Hematopoietic Growth Factors

Question 1

How early do anemic individuals show a response to iron sulfate?

Answer 1

Response within a week

Question 2

How long until anemic individuals’ hemoglobin levels return to normal following iron sulfate therapy?

Answer 2

1-3 months

Question 3

Adverse effects of oral ferrous sulfate

Answer 3

GI distress; black stool may obscure recognition of GI bleeding

Question 4

How to avoid GI distress with iron therapy

Answer 4

Take with meals

Question 5

What does parenteral iron consist of, and how is parenteral iron administered?

Answer 5

Iron dextran, IV or IM

Question 6

Indications of IV iron (3)

Answer 6

Post-gastrectomy/small bowel resection
Malabsorption syndromes
Intolerance of oral preps

Question 7

Indications of oral iron

Answer 7

Prevention or treatment of iron deficiency anemia (microcytic hypochromic anemia)

Question 8

Adverse effects of parenteral iron

Answer 8

Adverse effects: local pain and tissue staining with i.m., headache, fever, nausea, vomiting, back pain, arthralgias, urticaria, bronchospasm, anaphylaxis/death (rare)

Question 9

What causes acute iron toxicity?

Answer 9

Accidental ingestion of iron tablets

Question 10

What are the clinical features seen in acute iron toxicity? In what age group could it be fatal?

Answer 10

Necrotizing gastroenteritis
After short improvement, metabolic acidosis, coma and death

Children

Question 11

Treatment of acute iron toxicity (2)?

Would activated charcoal be effective?

Answer 11

(a) Gastric aspiration, lavage with phosphate or carbonate solution (get stomach pumped)
(b) Deferoxamine, a potent iron chelating substance, i.m. or i.v.

Activated charcoal is not effective

Question 12

Which patients show iron overload (chronic iron toxicity)?

Answer 12

Seen in an inherited disorder, hemochromatosis

Patients receiving repeated red cell transfusions

Question 13

Clinical features of iron overload?

Answer 13

Excess iron deposited in heart, liver and pancreas leading to organ failure

Question 14

Treatment of chronic iron toxicity (2)?

Answer 14

If no anemia, intermittent phlebotomy

Iron chelation via deferoxamine (parenteral) or deferasirox (oral)

Question 15

3 main causes of iron-deficiency anemia

Answer 15

Increased requirements

(1) Frequently present in premature infants
(2) Children during rapid growth period
(3) Pregnant and lactating women

Inadequate absorption: post-gastrectomy or severe small bowel disease

Blood loss

(1) Menstruation
(2) Occult gastrointestinal bleeding

Question 16

How do heme iron and non-heme iron enter the mucosal cell?

Answer 16

(1) Heme iron is absorbed intact from duodenum and jejunum
(2) Non-heme iron must be reduced to ferrous iron (Fe2+)
(3) The ferrous form is the absorbed through DMT1 by active transport

Question 17

How is the ferrous ion acted upon in the mucosal cell and how does it leave the mucosal cell?

Answer 17

(4) Within mucosal cell, ferrous iron is converted to ferric (Fe3+)
(5) Iron leaves the mucosal cell by passing through ferroportin
(6) Hepcidin downregulates ferroportin and regulates iron absorption

Question 18

Effects of iron deficiency and overload on transferrin and ferritin

Answer 18

In iron deficiency anemia, transferrin increases and ferritin decreases
In iron overload, transferrin decreases and ferritin increases

Remember, ferritin = liver and spleen stores, and plasma ferritin can approximate liver + spleen ferritin
Transferrin = hunts for for iron, transport to the bone marrow

Question 19

Active forms of B12

Is supplemental B12 given in its active forms?

Answer 19

Deoxyadenosylcobalamin and methylcobalamin are the active forms

No, cyanocobalamin and hydroxycobalamin (therapeutic drugs) are converted to the active forms. They are prodrugs.

Question 20

Absorption of B12
Distribution of B12
Storage of B12

Answer 20

Distal ileum, requires intrinsic factor
Bound to transcobalamin II
Liver, 3-5 mg

Question 21

Indications of B12 or folic acid

Answer 21

Vitamin B12 and folic acid used only for prevention or treatment of deficiencies. Need to differentiate to prevent nerve damage from B12.

Question 22

Time course of response (Return to normal) for B12 and folate deficiency

Answer 22

1-2 months, however if B12 deficiency is caused by malabsorption (loss of IF), usually requires lifelong parenteral injection.

