SACCM 89: Febrile Neutropenia

Question 1

What are the three ways neutrophils kill pathogens?

Answer 1

1. degranulation to release destructive peptides and proteases into EC matrix or intraplasmacytic phagosomes containing pathogens
2. NADPH oxidase complex (reactive oxygen species generator) on phagosome or cell membranes –> acitvated by microorganisms –> oxidative burst
3. NETs (Neutrophil extracellular traps) –> DNA, histones, etc. –> web of cytotoxic material

Question 2

Do neutrophils die during NETosis?

Answer 2

previously believed by actually no apoptosis –> Neutrophils continue live and retain normal behavior - can still phagocytize microbes

Question 3

What cytokines is most important to maintain neutrophil hemeostasis?

Answer 3

G-CSF (granulocyte colony-stimulating factor)

Question 4

Where is G-CSF produced?

Answer 4

primary bone marrow stromal cells
also: macrophages, monocytes, endothelial cells, fibroblasts

Question 5

How does G-CSF affect neutrophil hemeostasis?

Answer 5

• promotes progenitor differentiation into neutrophils
• increases cell division
• decreases time to maturation
• increases release of neutrophils from the bone marrow

Question 6

Explain why germ-free mice may have neutropenia

Answer 6

normal microflora suspected to induce steady-state neutrophil hematopoiesis through PRR signaling

Question 7

What cells produce neutrophils?

Answer 7

Progenitor cells

Question 8

name 5 signaling molecules leading to release of neutrophils from the bone marrow

Answer 8

• G-CSF
• GM-CSF (granulocyte-macrophage- colony stimulating factor)
• TNF-alpha
• TNF-beta
• Complement 5a

Question 9

What are the two pools of neutrophils within the blood circulation?

Answer 9

• circulating pool - in blood stream - what you get on blood sample
• marginated pool - roll slowly along the endothelium or small vessels/capillaries

Question 10

What is the percentage of neutrophils in the circulating versus marginated pool in dogs versus cats?

Answer 10

50:50 dogs
25:75 cats

Question 11

What are the three main causes for neutropenia?

Answer 11

1. 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
2. decreassed egress from bone marrow
   * depletion of granulocyte pogenitor cells
   * ineffective granulopoiesis

Question 12

What are causes for bone marrow hypoplasia (i.e., depletion of granulocyte progenitor cells)?

Answer 12

• infectious (Parvo, FeLV, FIV, Rickettsial disease)
• toxins/drugs
• radiation
• myelophthisis
• gray collie syndrome/cyclic hematopoiesis

Question 13

What are causes for ineffective granulopoiesis?

Answer 13

• infectious diseases (FeLV, FIV)
• myelodysplasia
• lithium administration in cats
• acute myeloid leukemia
• trapped neutrophil syndrome in border collies

Question 14

In parvovirus induced bone marrow hypoplasia, why are neutrophils affected first (i.e., neutropenia seen first)

Answer 14

because neutrophils have the shortest half-life and are also used extensively (i.e., intestinal)

Question 15

By what mechanisms do FeLV and FIV lead to neutropenia in cats?

Answer 15

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

Question 16

What group of drugs is the most common to cause neutropenia?

Answer 16

chemotherapeutic agents

Question 17

What are the two established causes for estrogen-induced neutropenia in dogs?

Answer 17

• exogenous estrogen administration
• estrogen-secreting sertoli cell tumors

Question 18

How is estrogen believed to cause myelosuppression?

Answer 18

not directly
evidence suggests thymic stromal cells exposed to estrogen start producing a myelopoiesis inhibitory factor

Question 19

In what intervals does neutropenia occur in gray collie syndrome?

Answer 19

every 10-14 days

Question 20

What are the three classifications of dysmyelopoiesis?

Answer 20

• myelodysplasdtic syndrome (MDS)
• secondary dysmyelopoiesis
• congenital dysmyelopoiesis

Question 21

What drugs have been shown to cause secondary dysmyelopoiesis?

Answer 21

• antineoplastic drugs
• estrogen
• phenobarbital
• cephalosporins
• chloramphenicol
• colchicine
• lithium in cats

Question 22

what are the mechanisms of action of recombinant G-CSF administration?

Answer 22

• increased differentiation of progenitor cells
• increased neutrophil release from bone marrow
• mature neutrohphils: increased chemothaxis, enhanced respiratory burst, improved IgA-mediated phagocytosis

Question 23

Does recombinant human G-CSF improve dogs with canine parvo virus?

Answer 23

No, administration in parvo dogs is not recommended because demonstrated to be ineffective

Question 24

What is the long-term risk of administering human recombinant G-CSF to dogs?

Answer 24

may lead to the development of Antibodies against rhG-CSF - can cross-react with and neutralize canine G-CSF –> chornic neutropenia