2. Introduction
Hematopoiesis
• is the process of production of erythrocytes, platelets and
leukocytes from undifferentiated stem cells.
• produces over 200 billion new blood cells per day in the
normal person and even greater numbers of cells in people
with conditions that cause loss or destruction of blood cells
• Haemopoietic system consists of blood, bone marrow, lymph
nodes and thymus, with the spleen, liver and kidneys as
important accessory organs.
3. Hematopoiesis ….
• The hematopoietic machinery requires a constant supply of
three essential nutrients - iron, vitamin B12 and folic acid - as
well as the presence of hematopoietic growth factors,
proteins that regulate the proliferation and differentiation of
hematopoietic cells.
• Inadequate supplies of either the essential nutrients or the
growth factors result in deficiency of functional blood cells.
4. Anemia
• is a reduction in RBC count, hemoglobin content, or both.
• During anemia oxygen (O2) transport capacity is decreased.
• It may give rise to fatigue, pallor, tachycardia, dizziness,
dyspnea
• Types of anemia:
1. Aplastic anemia
• Occurs as a result of decrease in pluripotent stem cells (bone
marrow depression), which can be caused by cancer therapy,
radiation therapy or bone marrow diseases.
5. Types of anemia ….
2. Hemolytic anemia
hemolysis (break down) of RBCs because of causative
agents such as antimalarial toxicities, infections etc
3. Nutritional anemias
i. Microcytic hypochromic anaemia
small red cells with low haemoglobin; caused by iron
deficiency
Hemoglobin synthesis is impaired.
arises in iron deficiency, since Fe2+ is a constituent of
hemoglobin
6. Types of anemia ….
ii. Macrocytic hyperchromic or Megaloblastic anemia
large red cells, few in number
Cell multiplication is inhibited because DNA synthesis is
insufficient.
This occurs in deficiencies of vitamin B12 or folic acid
Pernicious anemia: type of megaloblastic anemia caused by
Vit B12 deficiency.
Neurological abnormalities would occur
8. AGENTS USED IN TREATMENT OF ANEMIAS
1. Iron Preparations
• Liver, egg york and dry fruits are dietary sources of iron.
• Iron is usually given orally but may be given parenterally
• are used to treat iron deficiency anaemia, which can be
caused by:
– chronic blood loss (e.g. with menorrhagia, colon cancer)
– increased demand (e.g. in pregnancy and early infancy)
– inadequate dietary intake
– inadequate absorption (e.g. following gastrectomy).
• Iron forms the nucleus of the iron-porphyrin heme ring,
9. Iron Preparations …
Pharmacokinetics of Iron
Absorption
Iron is normally absorbed in the duodenum and proximal jejunum
absorption increases in response to low iron stores or increased
iron requirements
Iron in heme ( e.g. from meat) can be absorbed easily
Non-heme iron ( inorganic iron) need reduction to Fe2+ for
absorption
Divalent metal transporter, DMT1, transports ferrous iron across
the luminal membrane of the intestine
Iron crosses the basolateral membrane by the transporter known
11. Iron Preparations …
Transport
• bound to transferrin ( β-globulin that binds two molecules of
ferrous iron)
Storage
• sites: intestinal mucosal cells, macrophages, liver, spleen, and
bone, …as ferritin
• Apoferritin synthesis is regulated by the levels of free iron.
– Low Fe level…. apoferritin synthesis is inhibited and the balance
of iron binding shifts toward transferrin.
– High Fe levels … more apoferritin is produced to sequester
more iron.
12. Iron Preparations …
Elimination
• no mechanism for excretion of iron
– Small amounts are lost in the feces
– trace amounts are excreted in bile, urine, and sweat
• Therefore, regulation of iron balance must be achieved by
changing intestinal absorption & storage, in response to the
body's needs.
13. Iron Preparations …
A. Oral iron therapy
• Because ferrous iron is most efficiently absorbed, only ferrous
salts should be used.
• Ferrous sulfate, ferrous gluconate, and ferrous fumarate are
all effective and inexpensive and are recommended for the
treatment of most patients.
• Common adverse effects of oral iron therapy include nausea,
gastric discomfort, abdominal cramps, constipation, diarrhea,
metallic taste and black stool
15. Iron Preparations …
B. Parenteral iron therapy
• should be reserved for patients with documented iron
deficiency
– who are unable to tolerate or absorb oral iron
– for patients with extensive chronic blood loss who cannot
be maintained with oral iron alone.
– includes patients with various postgastrectomy
conditions, malabsorption syndromes, and advanced
chronic renal disease including hemodialysis and
treatment with erythropoietin.
16. Iron Preparations …
• adverse effects:
– local pain and tissue staining (brown discoloration) with
IM route and
– hypersensitivity reactions (especially with Iron dextran)
manifested as flushing, bronchospasm, headache, nausea
and vomiting.
• N.B. Iron preparations are contraindicated in case of
hemolytic anemia, due to excessive accumulation of Fe.
