Anemia and blood components Flashcards
A remarkable process that produces more than
200 billion new blood cells per day in the normal
person and even greater numbers of cells in
persons with conditions that cause loss or
destruction of blood cells
HEMATOPOIESIS
Hematopoietic machinery resides primarily in the
bone marrow in adults and requires a constant
supply of three essential nutrients:
○ Iron
○ Vitamin B12
○ Folic acid
proteins regulate the proliferation and differentiation of hematopoietic cells
Hematopoietic Growth Factors
deficiency in oxygen-carrying
erythrocytes, is the most common deficiency and
several forms are easily treated
anemia
So children with microcytic anemia as well as low
reticulocyte count most often have
defect in your
erythroid maturation and ineffective
erythropoiesis
Most common cause of chronic anemia
particularly in the pediatric population
IRON DEFICIENCY ANEMIA
iron deficiency anemia would present with
pallor, easy
fatigability, dizziness, exertional dyspnea and
generalized symptoms of tissue hypoxia.
The cardiovascular adaptations of chronic
anemia would include
tachycardia, increased
cardiac output, vasodilation
typical microscopic finding in px with Iron deficiency
microcytic hypochromic
anemia.
T or F
In the absence of adequate iron, small
erythrocytes with insufficient hemoglobin are
formed
T
also an essential
component of myoglobin, cytochromes, and other
proteins with diverse biologic functions
iron containing heme
Forms the nucleus of the iron-porphyrin heme
ring, which together with globin chains forms
hemoglobin.
iron
T or F
free inorganic iron is extremely toxic
T
peptide produced primarily by liver cells, serves as a key central regulator of the
system
Hepcidin
Nearly all of the iron used to support hematopoiesis is reclaimed from
catalysis of the
hemoglobin in senescent or damaged
erythrocytes.
The absorption of iron involves two mechanisms:
Intestinal epithelial cells actively absorb inorganic
iron via the divalent metal transporter 1 (DMT1)
and heme iron via the heme carrier protein 1
(HCP1).
Iron that is absorbed or released from absorbed
heme iron in the intestine (1) is actively transported into the blood by
ferroportin
Iron that is absorbed or released from absorbed
heme iron in the intestine (1) is stored into the blood by
ferritin
in the blood, iron is transported by __________ to erythroid precursor in the bone marrow for synthesis of Hgb in RBC
transferrin
The transferrin-iron complex binds to
transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized.
Hepatocytes use several mechanisms to take up
iron and store the iron as
ferritin
Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC
hemoglobin and either
export or store
hepcidin ______ ferroportin
inhibits
high hepatic iron stores ________ hepcidin synthesis
increases
what inhibits hepcidin
low hepatocyte iron and increased erythroferrone
absorbed iron can be oxidized to ferric iron by the
ferroxidase hephaestin
Excess iron is stored in ___________
as ferritin
intestinal epithelial cells
shell of a specialized storage protein
apoprotein
ferritin is a water-soluble complex consisting of a core of_________ covered by a shell of a specialized storage protein called apoferritin.
ferric hydroxide
average american diet (iron)
10-15mg elemental iron
Normal individual would absorb ___% iron
5-10 (1-2mg per day)
iron is absorbed in the
Duodenum and proximal jejunum (active transport)
for a dietary iron to be easily absorbed, it should be converted into
ferrous state (in an acidic environment)
ferrous form would then bind with _______ for transport in the bone marrow wherein it is incorporated into the hgb of mature erythrocyte
transferrin
GI absorption of iron is increased in
Iron deficiency states
erythropoeisis occurs at a more rapid rate
Iron crosses the luminal membrane of the
intestinal mucosal cell by two mechanisms:
Active transport of ferrous iron by the
divalent metal transporter DMT1
Absorption of iron complexed with heme
total iron absorption in pregnant women
3-4mg/day
Transported in the plasma bound to transferrin, a
β-globulin that can bind _____ molecules of ferric iron
two
Transferrin receptors—integral membrane
glycoproteins present in large numbers on
proliferating erythroid cells—bind and internalize
the transferrin-iron complex through the process
of receptor-mediated endocytosis
In endosomes, the ferric iron is released, reduced
to ferrous iron, and transported by ______ into the
cytoplasm, where it is funneled into hemoglobin
synthesis or stored as ferritin.
