hematopoetic factors

1. Hematopoietic Agents
(growth factors)

2. Introduction:
• Hematopoiesis is a natural process and can be increased many
folds in response to certain stimuli and diseases.
• Erythrocyte production : 20-fold in response to anemia or
hypoxemia
• leukocyte production increases dramatically in response to
systemic infections
• platelet production : 10- to 20-fold when platelet consumption
results in thrombocytopenia
• Sites of hematopoiesis: skull, vertebral bodies, pelvis, and
proximal long bones

3. Factors affecting hematopoiesis:
• Growth Factors
• Minerals
• Vitamins

4. HEMATOPOIETIC GROWTH FACTORS:
Erythropoietin (EPO)
Stem cell factor (SCF, c-kit ligand, Steel factor)
Interleukins
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
Granulocyte colony-stimulating factor (G-CSF)
Monocyte/macrophage colony-stimulating factor (M-CSF)
Thrombopoietin (TPO)

5. Growth Factor Physiology:
• Stem cells
• burstforming units (BFUs) & colony-forming units (CFUs)
• proliferation(upto 30 folds)
• lineage-committed growth factors(G-CSF, M-CSF, erythropoietin, and
thrombopoietin) effect
• proliferation and maturation of the CFU for each cell line(upto 30 folds)
• 1000 mature cells from each committed stem cell

7. Erythropoiesis-Stimulating Agents:
Erythropoietin:
• Most important regulator of the proliferation of committed erythroid
progenitors (CFU-E)
• feedback system: a sensor in the kidney detects changes in oxygen
delivery : modulate the erythropoietin secretion.
• Hypoxia-inducible factor(HIF-1α and HIF-1β) enhances
expression of genes for vascular endothelial growth factor and
erythropoietin
• HIF-2α contribute to iron absorption

8. continued…..
• With anemia or hypoxemia, synthesis rapidly increases by 100-fold or
more
• Acts by : Stimulating marrow progenitor cell survival, proliferation and
maturation
• feedback loop can be disrupted by:
• kidney disease
• marrow damage
• deficiency in iron or an essential vitamin
• Infection or an inflammatory state(cytokines action): suppression of
• erythropoietin secretion
• iron delivery
• progenitor proliferation
• Iron metabolism(effects on the hepatic protein hepcidin)
• Contributes to resultant anemia

9. Preparations:
epoetin alfa(nearly identical to the endogenous hormone),
epoetin beta,
epoetin omega,
and epoetin zeta,
Differ almost exclusively in carbohydrate modifications due to
manufacturing differences
t1/2 : 4–8 h(epoetin alfa)
once-weekly dosing

10. Therapeutic Uses:
• anemias associated with surgery,
• AIDS,
• cancer chemotherapy,
• prematurity,
• and certain chronic inflammatory conditions
• Darbepoetin alfa : approved for use in patients with anemia
associated with chronic kidney disease

11. Adverse Effects & abuses:
• absolute or functional iron deficiency
• Functional iron deficiency(i.e., normal ferritin levels but low
transferrin saturation)
• Supplemental iron therapy is recommended:
Serum ferritin is less than 100 μg/L
serum transferrin saturation is below 20%
• stimulation of tumor cells
• Increase hemoglobin levels and improve performance in athletes:
“blood doping”

12. Myeloid Growth Factors:
• GM-CSF, G-CSF, IL-3, M-CSF or CSF-1, and stem cell factor (SCF)
• Only G-CSF and GM-CSF have found meaningful clinical applications
• Produced naturally by: fibroblasts, endothelial cells, macrophages,
and T cells
• cytokine receptor superfamily: Jak/STAT signal transduction pathway
• GM-CSF
• Stimulates: CFU-GM, CFU-M, CFU-E, and CFU-Meg
• Also enhances: migration, phagocytosis, superoxide production, and
antibody-dependent cell-mediated toxicity of neutrophils, monocytes, and
eosinophils
• G-CSF: restricted to neutrophils
• Anti-inflammatory: inhibit IL-1, tumor necrosis factor, and interferon gamma
• mobilizes primitive hematopoietic cells

13. Granulocyte-Macrophage Colony-Stimulating
Factor(GM-CSF)
• Sargramostim : Recombinant human GM-CSF(a glycoprotein)
Uses:
• Shortens duration of neutropenia in
• transplant patients
• patients receiving intensive cancer chemotherapy
• stimulates myelopoiesis in some patients with
• cyclic neutropenia,
• myelodysplasia,
• aplastic anemia,
• or AIDS-associated neutropenia

14. Pharmacokinetics & dynamics:
• Subcutaneous injection or slow intravenous infusion(maintained over
3–6 h)
• t1/2 = 2–3 h
• (transient decrease in the absolute leukocyte count secondary to cell
margination and pulmonary vascular sequestration)
• Followed by dose dependent biphasic rise in leukocyte count: 7-10
days & return to normal in 2-10 days after discontinuation
• Low dose: primarily neutrophilic
• High dose: monocytosis, eosiniphilia

15. ADR:
• Bone pain,
• malaise,
• flu-like symptoms,
• fever,
• diarrhea,
• dyspnea,
• and rash.
• Acute reaction to the first dose: flushing, hypotension, nausea, vomiting, and
dyspnea, with a fall in arterial oxygen saturation due to granulocyte
sequestration in the pulmonary circulation(sensitive people)
• prolonged administration: capillary leak syndrome(rarely)
• Rare side effects: transient supraventricular arrhythmia, dyspnea, an elevation
of serum creatinine, bilirubin, and hepatic enzymes

16. Granulocyte Colony-Stimulating Factor(G-
CSF):
• Filgrastim: stimulates CFU-G to increase neutrophil production
• longer-acting pegylated forms: pegfilgrastim and lipegfilgrastim.
Uses:
• treatment of severe neutropenia after
• autologous hematopoietic stem cell transplantation
• high-dose cancer chemotherapy
• severe congenital neutropenias
• Myelodysplasia or marrow damage
• neutropenia of patients with AIDS receiving zidovudine
• patients undergoing PBSC collection for stem cell transplantation

17. Pharmacokinetics & dynamics:
• subcutaneous injection or intravenous infusion(over 30
mins)
• dose: 1–20 μg/kg/d.
• t1/2 = 3.5 h
• Pegfilgrastim: 6 mg for patients weighing more than 20 kg
once per chemotherapy cycle

18. Adverse Reactions:
• mild-to-moderate bone pain
• local skin reactions
• rare cutaneous necrotizing vasculitis.
• Mild-to-moderate splenomegaly
• Contra indicated:
patients with a history of hypersensitivity to proteins produced by
Escherichia
sickle cell anemia

19. Thrombopoietic Growth Factors:
Interleukin 11:
• Stimulates
• hematopoiesis,
• intestinal epithelial cell growth,
• and osteoclastogenesis
• Inhibits: adipogenesis
• enhances megakaryocyte maturation & thrombopoesis
Oprelvekin: Recombinant human IL-11
• t1/2 about 7 h
• Uses: chemotherapy for nonmyeloid malignancies with severe
thrombocytopenia
• ADR: fluid retention and associated cardiac symptoms

20. Thrombopoietin Receptor Agonists:
Thrombopoietin:
• Produced by the liver, marrow stromal cells, and other organs
• primary regulator of platelet production
• Uses:
• immune thrombocytopenia (ITP),
• severe aplastic anemia (SAA)
Romiplostim:
• administered weekly by subcutaneous injection to ITP patients
Eltrombopag:
• administered orally