17. Iron Preparations …
Iron toxicity
• Acute iron toxicity
– occurs after ingestion of large quantities of iron salts
(usually seen in young children)
– This can result in severe GI irritation with vomiting,
haemorrhage and diarrhea, followed by circulatory
collapse.
• Chronic iron toxicity or iron overload
– is virtually always caused by conditions other than
ingestion of iron salts, for example chronic hemolytic
18. Iron Preparations …
• The treatment of acute and chronic iron toxicity involves the
use of iron chelators, such as desferrioxamine.
• Desferrioxamine
– is not absorbed from the gut
– given intragastrically following acute overdose (to bind
iron in the bowel lumen and prevent its absorption) as well
as
– intramuscularly and, if necessary, intravenously.
– In severe poisoning, it is given by slow intravenous
infusion.
19. AGENTS USED IN TREATMENT OF ANEMIAS …
2. Vitamin B12 (cyanocobalamine)
• Liver, meat, fish and milk products are rich sources of the
vitamin.
• Enteral absorption of vitamin B12 requires intrinsic factor,
which is synthesized in from parietal cells of the stomach.
• The complex formed with this glycoprotein undergoes
endocytosis in the ileum.
• A deficiency of either vit. B12 or folic acid impairs DNA
synthesis
• Since tissues with the greatest rate of cell turnover show the
most dramatic changes, the hematopoietic system is
21. Vitamin B12 ….
Vitamin B12 is clinically used during
– Megaloblastic or Pernicious anemia (due to lack of intrinsic
factor or atrophic gastritis)
– increased demand (infants, pregnants etc)
– neuronal abnormalities.
Preparations
• Parentrals: Hydroxycobalamine and Cyanocobalamine.
– Hydroxocobalamin is preferred because it is more highly
protein-bound and therefore remains longer in the
circulation.
• Oral tablets: Methyl cobalamine.
22. AGENTS USED IN TREATMENT OF ANEMIAS …
3. Folic Acid
Folic acid FR Dihydrofolate DHFR Tetrahydrofolate
• FR: Folate reductase DHFR: Dihydrofolate reductase
• THF is a co-enzyme involved in one carbon transfer during
DNA synthesis.
• Deficiency of TH4, therefore causes default in DNA synthesis.
Folic acid is clinically used during
– Megaloblastic anemia
– Infants and pregnants
– Methotrexate toxicity (anticancer by inhibiting DHFR)
23. Folic Acid ….
• Folic acid preparations include folic acid tablets, folic acid
injection, and folinic acid injection (analogue of THF)
25. HAEMOPOIETIC GROWTH FACTORS ….
1. Erythropoietin
• is produced in juxtatubular cells in the kidney and in
macrophages.
• contains 193 amino acids, of which the first 27 are cleaved
during secretion. The final hormone is heavily glycosylated.
• After secretion, erythropoietin binds to a receptor on the
surface of committed erythroid progenitors in the marrow
and is internalized.
• Its action is to stimulate committed erythroid progenitor cells
to proliferate and generate erythrocytes.
26. Erythropoietin ….
• With anemia or hypoxemia, synthesis rapidly increases by
one hundredfold or more, serum erythropoietin levels rise,
and marrow progenitor cell survival, proliferation, and
maturation are dramatically stimulated.
• This finely tuned feedback loop can be disrupted by kidney
disease, marrow damage, or a deficiency in iron or an
essential vitamin.
• Two forms of recombinant human erythropoietin, epoetin
alfa and epoetin beta are available.
• Epoetin can be given IV, SC & IP.
– the response being greatest after subcutaneous injection
and fastest after intravenous injection.
27. Erythropoietin (EPO)…
Darbepoetin
– a long-acting version of erythropoietin
– Glycosylated erythropoietin
– Has a half-life about three times that of epoetin alfa
– Due to delayed onset of action, has no value in acute
treatment of anemia
– administered weekly
Methoxy polyethylene glycol-epoetin beta:
– Long-acting form; administered 1-2 times per month
27
28. Erythropoietin ….
Clinical uses of epoietin include:
• Anaemia of chronic renal failure
• Patients with anemia secondary to chronic kidney disease are ideal
candidates for epoetin alfa therapy.
• Anaemia during chemotherapy for cancer
• Prevention of the anaemia that occurs in premature infants
• Anaemia of AIDS (which is exacerbated by zidovudine treatment)
• Highly competitive athletes have used epoetin alfa to increase their
hemoglobin levels ("blood doping") and improve performance.
• Unfortunately, this misuse of the drug has been implicated in the
deaths of several athletes and is strongly discouraged.
29. Erythropoietin ….
Unwanted effects:
• Hypertension is common and can cause headache,
disorientation and sometimes convulsions.
• Iron deficiency can be induced because more iron is required
for the enhanced erythropoiesis.
• Blood viscosity increases as the haematocrit (i.e. the fraction
of the blood that is occupied by red blood cells) rises,
increasing the risk of thrombosis, especially during dialysis.
30. HAEMOPOIETIC GROWTH FACTORS ….
2. Colony-Stimulating Factors
• G-CSF (granulocyte colony-stimulating factor) and GM-CSF
(granulocyte-macrophage colony-stimulating factor), are the
two growth factors currently available for clinical use.
