1. 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

2. 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

3. 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.

4. 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.

5. 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 غضبًا) (up to thousands) but lowered in anemia of chronic renal failure.

6. Erythropoietin
Stimulates erythroid proliferation and differentiation by interacting with specific receptors( JAK/STAT cytokine receptor) on red cell progenitor.
Releases reticulocytes ( which means that there is an increased production of RBCs) from the bone marrow.
Remember from pathology:
Polycythemia Vera: mutation in JAK/ STAT

7. Indications: Erythropoietin 1. Anemia of chronic renal failure:
These are the patients most likely to benefit from treatment.
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.

8. 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( IU/kg).
Response is generally incomplete.

9. Indications ( of less importance):
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.

10. Erythropoietin Toxicity:
Due to rapid increases in hematocrit and hemoglobin: hypertension and thrombotic complications. As in polycythemia
Allergic reactions are infrequent and mild.

11. Myeloid Growth Factors
Originally purified from cultured human cells.
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.
Fill the BM with granulocytes (FilGrastim).

12. Myeloid Growth Factors
Sarg: سارق
السارق قادر على تغطية نفقات
granulocytes +
macrophages
rHuGM-CSF “Sargramostim”:
Produced in a yeast cell expression system.
127 amino acids, kD mol. wt.
Has a half life of 2-7 hours.

13. 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.

14. 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.
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)
Two  T-cells

15. 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)

16. Clinical Applications of Myeloid Growth Factors
Congenital neutropenia.
Cyclic neutropenia.
Myelodysplasia.
Aplastic anemia.

17. 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.

18. 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.

19. 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

20. 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.

21. 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.

22. 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).

23. Megakaryocyte Growth Factors
Thrombopoietin:
- It is still an investigational agent.
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.

24. Megakaryocyte Growth Factors
Toxicity:
Fatigue, headache, dizziness, anemia, dyspnea, transient atrial arrhythmias and hypokalemia.