Download slide_2

Edited slides #2
• Anything written in purple was said by Dr. Munir
• Anything in a box wasn’t said by the doctor but might be helpful for
memorizing
• Anything underlined is important
Hematopoietic Growth Factors
•
•
•
•
•
•
Erythropoietin (Epoetin alfa).
Colony Stimulating Factors:Granulocyte colony-stimulating factor(G-CSF).
Granulocyte-macrophage colony-stimulating factor (G-CSF).
Interleukin-11 (IL-11).
Thrombopoietin.
• These growth factors are given in the cases of:
• 1- anemia
• 2- leukopenia
• 3- thrombocytopenia
Hematopoietic Growth Factors
• Regulate the proliferation and differentiation of
hematopoietic progenitor cells in the bone marrow.
• Useful in hematologic as well as nonhematologic
conditions, potential anticancer and antiinflammatory
drugs.
Erythropoietin
• 34-39 kDa glycoprotein.
• Was the first isolated growth factor.
• Originally purified from urine of patients with severe anemia.
• Recombinant human erythropoietin (rHuEPO, or Epoietin alfa) is produced
in a mammalian cell expression system.
100% of human source
• Half-life after iv administration is 4-13 hours. short
• It is not cleared by dialysis.
Very important when given in anemia of chronic renal failure.
• Darbepoetin alfa has longer half life.
Erythropoietin
• Produced in the kidney in response to hypoxia through increased rate of
transcription of the gene .
• Needs active (responsive) bone marrow (no deficiency (It’s useless to give EP if
there is a deficiency in iron/ folic acid/ vitamin B12), no primary bone marrow
disease and no suppression by drugs or chronic diseases).
• Normal serum level 20 IU (international unit)/L.
• Elevated in most of anemias )‫( (يستشيط غضبًا‬up to thousands) but lowered in
anemia of chronic renal failure.
Erythropoietin
• Stimulates erythroid proliferation and differentiation by interacting with
specific receptors( JAK/STAT cytokine receptor) on red cell progenitor.
Remember from pathology:
Polycythemia Vera: mutation in JAK/ STAT
• Releases reticulocytes ( which means that there is an increased production of
RBCs) from the bone marrow.
Erythropoietin
Indications:
• 1.
Anemia of chronic renal failure:
• These are the patients most likely to benefit from treatment.
• 50-150 IU/kg IV or SC three times a week.
• Failure to respond is usually due to iron or folic acid deficiency. The most imp thing to
know.
Erythropoietin
Indications:
• 2. Primary bone marrow disorders and secondary
anemias: aplastic anemia, myeloproliferative and
myelodysplastic disorders, multiple myeloma and bone
marrow malignancies. Also anemia of chronic
inflammation, AIDS and cancer.
• Still not as effective as in the case of chronic renal failure
• Response is better with low baseline erythropoietin levels.
• Patients require higher doses(100-500 IU/kg).
• Response is generally incomplete.
Erythropoietin
Indications ( of less importance):
• 3. Anemia of zidovudine treatment. (antiviral drug used in HIV infection)
• 4 Anemia of prematurity.
• 5. After phlebotomies for autologous transfusion for elective surgery.
If a patient wants to do an elective surgery, we store blood from his own
(autologous) because it’s better than that from volunteers.
This patient needs EP to compensate the amount of blood he lost during
phlebotomy, in order to have normal blood at the time of surgery
• 6. Iron overload.
We either use chelating agents (defroxamine), or EP to activate its utilization in
BM.
• 7. Unethically, used by athletes  side effects.
Erythropoietin
Toxicity:
• Due to rapid increases in hematocrit and hemoglobin: hypertension
and thrombotic complications. As in polycythemia
• Allergic reactions are infrequent and mild.
Myeloid Growth Factors
• Originally purified from cultured human cells.
Fill the BM with granulocytes (FilGrastim).
• rHuG-CSF “Filgrastim” 1991:
•
•
•
•
Produced in a bacterial cell expression system.
175 amino acids, 18 kD mol. wt.
Has a half life of 2-7 hours. Short halflife
Pegfilgrastim= Filgrastim covalently conjugated with polyethylene glycol. Injected once
per chemotherapy cycle. (peglated)
PEG = polyethylene glycol  used to increase halflife. Also, can be used as an organic
solvent in pharmacological industried and other industries.
PEG is useful in interferons, which are used in treatment of hepatitis C.
Myeloid Growth Factors
rHuGM-CSF “Sargramostim”:
• Produced in a yeast cell expression system.
• 127 amino acids, 15-19 kD mol. wt.
• Has a half life of 2-7 hours.
