Disorders of Granulocyte Number Flashcards
Describe the production, distribution, and turnover of a neutrophil
**Be able to identify a neutrophil on histo slide
Production: bone marrow: storage pool for host defense (10-14 days).
Distribution: Released into peripheral blood (6 hr.), then move to tissues.
Turnover: 1-2 days.
Function: Major component of innate immune system: non-specific defense against microbes. Important response to tissue injury.
Describe the production, distribution, and turnover of a eosinophil
**Be able to identify on a histo slide
Production: Bone marrow under influence IL-5.
Morphologic features: - Mitotic and storage pool like neutrophils - Large “eosinophilic” granules, bi-lobed nuclei.
Distribution: - Released into peripheral blood, move to external surfaces (tracheobronchial tree, GI tract, etc.). Survive for weeks. - Can function as phagocyte.
Function: Roles allergies, parasite infection, response to tumors: may be immuno-enhancing or immuno-suppressive.
Describe the production, distribution, and function of a basophil
** Be able to identify on a histo slide
Production: bone marrow
Distribition: released in peripheral blood (seen infrequently), move to tissues.
Morphological features: Similar in size to eosinophils, bi-lobed nucleus, prominent primary granules (blue/purple).
Receptors for IgE.
Function: pathophysiology hypersensitivity reactions (allergic).
Describe the production, distribution, and turnover of a Monocyte/tissue Macrophage
**Be able to identify on a histo slide
Production: Marrow
Distribution/Turnover:
- Shorter time in marrow (7 days).
- Released after last mitotic division (no storage),
- Intravascular compartments (3-5 days)
- Move to tissues (days-months).
Morphology: Gray cytoplasm indented (kidney shaped) nucleus. Morphology changes in tissues.
Function: a) Move to sites of infection and inflammation; b) Filter function; c) Processing and presenting antigens; d) Clearance of apoptotic cells and debris.
Neutropenia
- Define
- Clinical consequences
Neutropenia: decrease in absolute neutrophil count (bands and segs) below accepted norms.
- Varies with age, race, ethnicity and altitude
- (ie: ˂3000/microL for neonate, ˂1100/microL 1-2 week old, ˂1500 microL for child or adult).
Consequences:
- Neutropenia may reflect a decrease in the marrow myeloid pools to such an extent that delivery of neutrophils to infected tissues is decreased enough to shift the balance in favor of the microbes.
What diseases cause neutropenia via decreased bone marrow production?
*Just list them out; there are other cards specific to each disease
-
Decreased bone marrow production
- Primary
- Kostmann Syndrome
- Shwachman Diamond Syndrome
- Cyclic Neutropenia
- Secondary
- Drug induced Neutropenia
- Viral Infection
- Nutritional deficiency
- Other
- Chediak-Higashi Syndrome
- Primary
What diseases cause neutropenia via increased turnover of neutrophils?
* This is a big picture card so just list them out; there are other cards that ask for details of each specific disease
Increased turnover of neutrophils
- Immune
- Chronic benign neutropenia of childhood
- Autoimmune neutropenia
- Alloimmune neutropenia
- Non-Immune
- Infection
- Splenomegaly and hypersplenism
- Pseudoneutropenia
Kostmann Syndrome
- How does it result in neutropenia?
- What genes need to be mutated to get it?
- Inheritance pattern? (AR or AD?)
- Symptoms?
- Congenital disease that results in decresed bone marrow production of neutrophils
Genetics
- Elastase gene mutation (ELA-1 or HAX-1 gene)
Inheritance
- AR or AD or sporadic
Symptoms
- Often results in severe infection or death
- Severe neutropenia
- Monocytosis
- Eosinophilia
- Myeloud hypoplasia
Survivors often develop myeloid leukemia or myelodysplastic syndrome (MDS)
Shwachman Diamond syndrome
- How does it result in neutropenia?
- What genes need to be mutated to get it?
- Inheritance pattern? (AR or AD?)
- Symptoms?
- Rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature.
- Inheritance: AR
- Symptoms: 50% have aplastic anemia of MDS/leukemia
- neutropenia, pancreatic insufficiency with fat malabsorption, bony abnormalities, and growth delay
- Genetics
- FAS associated apoptosis
- Defect in nurse cells in marrow stroma that support developing myeloid cells
- May have defect in SBDS gene
Cyclic Neutropenia
- How does it result in neutropenia?