DMT1
The transferrin-transferrin receptor complex is
recycled to the cell membrane, where the_______ dissociates and returns to the plasma.
transferrin
T or F
Inhibition of hepcidin would enhance iron absorption via ferroportin
T
menstruating women lose about __ mg of iron w each menstrual perion
30
iron administration preferred for pxs with CKD
parenteral
helps to increase GI tolerance and decrease the side effect and increase the bioavailability of most of these iron preparations
sustained release and enteric coated preparations
helps in increasing the absorption of iron
acidic env (vit c)
treatment with oral iron should be continued for ____ months after correction of the cause of the iron loss
3-6
In an iron-deficient individual, about ______
of iron can be incorporated into hemoglobin daily
50–100 mg
mg of elemental iron that should be given daily to corrects iron deficiency most rapidly
200-400mg
initially, if the dose of iron is adequate, your reticulocye count would begin to increase by
3rd-4th day and peak by 7th-10th day of therapy
the magnitude of the marrow response to iron therapy is
proportional to the severity of the anemia and the amount of iron delivered to marrow precursors
T or F
An increase in the reticulocyte count is not observed for at least 4 to 7 days after beginning therapy
T
An increase of _________ in the concentration
of hemoglobin by that time should be considered a positive response.
20 g/L or more
occult blood test or guiac test
to determine if the black stool is secondary to iron or bleeding (+) bleeding
would inhibit serum iron absorption by increasing the pH of the stomach and decreasing the solubility of the ferrous salt,
PPI
drugs that would enhance the absorption of iron
ascorbic acid, chloramphenicol
is a tatracycline that would decrease absorption of iron.
doxycycline
other drugs that would decrease absorption of iron
cephalosporin, fluoroquinolone, levodopa, levothyroxine, methyldopa
three traditional forms of parenteral iron:
○ Iron Dextran ○ Sodium ferric gluconate complex ○ Iron sucrose
colloidal iron preparation embedded within a carbohydrate polymer
ferric carboxymaltose
stable complex of ferric oxyhydroxide and dextran polymers
Iron dextran
mg elemental iron per mo solution of Iron dextran
50mg
iron dextran adverse effect
headache, light-headedness, fever, arthralgias, nausea and vomiting, back
pain, flushing, urticaria, bronchospasm,
and, rarely, anaphylaxis and death
colloidal iron preparation embedded within a carbohydrate polymer
Ferric Carboxymaltose
○ superparamagnetic iron oxide
○ nanoparticle coated with carbohydrate
ferumoxytol
in ferumoxytol, carbohydrate shell is removed in the _____________
reticuloendothelial system
t or f
Ferumoxytol may interfere with magnetic resonance imaging (MRI) studies.
acute iron toxicity in children
necrotizing gastroenteritis with
vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea
what should be done to flush out unabsorbed pills
Whole bowel irrigation
a potent iron-chelating
compound, can be given intravenously to bind iron that has already been absorbed and to
promote its excretion in urine and feces.
Deferoxamine
CHRONIC IRON TOXICITY (Iron overload)
Hemochromatosis
a disorder
characterized by excessive iron
absorption in patients who receive many
red cell transfusions over a long period of
time (eg, individuals with β-thalassemia)
Hemochromatosis
Chronic iron overload in the absence of anemia is
most efficiently treated by
intermittent phlebotomy
less efficient or
ineffective as well as more complicated,
expensive, and hazardous, but it may be the only
option for iron overload that cannot be managed
by phlebotomy
VITAMIN B12 (COBA
Iron chelation therapy using parenteral
deferoxamine or the oral iron chelators
deferasirox or deferiprone
serves as a cofactor for
several essential biochemical reactions in
humans.
cobalamin (vit b12)
Deficiency of vitamin B12 leads to
megaloblastic anemia
gastrointestinal symptoms
neurologic abnormalities.
Sometimes called extrinsic factor
vit b12
a protein
secreted by the stomach that is required for
gastrointestinal uptake of dietary vitamin B12
intrinsic factor
active form of b12 in humans
Deoxyadenosylcobalamin and
methylcobalamin
Ultimate source of vitamin B12 is
microbial synthesis (meat (especially liver), eggs, and dairy products. )
average american diet b12
5-30mcg daily (1-5mcg
absorbed)
avidly stored, primarily in the liver, with an average
adult having a total vitamin B12 storage pool of
3000–5000 mcg
the intrinsic factor–vitamin B12
complex is subsequently absorbed in the
e distal ileum
by a highly selective receptor-mediated transport
system.
Once absorbed, vitamin B12 is transported to the
various cells of the body bound to a family of
specialized glycoproteins,
transcobalamin I, II, and III.
Excess vitamin B12 is stored in the
liver
B12 is converted to coenzyme B12–
essential for
hematopoiesis, maintenance of myelin (reason for causing neurologic abnormality when B12 is deficient) throughout the entire nervous system and production of epithelial cells
is responsible for
transporting absorbed B12 to the cell membranes and delivering it to other
organ
transcobalamin
elimination of b12
urine and stool
Two essential enzymatic reactions in humans
that would require B12:
Methyltransfer (methylcobalamin would
serve as intermediate for the transfer of methyl from N5-methyltetrahydrofolate to
tetrahydrofolate and is necessary for the production of methionine from homocysteine.)