Question 23

Absorption and storage of folic acid

Answer 23

Polyglutamate forms must be hydrolyzed to monoglutamate. Monoglutamate form inters bloodstream by active and passive transport

5-20 mg of folates are stored in liver and other tissues. Folates are excreted and destroyed by catabolism.
Since normal daily requirements are ~ 50 μg, diminished intake will result in deficiency and anemia within 1-6 months

Question 24

Function of EPO
Where is it produced
When does it increase

Answer 24

Stimulates proliferation and differentiation of erythroid cells
Promotes release of reticulocytes from bone marrow

Produced by the kidney

Increases in anemia, with the exception of anemia secondary to chronic renal failure

Question 25

Indications for EPO (4)

Answer 25

a) Chronic renal failure
b) Some patients with aplastic anemia, hematologic malignancies, anemias associated with AIDS, cancer
c) Treatment of anemia of prematurity
d) Post phlebotomy

Question 26

Specific treatment of aplastic anemia, hematologic malignancies, anemias associated with AIDS, cancer

Answer 26

Erythropoietin therapy is most effective if endogenous EPO levels are disproportionately low
Higher does required than in chronic renal failure, but responses are still incomplete

Question 27

Route of administration for EPO

Time course for return to normal

Answer 27

Given IV or subcutaneously

Increase in reticulocyte count seen in about 10 days
Increase in hemoglobin seen in 2-6 weeks

Question 28

Adverse effects of erythropoietin therapy

Answer 28

4. Clinical toxicity
   a) Hypertension
   b) Thrombotic complications
   c) Allergic reactions
   d) Increased risk of tumor progression in cancer patients

Question 29

Functions of G-CSF and GM-CSF (both together, and individually)

Answer 29

(1) G-CSF (granulocyte colony stimulating factor) and GM-CSF (granulocyte-macrophage colony stimulating factor) are myeloid growth factors
(2) G-CSF promotes release of hematopoietic stem cells from bone marrow (GM-CSF is less efficient)
(3) GM-CSF also stimulates proliferation and differentiation of erythroid and megakaryocytic precursors

Question 30

Indications of G-CSF and GM-CSF

Answer 30

Generally used to restore or increase neutrophil count, so indications are disease states and interventions that reduce neutrophils.

a) After intensive myelosuppressive chemotherapy and chemoterapy for AML: to accelerate the rate of neutrophil recovery, reduce the duration of neutropenia and reduce chance of infection.
b) Chemotherapy for AML: to accelerates neutrophil recovery, reduce infection. Does not increase relapses.

c) Treatment of congenital neutropenia, cyclic neutropenia, neutropenia associated with
myelodysplasia and aplastic anemia

d) High dose chemotherapy with autologous stem cell rescue
e) Mobilization of peripheral blood stem cells for autologous transplant

Question 31

Adverse reactions to G-CSF and GM-CSF

Answer 31

b) G-CSF: bone pain, splenic rupture (very rare)
c) GM-CSF: fever, arthralgia, myalgia, peripheral edema, pleural/pericardial effusion
d) Allergic reactions

Question 32

Which is better tolerated: G-CSF or GM-CSF?

Answer 32

G-CSF! Only common adverse effect is bone pain

Question 33

Pharmacology of IL-11

Answer 33

a) IL-11 is produced by stromal cells in the bone marrow, and recombinant human IL-11 (oprelvekin) is produced in a bacterial expression system
b) Stimulates growth of megakaryocytic progenitors
c) Increases peripheral platelets

Question 34

Indications for IL-11

Answer 34

a) Patients with thrombocytopenia after cytotoxic chemotherapy.

Can be used if platelet transfusions are refractory, or to prevent adverse reactions of transfusions. Usually given for 14-21 days after chemotherapy, or until the platelet count rises
above 50,000/uL

Question 35

Adverse effects IL-11

Answer 35

a) Fatigue
b) Headache
c) Dizziness
d) Cardiovascular effects (dyspnea, atrial arrhythmia)
e) Hypokalemia

Question 36

Pharmocology of romiplostim

Answer 36

Two-domain “Peptibody”: a peptide domain

that binds the thrombopoietin receptor (MPL), and an antibody Fc domain that increases half-life.

Question 37

Indications of romiplostim

Answer 37

ITP

Question 38

Adverse effects: romiplostim and eltrombopag

Answer 38

Headache, myalgia, and bone marrow fibrosis (reversible).

Question 39

Pharmocology of Eltrombopag

Answer 39

A small molecule thrombopoietin receptor agonist

Question 40

Indications of eltrombopag

Answer 40

Aplastic anemia

ITP