Hematopoietic Agents:

Growth Factors, Minerals,

and Vitamins
dr. Hikmawan W. Sulistomo, Ph.D
Pharmacology Department
Faculty of Medicine
Brawijaya University
Hematopoiesis
• Hematopoiesis also requires an
adequate supply of minerals
(e.g., iron, cobalt, and copper)
and vitamins (e.g., folic acid,
vitamin B , pyridoxine, ascorbic
12

acid, and riboflavin)

Growth Factor Physiology
OUTLINE
1. Erythropoiesis-Stimulating Agents
2. Myeloid Growth Factors
• Myeloid Growth Factors
• Granulocyte Colony-Stimulating Factor
3. Thrombopoietic Growth Factors
• Interleukin 11
• Thrombopoietin Receptor Agonists
4. Iron Deficiency and Other Hypochromic Anemias
• Oral and parenteral iron
• Copper , Pyridoxine, and Riboflavin
5. Vitamin B12 , Folic Acid, and the Treatment of Megaloblastic Anemias
• Vitamin B12
• Folic Acid
Erythropoiesis-Stimulating
Agents
Erythropoiesis-stimulating agent (ESA) is the term given to a pharmacological
substance that stimulates red blood cell production
Erythropoietin
Physiology
• Erythropoietin is expressed
primarily in peritubular interstitial
cells of the kidney
• Erythropoietin contains 193 amino
acids
• With anemia or hypoxemia,
synthesis rapidly increases by 100-
fold or more, serum erythropoietin
levels rise, and marrow progenitor
cell survival, proliferation, and
maturation are dramatically
stimulated.
Erythropoietin
Preparations
• epoetin alfa,
• epoetin beta,
• epoetin omega, and
• epoetin zeta

When injected intravenously, epoetin alfas are cleared from plasma

with a t1/2 of 4–8 h
However, the effect on marrow progenitors lasts much longer, and
once-weekly dosing can be sufficient to achieve an adequate response.
 Erythropoietin
Blood Doping

This misuse of the drug has been implicated in the deaths of several athletes
and is strongly discouraged.
Erythropoietin
Therapeutic Uses, Monitoring, and Adverse Effects
Therapeutic Uses
• Anemia of Chronic Renal Failure
• Anemia in Patients With AIDS
• Cancer-RelatedAnemias
• Use in Perioperative Patients
• Other Uses
Adverse Effects
• The most common side effect of
epoetin alfa therapy is
aggravation of hypertension,
which occurs in 20%–30% of
patients and most often is
associated with a rapid rise in
hematocrit.
• ESAs should not be used in
patients with preexisting
uncontrolled hypertension.
Myeloid Growth Factors
The myeloid growth factors are glycoproteins that stimulate the proliferation and
differentiation of one or more myeloid cell types.
Myeloid Growth Factors
• Myeloid growth factors are
produced naturally by a number of
different cells, including fibroblasts,
endothelial cells, macrophages, and
T cells
• Recombinant forms of several
growth factors have been produced,
including GM-CSF, G-CSF, IL-3, M-
CSF or CSF-1, and stem cell factor
(SCF), although only G-CSF and GM-
CSF have found meaningful clinical
applications.
Granulocyte-Macrophage Colony-Stimulating
Factor
• Recombinant human GM-CSF (sargramostim) is
a glycoprotein with 127 amino acids
• The primary therapeutic effect of sargramostim
is to stimulate myelopoiesis
• Sargramostim is administered by subcutaneous
injection( t1/2 of 2–3 h) or slow intravenous
infusio
• Once the drug is discontinued, the leukocyte
count returns to baseline within 2–10 days
• Frequent blood counts are essential to avoid an
excessive rise in the granulocyte count. Higher
doses are associated with more pronounced
side effects, including bone pain, malaise, flu-
like symptoms, fever, diarrhea, dyspnea, and
rash.
Granulocyte Colony-Stimulating Factor
• Recombinant human G-CSF,
filgrastim, is a glycoprotein with
175 amino acids.
• The principal action of filgrastim
is the stimulation of CFU-G to
increase neutrophil production
• Filgrastim is effective in the
treatment of severe neutropenia
after autologous hematopoietic
stem cell transplantation and
high-dose cancer chemotherapy
Thrombopoietic Growth
Factors
Interleukin 11
• Interleukin 11 is a cytokine that stimulates
hematopoiesis, intestinal epithelial cell growth,
and osteoclastogenesis and inhibits
adipogenesis.
• IL-11 also enhances megakaryocyte maturation
in vitro.
• The major complications of therapy are fluid
retention and associated cardiac symptoms,
such as tachycardia, palpitation, edema, and
shortness of breath; this is a significant concern
in elderly patients and often requires
concomitant therapy with diuretics.
Thrombopoietin Receptor Agonists
Thrombopoietin
• Thrombopoietin, a glycoprotein
produced by the liver, marrow
stromal cells, and other organs,
is the primary regulator of
platelet production
• The agents are FDA approved for
use in patients with immune
thrombocytopenia (ITP)
Iron Deficiency and Other
Hypochromic Anemias
Iron deficiency
• Iron deficiency is the most
common nutritional cause of
anemia in humans.
• It can result from inadequate
iron intake, malabsorption,
blood loss, or an increased
requirement, as with pregnancy.
Metabolism of Iron

