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Pharm Exam 1
Set 16: Hematopoiesis
102
Pharmacology
Graduate
10/14/2011

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Cards

Term
Why is hematopoiesis necessary?
Definition
short life span of blood cells => need for continuous replacement
Term
def

anemia
Definition
significant reduction in functional red cell mass with consquent reduction in oxygen carrying capacity
Term
What are the 3 causes of anemia?
Definition
1) blood loss
2) reduced RBC production
3) production of abnormal RBCs or precursor cells
Term
What 9 cells are formed by hematopoiesis?
Definition
1) RBCs
2) eosinophils
3) basophils
4) ganulocytes
5) monocytes
6) platelets
7) B cells
8) T cells
9) NK cells
Term
What plays a role in synthesis of mature cells in hematopoiesis?
Definition
GFs & cell-cell interactions
Term
Where is erythropoietin synthesized?
Definition
proximal tubular cells of kidney
(sm. amount made in liver)
Term
Why is erythropoietin glycosylated?
Definition
to prolong half life (it is not essential)
Term
Function

erythropoietin
Definition
1) Reulation of proliferation of committed progenitors (CFU-E), maturation of erythroblasts, & release of reticulocytes
2) Synergistic with IL-3 & GM-CSF to expand BFU-E population
3) promote release of maturer reticulocytes into circulation from bone marrow
4) prevent anemia
Term
When will a patient have a rapid increase of erythropoietin?
Definition
anemia or hypoxia
Term
How does erythropoietin promote maturation of committed progenitors?
Definition
binds to membrane surface receptor of bone marrow cells
Term
What are myeloid GFs aka?
Definition
colony-stimulating GFs (CSFs)
Term
def

CSFs
Definition
glycoproteins that stimulate proliferation & differentiation of several types of hematopoietic precursor cells & enhance the function of mature leukocytes.
Term
What are the 4 human CSFs?
Definition
1) GM-CSF (granulocyte/macrophage)
2) M-CSF (macrophage)
3) G-CSF (granulocyte)
4) IL-3
Term
What synthesizes GM-CSF & IL-3?
Definition
T cells
Term
What synthesizes GM-CSF, G-CSF, & M-CSF?
Definition
monocytes, fibroblasts, & endothelial cells
Term
Function

IL-3
Definition
1) stimulate colony formation of most hematopoietic cell lines
2) synergistic with GM-CSF to increase neutrophils, monocytes & eosinosinophils
3) synergistic with erythropoietin to expanf BFU-E compartment & stimulate CFU-E proliferation
4) influence function of eosinophils & basophils
Term
Function

GM-CSF
Definition
1) synergistic with IL-3 to stimulate colony formation & proliferation of granulocytes, monocytes/macrophages, & megakaryocytes
2) synergistic with erythropoietin to promote formation of BFU-E
3) increases phagocytic & cytotoxic potential of mature granulocytes, but reduces motility & clearance from circulation
4) increases cytotoxicity of eosinophils & leukotriene synthesis
Term
Function

G-CSF
Definition
1) stimulate granulocyte colony formation
2) synergistic with GM-CSF to simulate granulocyte/macrophage colonies & with IL-3 to induce formation ot megakaryocytes
3) induce release of granulocytes from marrow
4) enhance phagocytic & cytotoxic activities of mature granulocytes
Term
Function

M-CSF
Definition
1) stimulate monocyte/macrophage colony formation alone & synergistically with GM-CSF & IL-3
2) induce synthesis of G-CSF & IL-1
3) enhance production of IFN & TNF
4) enhance function of monocytes & macrophages
Term
How is erythropoietin administered for therapeutic purposes?
Definition
parenterally, IV or sc
Term
How is erythropoietin used clinically?
Definition
1) anemia due to chronic renal failure
2) transfusion-dependent patients undergoing hemodialysis
3) anemia in patients with progressive renal failure (not requiring dialysis)
4) other anemias
5) preop to increase RBCs to allow storage of larger volumes of blood for autologous transfusion
Term
Do I hate learning about hematopoiesis?
Definition
yes!
(i hope someone reads this card, bc its true)
Term
What is the half life of patients on erythropoietin in chronic renal failure for IV administration?
Definition
~10 hrs
Term
When is peak plasma concentration seen in SC injection of erythropoietin
Definition
5-24 hrs
Term
Why must dose of erythropoietin be titrated?
Definition
to avoid excessively rapid increase in hematocrit early in therapy or a rise in hematocrit above 36% during maintenance
Term
Why might a patient need iron supplements in addition to erythropoietin?
Definition
erythropoietin requires adequate iron stores
Term
SE

erythropoietin toxicity
Definition
increase of RBC => HTN & thrombotic phenomena
possible mild allergic rxn
Term
How is erythropoietin SE avoided?
Definition
raising hematocrit slowly & closely monitoring BP
Term
What internal cell singals occur in the kidney to produce more erythropoietin?
Definition
Gs stimulation -> increase AC -> increase cAMP -> activation of Kinase A -> activation of phosphoproteins -> stimulation of mRNA production of erythropoietin
Term
What are the 4 major areas meyloid GFs (CSFs) are used clinically?
Definition
1) restoration of normal hematopoiesis in patients with malignancies or non-neoplastic diseases that interfere with marrow production
2) reduction in the morbidity of chemotherapy by diminishing duration of severe neutropenia
3) augmentation of host defenses against inf.
4) adjunct role in chemotherapy to improve cytotoxicity against tumor cells & promote cell maturation
Term
SE

