoid reactions

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Transient ... syndrome:

Occurs in young infants with trisomy 21

Accompanied by hepatosplenomegaly

Regresses spontaneously in 1-2 months

Blast clone always carries trisomy 21

Not an indication for immediate treatment, but does need to be followed
-Around 30% will progress to leukemia

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myeloproliferative

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The “viral” CBC:

In the patient for which a viral infection fits the clinical presentation:
-Normal to ... total WBC count
-Predominance of lymphocytes in the differential

Most of the time it probably IS a virus, but, be alert for
-Presence of “Angry Neutrophils”
-Low WBC counts in a sick patient
-Low platelet counts

... of the patient is your first consideration

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low
Clinical appearance