- What genes need to be mutated to get it?
- Inheritance pattern? (AR or AD?)
- Symptoms?
Decreased bone marrow production of neutrophils
- Genetics
- Linked to apoptosis of precursors in bone marrow and mutations in the elastase gene.
- Inheritance
- AR, AD and sporadic.19p13.3/ELA-2:
- Most single base mutations.
- Symptoms
- Recurrent fevers, pharyngitis, gingivitis, and mouth ulcers may accompany fevers
- Cycles of 21 days +/- 4 days
Drug-induced neutropenia
- What [broad] class of drugs cause it?
- What is the general mechanism by which it induces neutropenia?
- Caused classically by Chemotherapy drugs (can be induced by other drugs too though)
Pathway
- Chemo is used for malignant conditions - direct effects on myeloid precursors (bone marrow) and stem cells and leaves patient with reduced production and at high risk for infection (other cytopenias present)
- Chloramphenicol also has direct effect on precursors.
Viral Infection neutropenia
- What are some common viruses that cause neutropenia?
- What is the [broad] mechanism of action?
Viruses
- EBV
- Varicella
- Measles
- CMV
- Hepatitis
- HIV
Mechanism
- Suppress the bone marrow production or cause an increase in turnover peripherally
Nutritional deficiency neutropenia
- What are some common nutritional deficincies that can cause neutropenia?
- What is the mechanism of action?
Common Nutritional deficincies causing neutropenia
- Folate
- B12
- Copper and protein calorie malnutrition
Mechanism
- Can cause ineffective myelopoiesis and neutropenia, other cytopenias, and megaloblastic changes in bone marrow
Chediak-Higashi Syndrome
- What does it cause?
- How does it cause it?
- Inheritance? (AR or AD)
Neutropenia
Variety of mutations in coding region
Autosommal Recessive
Decreases bone marrow production of neutrophils
(I think this is unlikely test material, but now you know)
Chronic benign neutropenia of childhood
- Mechanism? (broad)
Increased turnover of neutrophils
- Immune production of antibodies cross react with neutrophils
- Typically affects newborns (8-11 mo)
- Typically resolves within 6 - 54 months with 20 months being average
Autoimmune neutropenia
- Mechanism?
Increased neutrophil turnover
- Immunity antibodies to specific determinants on the neutrophil
- Assoc w/ Lupus, Evan’s syndrome, or Felty’s syndrome
Alloimmune neutropenia
- Define
- Mechanism?
* Hint: remember what the underlined means
Increased turnover of neutrophils
- Passive transfer of antibody from mother’s circulation (which is why its allo) attacking babies cell -> neutropenia
Mechanism
- Transplacental passage of neonatal cells which contain antigens not expressed by maternal cells into maternal circulation sensitizes the mother to produce antibodies against the infant’s antigens. Accumulation of IgG antibodies by the fetus provides a pool of antibodies which bind the infant’s neutrophils and cause neutropenia
* Allo means other - so alloimmune is neutropenia induced by some “other” immune system
Infection induced neutropenia
- Mechanism
- What are the viral sources that can cause it?
- What are the bacterial sources that can cause it?
- What are the protozoan sources that can cause it?
Most common neutropenia; acute; resolves in days to months
Mechanism
- Big picture: Increased turnover of neutrophils
- Detailed: Increased utilization, Complement mediated margination, Marrow suppression/failure, direct effect, Cytokine/chemokine induced margination, Antibody production.
Viral: Hepatitis, roseola, parvovirus, RSV, HIV, CMV, influenza
Bacterial: gram (-) sepsis, brucellosis, tuberculosis, typhoid, tularemia, paratyphoid
Protozoan: malaria, Leishmaniasis
Splenomegaly & hypersplenism induced neutropenia
- Mechanism?
Big picture: Increased neutrophil turnover
Detailed:
- Excessive sequestration of neutrophils in the spleen
- May be associated with sequestration of red cells and platelets.
Pseudoneutropenia
- Mechanism?
Big picture: Increased turnover of neutrophils
Detailed:
- Severe infection, bacterial pathogens and activation of complement (C5a)
- Causes excessive demargination of neutrophils.