The two predominant sites of iron

storage are the reticuloendothelial
system and the hepatocytes
The limited physiological losses of iron
point to the primary importance of
absorption in determining the body’s iron
content
Iron Requirements; Availability of Dietary
Iron
Treatment of Iron Deficiency
• The response of iron deficiency anemia to iron therapy is influenced
by several factors:
• the severity of anemia,
• the ability of the patient to tolerate and absorb medicinal iron,
• the presence of other complicating illnesses.
Treatment of Iron Deficiency
• Therapeutic effectiveness is best measured by the resulting increase in the rate of
production of red cells.
• Clinically, the effectiveness of iron therapy is best evaluated by tracking the
reticulocyte response and the rise in the hemoglobin or the hematocrit. An increase
in the reticulocyte count is not observed for at least 4–7 days after beginning therapy.
• A measurable increase in the hemoglobin level takes even longer. A decision regarding
the effectiveness of treatment should not be made for 3–4 weeks after the start of
treatment.
• An increase of 20 g/L or more in the concentration of hemoglobin by that time should
be con- sidered a positive response, assuming that no other change in the patient’s
clinical status can account for the improvement and that the patient has not been
transfused.
Therapy With Oral Iron
Oral iron
• Ascorbic acid (≥200 mg)
increases the absorption of
medicinal iron by at least 30%.
• The average dose for the
treatment of iron deficiency
anemia is about 200 mg of iron
per day (2–3 mg/kg), given in
three equal doses of 65 mg.
Side effects of oral iron preparations
• Heartburn, nausea, upper gastric discomfort, and diarrhea or
constipation.
• A good policy is to initiate therapy at a small dosage and then
gradually to increase the dosage to that desired.
Iron Poisoning
• Large amounts of ferrous salts are toxic, but fatalities are rare in adults.
• Most deaths occur in children, particularly between the ages of 12 and
24 months. As little as 1–2 g of iron may cause death, but 2–10 g
usually is ingested in fatal cases.
• Signs and symptoms of severe poisoning may occur within 30 min after
ingestion or may be delayed for several hours.
• They include abdominal pain, diarrhea, or vomiting of brown or bloody
stomach contents containing pills. Of particular concern are pallor or
cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and
cardiovascular collapse.
Iron chelator
Therapy With Parenteral Iron
• When oral iron therapy fails, parenteral iron administration may be an
effective alternative.
• Common indications:
• Iron malabsorption (e.g., sprue, short-bowel syndrome),
• Severe oral iron intolerance,
• a routine supplement to total parenteral nutrition,
• Patients who are receiving erythropoietin.
Parenteral iron preaparations
Therapy With Parenteral Iron
• Parenteral iron therapy should
be used only when clearly
indicated because acute
hypersensitivity, including
anaphylactic and anaphylactoid
reactions, can occur.
Copper
• In mammals, the liver is the
organ most responsible for the
storage, distribution, and
excretion of copper.
• Copper deficiency is extremely
rare; the amount present in food
is more than adequate to
provide the needed body
complement of slightly more
than 100 mg.
Pyridoxine
• Oral therapy with pyridoxine is
of proven benefit in correcting
the sideroblastic anemias
associated with the
antituberculosis drugs isoniazid
and pyrazinamide, which act as
vitamin B6 antagonists.
• if pyridoxine is given to
counteract the sideroblastic
abnormality associated with
administration of levodopa, the
effectiveness of levodopa in
controlling Parkinson disease is
decreased.
• Pyridoxine therapy does not
correct the sideroblastic
abnormalities produced by
chloramphenicol or lead.
Riboflavin
• The spontaneous appearance in humans of red cell aplasia due to
riboflavin deficiency undoubtedly is rare, if it occurs at all.
• Riboflavin deficiency has been described in combination with
infection and protein deficiency, both of which are capable of
producing hypoproliferative anemia.
Vitamin B12 , Folic Acid, and the
Treatment of Megaloblastic
Anemias
Cellular Roles of Vitamin B12 and Folic
Acid
• Intracellular vitamin B12 is maintained as
two active coenzymes: methylcobalamin
and deoxyadenosylcobalamin
• Methylcobalamin (CH3B12) supports the
methionine synthetase reaction, which is
essential for normal metabolism of folate
(Weissbach, 2008). Methyl groups
contributed by methyltetrahydrofolate
(CH3H4PteGlu1) are used to form
methylcobalamin, which then acts as a
methyl group donor for the conversion of
homocysteine to methionine.
• This folate-cobalamin interaction is pivotal
for normal synthesis of purines and
pyrimidines, and therefore of DNA.
Vitamin B and Human Health
Deficiency of vitamin B12
1. Inadequate dietary supply;
2. Inadequate secretion of intrinsic factor
(classical pernicious anemia);
3. Ileal disease;
4. Congenital absence of TcII;
5. Rapid depletion of hepatic stores by
interference with reabsorption of vitamin
B12 excreted in bile.
6. The appearance of abnormal amounts of
TcI and TcIII in plasma.
7. The formation of methylcobalamin
requires normal transport into cells and an
adequate supply of folic acid as
CH3H4PteGlu1.
Cyanocobalamin
• Cyanocobalamin is administered in doses of 1–1000 μg. Tissue uptake,
storage, and utilization depend on the availability of transcobalamin II.
• Doses greater than 100 μg are cleared rapidly from plasma into the
urine, and administration of larger amounts of vitamin B12 will not
result in greater retention of the vitamin.
• Administration of 1000 μg is of value in the performance of the Schilling
test. After isotopically labeled vitamin B12 is administered orally, the
compound that is absorbed can be quantitatively recovered in the urine
if 1000 μg of cyanocobalamin is administered intramuscularly.
Folic Acid and Human Health
General Principles of Therapy
• Dietary supplementation is necessary when there is a requirement
that may not be met by a “normal” diet.
• Any patient with folate deficiency and a megaloblastic anemia should
be evaluated carefully to determine the underlying cause of the
deficiency state.
• Therapy always should be as specific as possible.
• The potential danger of mistreating a patient who has vitamin B12
deficiency with folic acid must be kept in mind.
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