Isomerisation of L-Methylmalonyl-CoA (In the absence of B12 there is an
increase/accumulation of methylmalonic
acid in urine.)
Methylcobalamin serves as an intermediate in the
transfer of a methyl group from N5-
methyltetrahydrofolate to homocysteine, forming
methionine
measures absorption and urinary excretion of radioactively labeled vitamin B12 used to further define the mechanism of vitamin B12 malabsorption when this is found to be the cause of the megaloblastic anemia
Schilling test
serves as a
cofactor for the synthesis of purine and dTMP.
THF
T or F
Folic acid can correct the neurologic manifestation in b12 deficiency
F
The accumulation of folate as N5-
methyltetrahydrofolate and the associated
depletion of THF cofactors in vitamin B12
deficiency
“methylfolate trap”
The most characteristic clinical manifestation of
vitamin B12 deficiency is
megaloblastic,
macrocytic anemia
The neurologic syndrome associated with vitamin
B12 deficiency usually begins with
paresthesias in peripheral nerves and weakness and
progresses to spasticity, ataxia, and other CNS
dysfunctions
The most common causes of vitamin B12
deficiency are:
○ Pernicious anemia ○ Partial or total gastrectomy ○ Conditions that affect the distal ileum ■ Malabsoption syndromes ■ IBD ■ Small bowel resection ○ Strict vegans eating a diet free of meat and dairy products may become B12 deficient
VITAMIN B12 DEFICIENCY CAUSES
● Inadequate dietary supply
● Inadequate secretion of intrinsic factor (classical
pernicious anemia)
● Ileal disease
● Congenital absence of TcII (transcobalamin)
● Rapid depletion of hepatic stores by interference
with reabsoption of vitamin B12 excreted in bile
● Appearance of abnormal amounts of TcI and TcIII
in plasma
● Inadequate supply of folic acid as CH3H4PteGlu1
Results from defective secretion of
intrinsic factor by the gastric mucosal
cells
PERNICIOUS ANEMIA
Almost all cases of vitamin B12 deficiency are
caused by malabsorption of the vitamin;
HYDROXOCOBALAMIN
○ Hydroxocobalamin is preferred
because
it is more highly protein-bound
and therefore remains longer in the
circulation
are usually
sufficient to treat pernicious anemia who
refuse/cannot tolerate injection
Doses of 1000mcg of B12 daily
Initial therapy should consist of _________ of
vitamin B12 intramuscularly (IM) daily or every
other day for 1-2 weeks to replenish body stores
100-1000 mcg
Maintenance therapy consists of
100-1000 mcg
IM once a month for life
If neurologic abnormalities are present,
maintenance therapy injections should be given
every
1-2 weeks for 6 months before switching to
monthly injections
Folic acid (pteroylglutamic acid) is composed of
heterocycle (pteridine), p-aminobenzoic acid, and
glutamic acid
Various numbers of glutamic acid moieties are attached
to the petroleum portion of the molecule, resulting in
mono glutamates, tri glutamates, or polyglutamates.
Folic acid undergoes reduction, catalyzed by the
enzyme dihydrofolate reductase (“folate reductase”), to
give
dihydrofolic acid.
subsequently transformed to folate
cofactors possessing one-carbon units attached to the
5-nitrogen, to the 10-nitrogen, or to both positions
Tetrahydrofolate
Average American Diet: folates
500-700mcg of folates daily
50-200mcg usually absorbed
Intake of folates for pregnant women
300-400mcg daily
richest source of folate
yeast, liver, kidney and green
vegetables
Folate is stored in the
liver and other tissues
Folate is absorbed in the
proximal jejunum.
Tetrahydrofolate cofactors participate in
one-carbon
transfer reactions.
In this reaction, the enzyme thymidylate synthase
catalyzes the transfer of the one-carbon unit of
N5, N10-methylenetetrahydrofolate to
deoxyuridine monophosphate (dUMP) to form
dTMP
dTMP CYCLE
The cofactor is oxidized to dihydrofolate, and for
each mole of dTMP produced,
1 mole of
tetrahydrofolate is consumed.
DNA synthesis requires continued
regeneration of tetrahydrofolate by
reduction of
dihydrofolate, catalyzed by the enzyme
dihydrofolate reductase
dihydrofolate reductase
• The tetrahydrofolate thus produced can then
reform the cofactor N5 , N10-
methylenetetrahydrofolate by the action of
serine
transhydroxymethylase and thus allow for the
continued synthesis of dTMP.
The combined catalytic activities of
dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are referred to as
the
dTMP synthesis cycle.
