Neutrophilia

Question 1

granulocytes

Answer 1

neutrophils, eosinophils and basophils.

Question 2

neutrophilia

Answer 2

elevated neutrophil count (>9 x 109)

this includes
polymorphonuclear cells
(PMNs also known as
neutrophils) AND bands
 Unusual to see
metamyelocytes
 Should not see more
primitive neutrophil
precursors (i.e.
myelocytes,
promyelocytes, blasts)

Question 3

lymphocytosis

Answer 3

– elevated lymphocyte count (>3.5 x109/L)
– not necessarily associated with leukocytosis

Question 4

neutrophils are formed from ____ stem cells/progenitors under the influence of____ ___ ___

Answer 4

Formed from
hematopoietic stem
cells under the
influence of
hematopoietic grow
factors

– GM-CSF (granulocyte
macrophage colony
stimulating factor)
– G-CSF (granulocyte
colony stimulating
factor)
– SCF (stem cell factor) – other: IL3, Flt3 ligand

Question 5

marginal vs circulating pool

Answer 5

Question 6

outline the maturation stages of a neutrophil

Answer 6

Question 7

neutrophil kinetics: where are the neutrophil reserves stored for acute neutrophilia that occurs with infection and inflammation

Answer 7

bone marrow has reserve that is 10-20x that in circulating blood pool. marginal pool also mobilized

Question 8

what is the”left shift” of neutrophilia

Answer 8

Mobilization of neutrophils often accompanied by
increased number & proportion of immature
blood neutrophils (bands, sometimes
metamyelocytes), called left shift

Question 9

neutrophil function

Answer 9

tissue phagocytes
– enter circulation &
adhere to vascular
endothelial cells at sites
of inflammation then
migrate to tissues
– at site of infection
engage in phagocytosis
& killing of
microorganisms
THEY ALOS RELEASE CYTOTOXIC GRANULES

Question 10

critical features of a neutrophil that allows it to function

Answer 10

1. surface proteins.
   - interacts with specific ligands and receptors on the endothelial cells
2. chemotactic factor receptors on neutrophil surface
   - facilitates subendothelial cell migration towards a stimulus.
3. Ig and complement surface receptors: enhances ingestion and killing of microorganisms
4. NADPH oxidase system– intracellular oxidative burst that accompanies phagocytosis that kills and digests microorganisms.

Question 11

reactive vs neoplastic neutrophilia

Answer 11

reactive has an “orderly” WBC differential– still follows the NLMEB pattern

neoplastic is disorderly– some leukocytes might be irregularly higher than others.

Question 12

reasons for reactive neutrophilia

Answer 12

Question 13

pathophysiology of reactive neutrophilia when caused by infection and inflammation

Answer 13

neutrophilia in infection and inflammation

• release from marrow reserve in response to cytokinds (g-csf, gm-csf, cortisol)
• stimulation of neutrohpil production with sustained cytokine response
• change in morphology– vacuoles, toxic granules, dohle bodies (retained aggregates of rough endoplasmic reticulum)

Question 15

pathophysiology of reactive neutrophilia when due to acute stress, exercise, anxiety.

Answer 15

due to demargination of cells and NOT to releae of cells from marrow reserve.

• cells in marginal pool are swept into the circulating pool usually by events that increase the cardiac output and tissue blood flow.

Question 16

pathophysiology of reactive neutrophilia when due to hyposplenism

Answer 16

due to decreaed splenic trapping

Question 17

pathophysiology of neutrophilia when due to neoplastic condiions

Answer 17

increased production and or marrow release as a result of excess cytokines.

Question 18

what is a leukoerythroblastic picture

Answer 18

Increase in immature RBCs
and WBCs seen in differential and on blood film … caused by marrow infiltration, severe marrow stress, etc.

Question 19

what is a leukemoid reaction

Answer 19

a neutrophilic leukocytosis above 50,000 cells/uL when the cause is other than leukemia.

Question 20

outline the quantitative and qualitative neutrophilias and WBC changes that happen when a person takes glucocorticoids/steroid/prednisone

Answer 20

quantitative

1. neutrophilia because of neutrophil releaes from marrow, demargination, and less of them going into tissues so they stay in blood (impaired chemotaxis)
2. lymphopenia, eosinopenia, monocytopenia (inceased destruction of these WBCs)

QUALITATIVE

• decreased IgG synthesis because of decreased B cell so therefore there is immunosuppression
• impaired antigen presentation
• impaired chemotaxis by phagocytic cells
• decreasded Fc receptor expression by phagocytic cells
• impaired phagocytosis.