Sarg: ‫سارق‬
‫السارق قادر على تغطية نفقات‬
- granulocytes +
- macrophages
Myeloid Growth Factors
G-CSF:
• Works on( JAK/STAT receptors.
• Stimulates (1) proliferation and differentiation of progenitors committed to the
neutrophil (very imp) lineage.
• (2) Activates the phagocytic activity of mature neutrophils and prolongs their
survival in the circulation.
• (3) Mobilizes hemopoietic stem cells into the peripheral circulation.
Myeloid Growth Factors
GM-CSF:
• Has broader actions. Also works on JAK/STAT receptors.
• Stimulates proliferation and differentiation of early and
late granulocytic (leukocytes) progenitor cells as well as
erythroid (RBCs) and megakaryocyte (platelets)
progenitors.
• With interleukin-2, also stimulates T-cell proliferation.
Two  T-cells
• Locally, it is an active factor of inflammation.
• Mobilizes peripheral blood stem cells, but less than G-CSF
(No need to know these small differences, just focus on the cells activated
(targeted) by each GF)
Clinical Applications of Myeloid Growth Factors
Cancer Chemotherapy-Induced Neutropenia (Main
indication):
• Granulocyte transfusion is not practical.
1- very short half-life
2- some cells might have been already old at the time of transplant
• G-CSF accelerates neutrophil recovery, leading to reduced:
1-episodes of febrile neutropenia
2- need for antibiotics
3- days of hospitalization
but do not improve survival.
• G-CSF is reserved for risky patients.
(bcoz new drugs aren’t as harmful as old ones in targeting BM)
• GM-CSF can produce fever on its own.
• They are safe even in the postchemotherapy supportive care of
patients with AML.
(So you get rid of old cells and stimulate synthesis of new ones  might seem against logic)
Clinical Applications of Myeloid Growth Factors
• Congenital neutropenia.
• Cyclic neutropenia.
• Myelodysplasia.
• Aplastic anemia.
Clinical Applications of Myeloid Growth Factors
1- Autologous Stem Cell Transplantation:
• High dose chemotherapy regimens produce extreme
myelosuppression, which is counteracted by reinfusion of the
patient’s own hematopoietic stem cells which are collected
before the chemotherapy.
2- Allogenic Bone Marrow Transplantation.
3- Mobilization of peripheral blood stem cells (PBSCs).
• Patients or donors are given GM-CSF (5-10 mcg/kg/day) for 4
days, then leukapheresis, CD34 is used as a marker for the stem
cells. At least 5x106 CD34 cells/kg should be reinfused to ensure
effective engraftment.
“2+3 are not clear techniques”. However, they are easy to
remember.
Toxicity of Myeloid Growth Factors
• Bone pain.
• Fever, malaise, arthralgia, myalgia.
• Capillary Leak Syndrome (imp): peripheral edema, pleural or pericardial
effusions.
• Allergic reactions.
• Splenic rupture.
Megakaryocyte Growth Factors
• Interleukin-11 (IL-11):
• 65-85 kDa protein.
• Produced by fibroblasts and stromal cells in the bone marrow.
• Half life is 7-8 hours after sc injection.
• Oprelvekin:
• Is the recombinant form of IL-11.
• Produced by expression in E.coli.
Opa leukin style
Megakaryocyte Growth Factors
• Interleukin-11 (IL-11):
•
•
•
•
Acts through a specific receptor.
Stimulates the growth of multiple lymphoid and myeloid cells.
Stimulates the growth of primitive megakaryocytic progenitors.
Increases the number of peripheral platelets and neutrophils.
Megakaryocyte Growth Factors
Clinical Applications of IL-11:
• Thrombocytopenia
Platelets transfusion is an alternative.
Approved for the secondary prevention of thrombocytopenia in patients receiving
cytotoxic chemotherapy for treatment of nonmyeloid cancers.
Megakaryocyte Growth Factors
Clinical Applications of IL-11 :
• Does not appear to have an effect on leukopenia caused by myelosuppressive
chemotherapy.
• Given by SC injection, 50mcg/kg/day for 2-3 weeks after chemotherapy. Or,
until platelet count rises to <50,000 cells/µl (numbers are for your general
knowledge).
Megakaryocyte Growth Factors
Thrombopoietin:
- It is still an investigational agent.
- 65-85 kDa glycoprotein.
- Recombinant form is produced by
expression in human cells.
- Independently stimulates the growth of primitive
megakaryocytic progenitors.
- Also stimulates mature megakaryotes.
- Activates mature platelets to respond to
aggregation-inducing stimuli.
Megakaryocyte Growth Factors
Toxicity:
•Fatigue, headache, dizziness, anemia,
dyspnea, transient atrial arrhythmias and
hypokalemia.