Methotrexate inhibits
dihydrofolate
reductase
Metabolite of 5-fluorouracil inhibits
thymidylate synthase
required for the
vitamin B12-dependent reaction that generates
methionine from homocysteine
N5 -Methylenetetrahydrofolate
Drugs which inhibit dihydrofolate
reductase.
(Methotrexate, Trimethoprim (TMP),
Pyrimethamine; Phenytoin)
Folic acid supplementation to prevent folic acid
deficiency should be considered in high-risk
patients
o pregnant women o patients with alcohol dependence o hemolytic anemia o liver disease o certain skin diseases o patients on renal dialysis
Glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow
HEMATOPOIETIC GROWTH FACTORS
○ first growth factors to be identified
○ stimulate the growth of colonies of
various bone marrow progenitor cells in
vitro
● Colony-stimulating factors
Stimulates RBC
production
Erythropoietin
stimulates Neutrophil
Granulocyte colony-stimulating factor
Thrombopoietin receptor agonists
(romiplostim and eltrombopag)
The preparation for Recombinant human
erythropoietin (rHuEPO) will include
alpha , beta
, omega and zeta
is producing your
mammalian cell expression system and it is given
3x/week.
is producing your
mammalian cell expression system and it is given
3x/week.
After intravenous administration,
erythropoietin has a serum half-life of
4–
13 hours in patients with chronic renal
failure.
○ 1x/week
○ modified form of erythropoietin
○ more heavily glycosylated as a result of
changes in amino acids
○ has a twofold to threefold longer half-life
than epoetin alfa
○ administered weekly
● Darbepoetin alpha
● Methoxy polyethylene glycol epoetin beta is administered
Single IV/SQ at 2 weeks or monthly
interval.
isoform of erythropoietin covalently
attached to a long polyethylene glycol
polymer
Methoxy polyethylene glycol epoetin beta .
● Stimulates erythroid proliferation and
differentiation by interacting with erythropoietin
receptors on red cell progenitors
● Induces release of reticulocytes from the bone
marrow.
Erythropoeitin
Normally, an inverse relationship exists between
the hematocrit or hemoglobin level and the serum
erythropoietin level.
○ EXCEPT
Anemia of CRF
Nonanemic individuals have serum erythropoietin
levels of
less than 20 IU/L.
T or F
As the hematocrit and hemoglobin levels fall and
anemia becomes more severe, the serum
erythropoietin level rises exponentially.
T
Patients with moderately severe anemia usually
have erythropoietin levels in the
100–500 IU/L
range,
How would you maintain the anemia of the
patient with CRF?
by giving Supplements with
Erythropoietin
Erythropoeitin clinical manifestations
● Anemia secondary to chronic Kidney disease .
● Patients undergoing myelosuppressive cancer
chemotherapy who have a hemoglobin level of
less than 10g/dl.
● Used illegally by endurance athletes to enhance
performance .
● In patients treated with an ESA , an increase in
reticulocyte count is usually observed in about 10
days .
● An increase in hematocrit and hemoglobin levels
in 2-6 weeks.
enhance the expression of your multiple hypoxia
inducible genes such as your Vascular
endothelial growth factor as well as
erythropoietin.
hypoxia inducible factor (HIF)
Most Common AE erythropoeitin
hypertension and thrombotic
complications
uncommon:
There have been small number of cases of pure
red cell aplasia (PRCA) accompanied by
neutralizing antibodies to erythropoietin
GCSF
○ Filgrastim (rHuGCSF)
○ Tbofilgrastim
○ Pegfilgrastim
○ Lenograstim
Has the ability to mobilize hematopoietic
stem cells, to increase their
concentration in peripheral blood
GCSF
use of peripheral blood stem cells (PBSCs) rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell transplantation
GCSF
Multipotential hematopoietic growth
factor that stimulates proliferation and
differentiation of early and late
granulocytic progenitor cells as well as
erythroid and megakaryocyte
progenitors.
GMCSF
Sargramostim (rHuGMCSF)
Stimulate the function of mature
neutrophils
GMCSF
GMCSF Acts together with ________ to
stimulate T-cell proliferation and appears
to be locally active factor at the site of
inflammation
interleukin-2
clinical uses of Myeloid growth factors
Cancer Chemotherapy induced Neutropenia ● Congenital Neutropenia. ● Cyclic Neutropenia. ● Myelodysplasia. ● Aplastic anemia. ● Autologous stem cell transplantation.
megakaryocyte growth factors
● Thrombopoietin 1. Romiplostim. 2. Eltrombopag. 3. Avatrombopag ● IL11 ○ Oprelvekin ● Fostamatinib
is a tyrosine kinase inhibitor
prodrug approved for use in patients with chronic
immune thrombocytopenia who have had an
inadequate response to other therapies
Fostamatinib