CSF toxicity
Definition
site of injection: local induration
site of infusion: thrombophlebitis
fever, myalgia, fatigue, rash, GI Sx, bone pain (common, but dose dependent)
pericarditis, pleuritis, pleural effusions, & pulmonary emboli (dose-limiting)
G-CSF associated with: mild/moderate bone pain, vasculitis & worsening of psoriasis
may have ongogenic potential
Term

Hematopoietic GFs

[image]

Definition
1) GM-CSF/IL-3
2) Erythropoietin
3) GM-CSF/G-CSF
4) GM-CSF/M-CSF
Term
A 60 yo woman presents with stage IV ovarian cancer. The standard of care Tx is cytoreductive surgery followed by administration of systemic chemotherapy.

1st line therapy consists of carboplatin in combination with paclitaxel. The drugs are given via IV infusion. The "madir" occurs b/w days 10-14.

What can be done to mitigate leukopenia & anemia?
Definition
Administration of one of the CSFs to promote maturation of the progenitive cells.
Term
An obese woman of child bearing age with fertility issues presents for couseling. Blood tests show hemoglobin values <130 g/L.

Example questions: Which follow up tests would you order & what are the likely causes of her anemia? How could this anemia be treated? What impact would be had on a developing fetus if left untreated?

What is this case study illustrating (the only actual question answered on card)?
Definition
It's important to understand the etiology of an anemia before any Tx is delivered or prognosis.
Term
What is the most common cause of nutritional anemia?
Definition
iron deficiency
Term
What is the characteristic result of severe iron deficiency?
Definition
microcytic, hypochromic anemia secondary to reduction in synthesis of Hb
Term
Why does iron deficiency have effects besides those on RBCs?
Definition
Iron is a required group in many other proteins.
Term
Besides its affect of RBCs, what other effects might occur in iron deficiency?
Definition
altered muscle metabloism independent of the effect on oxygen delivery via blood
Term
What are the 3 causes of iron0deficiency anemia?
Definition
1) inadequate dietary iron
2) blood loss
3) interference with iron absorption
Term
What is the cause of most nutritional iron deficiency in the U.S.?
Definition
blood loss
1) by the GI
2) by the uterus
Term
How is iron found in the body?
Definition
1) in essential iron containing compounds
2) stored (excess)
Term
Where is 70% of the iron in our body found?
Definition
Hb in RBCs
Term
What is the storage form of iron?
Definition
ferritin
Term
How much is ferritin found (molecules or aggregates)?
Definition
either individual molecules or aggregated form
Term
How many atoms of iron can each ferritin molecule bind?
Definition
4000 atoms
Term
def

hemosiderin
Definition
aggregated ferritin
Term
Where is hemosiderin predominately found?
Definition
reticuloendothelial system in liver
(some in muscle)
Term
What is the plasma protein for iron transport?
Definition
transferrin
Term
What regulates sysnthesis of transferrin receptors & ferritin?
Definition
iron supply
1) when high, sysnthesis of transferrin receptors are reduced & ferritin production is increased
2) if low, tranferrin receptors are increased and ferritin production is decreased
Term
Why is dietary intake or realease from body stores the primary determinant of iron content in cells?
Definition
low body turnover of iron
Term

Where does each stage of Fe absorption pathway occur?

[image]

Definition
1) intestinal lumen
2) mucosa
3) blood
4) tissue
Term
What determines iron requirements?
Definition
Obligatory physiological losses & need for growth
Term
Why do females require more iron/day than males?
Definition
obligatory loss (menses)
Term
When do females need 4x the normal amount of iron/day?
Definition
last 2 trimesters of pregnancy
Term
When else might a patient need 4x the daily dose of iron?
Definition
infants (due to rapid growth)
Term
What are the dietary sources of iron?
Definition
Good: organ meats, egg yolk, oyster, certain dried beans & fruit
Poor: dairy, non-green vegetables
Term
What is the most readily bioavailable form of iron?
Definition
heme iron (but non heme iron is the majority of dietary iron)
Term
What helps the absorption of nonheme iron?
Definition
ascorbate
Term
How does ascorbate increase nonheme iron absorption?
Definition
1) complexing with iron 2) reducing Fe3+ to Fe2+
Term
What are the 2 options of iron deficiency Tx?
Definition
1) Oral iron therapy
2) parenteral iron therapy
Term
SE

oral iron therapy
Definition
nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea (dose related)
Term
How are oral iron therapy SE avoided?
Definition
taking tablets with meals
Term
When might an iron deficient patient recieve parenteral iron therapy?
Definition
1) cannot tolerate or absorb oral iron
2) chronic blood loss

