SACCM 89: Febrile Neutropenia Flashcards
What are the three ways neutrophils kill pathogens?
- degranulation to release destructive peptides and proteases into EC matrix or intraplasmacytic phagosomes containing pathogens
- NADPH oxidase complex (reactive oxygen species generator) on phagosome or cell membranes –> acitvated by microorganisms –> oxidative burst
- NETs (Neutrophil extracellular traps) –> DNA, histones, etc. –> web of cytotoxic material
Do neutrophils die during NETosis?
previously believed by actually no apoptosis –> Neutrophils continue live and retain normal behavior - can still phagocytize microbes
What cytokines is most important to maintain neutrophil hemeostasis?
G-CSF (granulocyte colony-stimulating factor)
Where is G-CSF produced?
primary bone marrow stromal cells
also: macrophages, monocytes, endothelial cells, fibroblasts
How does G-CSF affect neutrophil hemeostasis?
- promotes progenitor differentiation into neutrophils
- increases cell division
- decreases time to maturation
- increases release of neutrophils from the bone marrow
Explain why germ-free mice may have neutropenia
normal microflora suspected to induce steady-state neutrophil hematopoiesis through PRR signaling
What cells produce neutrophils?
Progenitor cells
name 5 signaling molecules leading to release of neutrophils from the bone marrow
- G-CSF
- GM-CSF (granulocyte-macrophage- colony stimulating factor)
- TNF-alpha
- TNF-beta
- Complement 5a
What are the two pools of neutrophils within the blood circulation?
- circulating pool - in blood stream - what you get on blood sample
- marginated pool - roll slowly along the endothelium or small vessels/capillaries
What is the percentage of neutrophils in the circulating versus marginated pool in dogs versus cats?
50:50 dogs
25:75 cats
What are the three main causes for neutropenia?
- increased utilization
* PAMP/DAMP exposure –> macrophages and neutrophils generate chemokines and cytoklines –> promotes margination and extravasation of circulating neutrophils
* depletes neutrophils from circulation if not restored from bone marrow - decreassed egress from bone marrow
* depletion of granulocyte pogenitor cells
* ineffective granulopoiesis
What are causes for bone marrow hypoplasia (i.e., depletion of granulocyte progenitor cells)?
- infectious (Parvo, FeLV, FIV, Rickettsial disease)
- toxins/drugs
- radiation
- myelophthisis
- gray collie syndrome/cyclic hematopoiesis
What are causes for ineffective granulopoiesis?
- infectious diseases (FeLV, FIV)
- myelodysplasia
- lithium administration in cats
- acute myeloid leukemia
- trapped neutrophil syndrome in border collies
In parvovirus induced bone marrow hypoplasia, why are neutrophils affected first (i.e., neutropenia seen first)
because neutrophils have the shortest half-life and are also used extensively (i.e., intestinal)
By what mechanisms do FeLV and FIV lead to neutropenia in cats?
FeLV - **myelophthisis
** and meylodysplastic syndrome secondary to round cell neoplasms in the bone marrow
FIV -infected stromal cells in the bone marrow secrete myelosuppression factors –> suppress granulopoiesis
FIV - myelodysplasia of infected bone marrow and stromal cells
What group of drugs is the most common to cause neutropenia?
chemotherapeutic agents
What are the two established causes for estrogen-induced neutropenia in dogs?
- exogenous estrogen administration
- estrogen-secreting sertoli cell tumors
How is estrogen believed to cause myelosuppression?
not directly
evidence suggests thymic stromal cells exposed to estrogen start producing a myelopoiesis inhibitory factor
In what intervals does neutropenia occur in gray collie syndrome?
every 10-14 days
What are the three classifications of dysmyelopoiesis?
- myelodysplasdtic syndrome (MDS)
- secondary dysmyelopoiesis
- congenital dysmyelopoiesis
What drugs have been shown to cause secondary dysmyelopoiesis?
- antineoplastic drugs
- estrogen
- phenobarbital
- cephalosporins
- chloramphenicol
- colchicine
- lithium in cats
what are the mechanisms of action of recombinant G-CSF administration?
- increased differentiation of progenitor cells
- increased neutrophil release from bone marrow
- mature neutrohphils: increased chemothaxis, enhanced respiratory burst, improved IgA-mediated phagocytosis
Does recombinant human G-CSF improve dogs with canine parvo virus?
No, administration in parvo dogs is not recommended because demonstrated to be ineffective
What is the long-term risk of administering human recombinant G-CSF to dogs?
may lead to the development of Antibodies against rhG-CSF - can cross-react with and neutralize canine G-CSF –> chornic neutropenia
