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HEMATOPOIETIC AND ANTIANEMIA AGENTS

February 13, 2013

Thomas M. Guenthner, PhD

E-418, MSB
996-7635
tmg@uic.edu

Learning Objectives:
1.

Basic knowledge of the epidemiology, pathophysiology, and etiology of common

anemias
2. Controlling factors in erythrocyte and heme biosynthesis
3. Role of dietary iron and iron supplements in the therapy of iron-deficiency (microcytic)
anemia
4.
Consequences of iron overdose toxicity, and its treatment with chelating agents
5. Role of vitamin B12 and folic acid deficiency in megaloblastic (macrocytic) anemia
6. Cause of Pernicous anemia
7. Role of hematopoietic growth factors in erythrocyte maturation
8. Proper therapeutic role of erythropoietin
9. Consequences of improper use of erythropoietin
10. Basic knowledge of common hemoglobinopathies (Thalassemias, Sickle Cell Disease)
11. Current status of drug therapy for Sickle Cell Disease

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Anemia (from Ancient Greek: anaimia,

meaning lack of blood, from - an-, "not"
+ haima, "blood") is a decrease in the
number of erythrocytes or in the normal
quantity of hemoglobin in the blood. It can
also include decreased oxygen-binding
ability of the hemoglobin molecule due to
structural abnormality.

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Erythrocyte Development
Normal total circulating erythrocyte population (adult) = 25 x
1012 (5 x 106 /l)
Circulating RBCs collectively contain 2.5 - 3 g heme iron
(~65% of total body iron)

Life span of one RBC is ~120 days

Turnover of circulating RBCs is 1-5 x 106 cells/second
Maturation of a circulating RBC requires ~ 7 days

Hemoglobin Biosynthesis

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Normal Hemoglobin
HbA (22)
Heme

subunit

Heme

subunit

subunit
Heme

subunit

Heme

Pathologies associated with anemia

Iron Deficiency (Microcytic) Anemia

Vitamin Deficiency (Macrocytic/Megaloblastic) Anemia
Anemias due to hematopoietic growth factor deficiency
Functional Anemias due to hemoglobinopathies
(Thalassemias, Sickle Cell Disease)

Normocytic Anemia (Excessive blood loss, Hemolytic

Anemia, Aplastic Anemia)

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Iron Deficiency (Microcytic) Anemia

RBC numbers in normal range
Cells are hypochromic
Mean cell size is < 80% normal
Due to insufficient iron to maintain normal Hemoglobin
biosynthesis

Microcytic Anemia

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Incidence of Microcytic Anemia

Iron metabolism in the Body

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Dietary Iron requirements in different

populations

Iron demands of pregnancy

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Treatment of Iron Deficiency Anemia

Increase Dietary Iron
Oral Iron Supplement

Complications
Hindered ability to absorb iron

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Parenteral Iron Preparations

Iron dextran
Sodium ferric gluconate complex
Iron sucrose

Complication Iron overdose toxicity

Acute Iron Overdose
Corrosion of GI epithelium
Severe acidosis
Coma
Death

Chronic Iron Overdose (Hemochromatosis)

Iron deposition in tissues as hemosiderin
(hemosiderosis)

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Hemosiderosis

Antidote Chelation Therapy

Deferoxamine (Desferal)

Deferasirox

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Macrocytic/Megaloblastic Anemia

Fewer, larger RBCs

Hematocrit may approximate normal value
Cells are normochromic, but fewer cells = less oxygen-carrying capacity
Functional Anemia
Many ovoid (football-shaped) erythrocytes, up to 2 -3 x normal size

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Treatment Folate and Vitamin B12

Supplementation

Pernicious Anemia Inability to absorb

dietary Vitamin B12

Treatment Parenteral B12 (Hydroxocobalamin, Cyanocobolamin)

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Erythropoietin

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Erythropoietin Supplementation

Erythropoietin

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Other Hemopoietic Growth Factors

Multilineage Growth Factors
Granulocyte-Myocyte Colony-Stimulating Factor (GM-CSF)
Sargramostim

Leukocyte Growth Factors

Granulocyte Colony-Stimulating Factor (G-CSF)
Filgrastim

Thrombopoietic Growth Factors

Thrombopoietin
Interleukin 11
Oprelvekin

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Hemoglobinopathies Sickle Cell Disease and Thalassemias

Heme

subunit

Heme

subunit

subunit
Heme

subunit

Heme

Normal Hemoglobin A
(22)

Types of Thalassemias

Thalassemias result in decreased alpha-globin production, therefore fewer alphaglobin chains are produced, resulting in an excess of chains in adults and excess
chains in newborns. The excess chains form unstable Hb tetramers, which have
abnormal oxygen dissociation curves. However, even in the homozygous state this
disorder will result only in a mild microcytic anemia.

o or Thalassemia major prevents any formation of chains, the most severe form
of thalassemia. + or Thalassemia intermedia allow some chain formation to
occur. In either case, there is a relative excess of chains, but these do not form
tetramers. Rather, they bind to the red cell membrane, producing membrane
damage, and at high concentrations they form toxic cell aggregates.

Thalassemia About 3% of adult hemoglobin is made of alpha and delta chains.

Mutations can occur which affect the ability to produce delta chains. Hematologically,
however, this is innocuous because only 2-3% of normal adult hemoglobin is
hemoglobin A2. The individual will have normal hematological parameters
(erythrocyte count, total hemoglobin, mean red cell volume)

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Treatment of Thalassemias
No drug treatment known. Palliative treatment involves
blood transfusions. Curative treatment involves bone
marrow transplant. Frequent transfusion can produce
iron overload toxicity.

Sickle Cell Disease

A hemoglobinopathy involving a point mutation on the beta chain
In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in the
beta chain) is mutated to valine. This change allows the
deoxygenated form of the hemoglobin to adhere to itself and form
large Hb aggregates.

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Sickle Cell Erythrocytes

Drug Therapy of Sickle Cell Disease

Strategy involves promoting production of Fetal Hemoglobin (HbF) subunit
Even 20% replacement of chain with chain provides significant relief from
sickling.

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Treatment of Sickle Cell Disease

Transfusion
Bone Marrow Transplant
Drugs
Hydroxyurea

Increases globin gene expression and HbF production

Mechanism of action not well understood
Well tolerated
Effective in ~60% of patients

(5-Azacytidine)

Increases globin gene expression and HbF production

Mechanism of action related to DNA demethylation
Poorly tolerated
Major cytotoxicity and carcinogenic potential
Not considered useful

Drugs to know
IRON SUPPLEMENTS
Ferrous Sulfate
Ferrous Gluconate
Iron Dextran
Iron Sucrose
(Deferoxamine)
VITAMINS
Folic Acid
Vitamin B12 (Cyanocobalamin)
Hydroxocobalamin
HEMATOPOIETIC GROWTH FACTORS
Erythropoietins
Epoetin Alfa
Darbepoetin
Myeloid Growth Factors
Filgrastim
Sargramostim
Thrombopoietic Growth Factors
Interleukin-11
Thrombopoietin
SICKLE CELL DRUGS
Hydroxyurea
(5-Azacytidine)

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