(since iron stores are repleated more rapidly than by oral therapy)
Term
How are Vit B12 & folic acid deficiencies interconnected?
Definition
Vit B12 is needed for folic acid to work => deficiency of either results in decreased synthesis of methionine & S-adenosylmethionine => interference with protein synthesis & methylation rxns
Term
What does Vit B12 complex with in the stomach in order to be absorbed?
Definition
intrinsic factor (IF)
Term
What secretes IF in the stomach?
Definition
parietal cells
Term
What plasma protein transports Vit B12?
Definition
transcobalamin II
Term
What happens to excess Vit B12?
Definition
stored in liver or excreted in urine
Term
What is the source of Vit B12?
Definition
microorganisms only
Term
Why is Vit B12 deficiency rare?
Definition
It would take 3-4 yrs to develop b/c of liver storage
Term
What does absorption of folate require?
Definition
transport & a pteroyl-γ-glutamyl carboxypeptidase associated with intestinal muscoal membranes
Term
Where does most absorption of folate occur?
Definition
duodenum & upper jejunum
Term
What form are folates transported to tissus?
Definition
MeFH4
Term
How are folates uptaken into cells?
Definition
receptor mediated endocytosis
Term
What are the sources of folates?
Definition
almost all foods, esp. green vegetables, liver, yeast, and some fruit (tho cooking can destroy up to 90% of folate content in foods)
Term
What 2 systems are effected by Vit B12 deficiency?
Definition
hematopoietic and nervous systems
Term
Why is hematopoiesis sensitive to Vit B12 deficiency?
Definition
due to its high rate of cell turnover which means it requires high reates of DNA synthesis
Term
What does insufficient Vit B12 do to DNA synthesis & eventually cell maturation?
Definition
results in highly abnormal DNA => inability of maturing cells to complete nuclear divisions (tho cytoplasmal maturation occurs normally) => production morphologically abnormal cells that die during maturation (most profound effect is in producing abnormally large RBCs - megaloblastic anemia)
Term
What causes for Vit B12 deficiencies?
Definition
malabsorption due to deficiency in IF or in absorption of IF-B12 complex
Term
How is Vit B12 deficiency treated?
Definition
parenteral injections of Vit B12 (usually lifelong do to incurable syndromes)
Term
How is Vit B12 deficiency diagnosed?
Definition
serum measurement of Vit B12 &/or methylmalonic acid
Term
What causes folic acid deficiency?
Definition
inadequate dietary intake
Term
Who often develops folic acid deficiencies?
Definition
Elderly
Poor
Diets lacking vegetables, eggs & meat
Alcoholics & other patients with liver disease
Term
Does megaloblastic anemia differentiate b/w Vit B12 or folate deficiencies?
Definition
no, they both cause it
Term
Tx

folic acid deficiencies
Definition
1) proper diagonosis so you don't treat for folic acid deficiency when it's more rare Vit B12 deficiency 2) folate therapy
Term
What does folate therapy do in Vit B12 deficiency?
Definition
relieves the megaloblastic anemia, but doesn't alter neurological defects due to the Vit B12 deficiency
Term
When can Cu deficiency occur (very rare)?
Definition
intestinal bypass surgery, parenteral nutrition, malnourished infants, Zinc overdose

(NOT usually seen in those with hypocupremia)
Term
def

Menke's disease
Definition
decrease activity of Cu-dependent enzymes due to decreased Cu transport (NO hematological abnormalities)
Term
Sx

Cu deficiency
Definition
leukopenia (esp. granulocytopenia)
anemia
Term
When is Cu therapy indicated?
Definition
with low plasma [Cu], leukopenia & anemia
Term
What is Cu deficiency usually comorbid with?
Definition
other nutritional deficiencies
Term
Can humans have Cobalt (Co) deficiency?
Definition
None reported
Term
When is Co therapy beneficial?
Definition
pure red-cell aplasia
Term
What is Co effect on the body?
Definition
inhibit enzymes in oxidative metabolism => tissue hypoxia => erythropoietin increase
Term
What happens in Co intoxication?
Definition
depress erythropoiesis

in children: cyanoisis, coma, death
Term
When can oral therapy with pyridoxine Vit B6 increase hematopoiesis?
Definition
hereditary or acquired sideroblastic anemia
Term
What characterizes sideroblastic anemia?
Definition
impaired Hb synthesis & accumulation of iron in mitochondria of erythroid precursor cells.
Term
What causes hereditary sideroblasic anemia?
Definition
x-linked recessive trait (variable penetrance & expression)
Term
What causes acquired sideroblastic anemia?
Definition
number of drugs
inflammatory states
neoplastic disorders
preleukemic syndromes
Term
What rare syndromes can be seen due to riboflavin deficiency?
Definition
spontaneous red-cell aplasia
hypoproliferative anemia
Term
When is riboflavin administration reported to be beneficial?
Definition
correcting red-cell aplasia in patients with protein depletion
Term
def

red cell aplasia
Definition
anemia effecting RBC precursors
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