Question 21

Question 22

outline the pathobiology of CML

Answer 22

clonal disorder of
hematopoiesis that arises
in a hematopoietic stem
cell or early progenitor cell – characterized by the
dysregulated production of
a particular lineage of
mature myeloid cells with
fairly normal
differentiation – exhibits a variable
tendency to progress to
acute leukemia

Question 23

which chromsome is associated with the CML

Answer 23

philadelphia chromosome.

• translocation between chromosomes 9 and 22.

Chimeric BCR-ABL mRNA
Image copyright unknown
translated into function
protein

Question 24

role of BCR gene mutation

Answer 24

Transforms cytokine-dependent (normal) lymphoid and myeloid hematopoietic cell lines to become cytokine- independent for survival & proliferation

 BCR-ABL fusion protein (from philedelphia chromosome)
– constitutively active tyrosine kinase that can phosphorylate a number of cytoplasmic substrates – acts on a number of signalling pathways & intermediates to promote leukemogenesis – leads to alterations in cell proliferation, differentiation,
adhesion, & survival

 Tyrosine kinase activity is absolutely required for
transformation by BCR-ABL
– attractive and rational target for therapy

Question 26

clinical course of CML

Answer 26

1. chronic
2. accelerated
3. blast phases (defined by marrow blast %)

Question 27

clinical features of CML

Answer 27

• fatigue, weightloss, nightsweats
• splenomegaly, sometimes hepatomegaly, causing abdominal pain and early satiety
• anemia causing palpations and dyspnea
• platelet dysfunction (purpura common, bleeding is increased in blast phase)
• priapism in males with hyperleukocytosis
• acute gouty arthritis (cytokine increases and uric acid)
• sternal tenderness, low back pain (due to bone marrow expansion)

Question 28

lab features of CML

Answer 28

• high WBC
• mature and immature neutrophils

myelocytes>metamyelocytes

• basophilia
• anemia
• thrombocytosis
• increased LDH, uric acid levels because of increased cell turnover.

Question 29

bone marrow findings

Answer 29

the bone marrow willlook super homogenous – too many WBC in the bone marrow. there will be increased reticulin fibrosis and vascularity.

Question 30

required findings for diagnosis of CML

Answer 30

• detection of Ph chromosome or its products (BCL-ABL fusion mRNA or protein) is REQUIRED for the diagnosis of CML.
• You can tell CML on PBS but you still need to stage it on a biopsy or physical exam, and then confirm it with pH chromosome identification
• can confirm it with karyotyping, FISH**, RT-PCR

Question 31

natural history of CML before imatinib

Answer 31

1. Remained stable for 3-4 years before
   evolution to accelerated or blast
   phase
    Prior to imatinib, those who did not
   undergo stem cell transplantation
   had 10-yr survival <30%
   – rate of transformation to blast phase 5-
   10%/year x 2years, then 25%/year
   thereafter
2. Acquisition of other chromosomal changes and/or dysregulation of differentiation-regulatory genes
    Accumulation of immature precursors & blasts in
   marrow, blood, and extramedullary tissue
    Accelerated phase
   – marrow blasts 10-19%
   – without SCT or TKI (tyrosine kinase inhibitor) therapy
   median survival 12-18 months
   3. death due to transformation to blast phase & associated
   life-threatening conditions

Question 33

based on the image, this patient is in ____ phase

Answer 33

blast phase. acute leukemia with >20% blasts. Can be myeloid or lymphoid.

Without SCT or
imatinib median
survival 3-6 months
– death from infection,
Image copyright unknown
bleeding, end-organ
extramedullary
leukemic infiltration

Question 34

Broad therapy options for CML

Answer 34

 Tyrosine kinase inhibitors
 Allogeneic HSCT (second line)
 Other therapies
– IFN & cytarabine
– novel therapies
 Palliative therapy

Question 35

outline the general mechanism of TKIs

Answer 35

Question 36

standard of care for CML treatment

Answer 36

1. TKI first line therapy. despite great results, 16% progress ontol imatinib therapy because they developed TKI resistance.

Second generation and third generation TKIs have been
shown to be more effective at achieving remissions
– better than imatinib (head-to-head) in achieving molecular
remissions; awaiting long-term results to show durability – Each have their own side effect profile that needs to be
considered – possibility of cure under study meaning could possibly stop the
drugs

2. imatinib
3. stem cell line therapy/transplant (if they failed TKI therapy or those who initially present in accelerated or blast phases)

** ALSO there is interferon alpha (significant side effects) as well as palliative care like hydroxyurea (– effectively controls splenomegaly, hypercatabolic symptoms increased WBC & platelet counts during chronic phase of disease but does not alter natural history, rare cytogenetic responses)

Question 37

palliative care options for CML

Answer 37

1. hydroxyurea to control symptoms like splenomegaly
2. bysulfuram
3. splenic irradiation or splenectomy