• Both GM-CSF and G-CSF can be given either SC or IV
infusion.
• They are used to stimulate synthesis of leukocytes.
31. Haemopoietic Growth Factors ….
G-CSF and GM-CSF
– Filgrastim: recombinant human G-CSF
– Sargramostim: recombinant human GM-CSF
They Stimulate proliferation and differentiation by
interacting with specific receptors found on myeloid
progenitor cells
31
32. Haemopoietic Growth Factors ….
Clinical use of filgrastim : IV/SC
– To reduce risk of neutropenia following chemotherapy
(high dose) and bone marrow transplantation
(prophylactically)
– Neutropenia associated with congenital neutropenia
and aplastic anemia
– Mobilization of peripheral blood cells in preparation
for autologous and allogeneic stem cell
transplantation
Adverse effect: Bone pain
32
33. Haemopoietic Growth Factors ….
GM-CSF (sargramostim): IV/SC
– Has similar clinical uses to those of G-CSF, but it is more
likely than G-CSF to cause fever, arthralgia, myalgia, and
capillary leak syndrome
– at lower doses: the response is primarily neutrophilic
– at larger doses: monocytosis and eosinophilia
33
34. Haemopoietic Growth Factors ….
Megakaryocyte growth factors
Thrombopoietin & IL-11:
key endogenous regulators of platelet production
Recombinant IL-11 (Oprelvekin)
– stimulate the growth of multiple lymphoid & myeloid
cells
– the number of peripheral platelets and neutrophils
– Use: Prevention of thrombocytopenia in pts
undergoing cytotoxic chemotherapy for non-myeloid
cancers 34
35. Haemopoietic Growth Factors ….
Romiplostim: Thrombopoitin receptor agonist
Causes a dose-dependent increase in platelet
count
Use: treatment of idiopathic thrombocytopenic
purpura
ADR: mild headache on the day of administration
35
Notas do Editor
Because ferrous iron is most efficiently absorbed, ferrous salts should be used
More recently, a novel erythropoiesis-stimulating protein, darbepoetin alfa (ARANESP), has been approved for clinical use in patients with indications similar to those for epoetin alfa. It is a genetically modified form of erythropoietin in which four amino acids have been mutated such that additional carbohydrate side chains are added during its synthesis, prolonging the circulatory survival of the drug to 24-26 hours
The myeloid growth factors are glycoproteins that stimulate the proliferation and differentiation of one or more myeloid cell lines. They also enhance the function of mature granulocytes and monocytes
The myeloid growth factors are produced naturally by a number of different cells, including fibroblasts, endothelial cells, macrophages, and T cells.
GM-CSF is capable of stimulating the proliferation, differentiation, and function of a number of the myeloid cell lineages
The activity of G-CSF is restricted to neutrophils and their progenitors, stimulating their proliferation, differentiation, and function. It acts primarily on the CFU-G, although it also can play a synergistic role with IL-3 and GM-CSF in stimulating other cell lines.
- G-CSF enhances phagocytic and cytotoxic activities of neutrophils. Unlike GM-CSF, G-CSF has little effect on monocytes, macrophages, and eosinophils and reduces inflammation by inhibiting IL-1, tumor necrosis factor, and interferon gamma. G-CSF also mobilizes primitive hematopoietic cells, including hematopoietic stem cells, from the marrow into the peripheral blood. This observation has virtually transformed the practice of stem cell transplantation, such that >90% of all such procedures today use GCSF– mobilized peripheral blood stem cells as the donor product.
Neutropenia is a common adverse effect of the cytotoxic drugs used to treat cancer and increases the risk of serious infection in patients receiving chemotherapy. Unlike the treatment of anemia and thrombocytopenia, transfusion of neutropenic patients with granulocytes collected from donors is performed rarely and with limited success. The introduction of G-CSF in 1991 represented a milestone in the treatment of chemotherapy-induced neutropenia. This growth factor dramatically accelerates the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy.
Filgrastim is routinely used in patients undergoing peripheral blood stem cell (PBSC) collection for stem cell transplantation. It promotes the release of CD3 4+ progenitor cells from the marrow, reducing the number of collections necessary for transplant.
is a 127–amino acid glycoprotein produced in yeast
Except for the substitution of a leucine in position 23 and variable levels of glycosylation, it is identical to endogenous human GM-CSF.
Although sargramostim, like natural GM-CSF, has a wide range of effects on cells in culture, its primary therapeutic effect is to stimulate myelopoiesis
Because neither G-CSF nor GM-CSF stimulates the formation of erythrocytes and platelets, they are sometimes combined with other growth factors for treatment of pancytopenia.
Side effects
bone pain, malaise, flu-like symptoms, fever, diarrhea, dyspnea, and rash
transient supraventricular arrhythmia, dyspnea, and elevation of serum creatinine, bilirubin, and hepatic enzymes
The high-dose regimens produce extreme myelosuppression; the myelosuppression is then counteracted by reinfusion of the patient’s own hematopoietic stem cells (which are collected prior to chemotherapy).