Haematinic Agents

The Haematinic Agents

stimulates the production of red blood cells
or increases the amount of haemoglobin in
the blood.
They are used to treat various types of
anemias.
These include:

Iron
Vitamin B12
Folic Acid

Iron
Adult body contains:
About 3 - 4 grams of iron

2.5 grams of total body iron exist as haemoglobin

Only 1-2 mg of iron is taken up daily from the diet
(which contains 10-20mg iron)

Duodenal Iron Absorption

Iron Metabolism

Cellular Iron Uptake

Regulation of iron metabolism:

There is no pathway for iron excretion from the body

therefore

Total body iron level is regulated only at the level of

iron absorption from the small intestine

Regulatory Mechanism

Iron Toxicity
Iron toxicityis aniron overloadcaused by
a large excess ofironintake.
In terms ofblood values

iron levels > 350-500g/dL are considered toxic

levels over 1000 g/dL indicate severe iron
poisoning

Treatment
cleaning the iron from the blood, using a chelating
agent such asdeferoxamine.
dialysis

Syeda Nosheen Wilayat

BBC-01093005
BS-8th semester

Vitamin B12

Vitamin B12, also called Cobalamin, is necessary

for the production of red blood cells and plays an
important role in maintaining the health of nerve
cells and in the formation of genetic material

Sources of Vitamin B12

Fish
Eggs
Meat
Dairy Products

Vitamin B12 deficiency

Cobalamin

level in blood = below 200

pg/ mL
Deficiency of vitamin B12 affects both
men and women in equal numbers.
Deficiency can result in anaemia and
damage to the nervous system

Vitamin B12 deficiency is most commonly caused

by a lack of intrinsic factor, a substance produced
in the stomach that is necessary for the
absorption of vitamin B12 from food.

When intrinsic factor is lacking, vitamin B12 is

unable to be absorbed and is therefore unable to
be utilised by the body. Pernicious anaemia is one
such condition where the production of intrinsic
factor is impaired.


Other causes of vitamin B12 deficiency include

A diet inadequate in vitamin B12 rich foods particularly so in vegetarians who dont eat any
animal products, meat, fish, milk, eggs, butter,
cheese and other dairy products (vegans).
Inadequate absorption or utilisation of B12 because
of gastric abnormalities such as coeliac disease,
An increase in certain intestinal organism.
Drugs that may interfere with the absorption of
vitamin B12.
Heavy alcohol consumption.
Rare congenital disorders.

Symptoms

Initial symptoms of vitamin B12 deficiency can include

Dizziness.
Paleness.
Shortness of breath.
Fatigue.
Anaemia.
Hearing difficulties

If left untreated Vitamin B12 deficiency can

cause progressive damage to the nervous
system, especially the nerves outside the brain
and spinal cord.
When the spinal cord is involved, the first
symptoms include difficulty in feeling vibrations
in the feet, loss of position sense, and loss of
muscle co-ordination (ataxia).

Other symptoms of untreated vitamin B12

deficiency may include:

Weight loss.
An enlarged spleen and liver
(hepatosplenomegaly).
Exaggerated reflexes.
Mild depression and confusion.
Hallucinations, personality and mood
changes.
Irritability.
Damage to the optic nerve

Actions

1.Conversion of methylFH4 to FH4

2.isomerization of
methylmalonyl-CoA to
succinyl-CoA

1.Conversion of methylFH4 to
FH4
It is through these mechanisms that the
metabolic activities of vitamin B12 and folic
acid are linked and implicated in the
synthesis of DNA.
It is through this pathway that
folate/vitamin B12 treatment can lower
plasma homocystein concentration.

Isomerization of methylmalonylCoA to succinyl-CoA

Through this pathway cholestrol,some

amino acids can be used for
gluconeogenesis.

So, methylmalonyl-CoA accumultates in

vitamin B12 deficiency.

Treatment (injections)

In most cases of vitamin B12 deficiency,

intramuscular injections of vitamin B12 are
given.
To begin with, regular injections of 1000
micrograms are usually given every week
for 4-6 weeks.
This frequency allows the bodys physiology
to start producing red cells normally.

Folic Acid

Muhammad Awais

Folic acid known as Vitamin B9, is also referred

to as folacin or folate and its chemical name is
pteroylglutamic acid.
It received its name from the Latin word folium,
meaning "foliage," because folic acid is found in
naturals leafy green vegetables.

Folacin, a derivative of folic acid, is a

dull yellow crystalline substance made
up chemically of a pteridine molecule,
para-aminobenzoic acid (PABA), and
glutamic acid.

 Folic acid acts as a coenzyme with vitamins C and

B12 in numerous essential metabolic reactions.
It acts as a carbon carrier in the formation of heme
and is necessary for the formation of red blood
cells.
Folic acid is required to make "SAMe" (S-adenosyl
methionine). It is involved in the synthesis of
nucleic acids, is essential for proper growth.

Folic acid is required for DNA synthesis

and cell growth and is important for red
blood cell formation, energy production
as well as the forming of amino acids.

 It is important for healthy cell division and

replication, since its involvement as
coenzyme for RNA and DNA synthesis.
It is also required for protein metabolism
and in treating folic acid anemia.
Folic acid also assists in digestion, and the
nervous system, and works at improving
mental as well as emotional health.
This nutrient may be effective in treating
depression and anxiety.

Folic acid is metabolized in the liver to 7, 8dihydrofolic acid and eventually to 5, 6, 7, 8tetrahydrofolic acid with the aid of reduced
diphosphopyridine nucleotide (DPNH) and folate
reductases.

Growth Factors of
Hematopoeitic
System

Erythropoietin
Glycoproteinhormonethat controls
erythropoiesis
EPO is a protein signaling molecule
forerythrocyte precursors in thebone
marrow
Sites of production

Kidneys
Liver

Biological Functions

As its name suggests, EPO stimulates

growth of Erythrocytes
Stimulates Proerythroblasts formation
Causes cells to pass through various

stages of erythropoiesis rapidly

Carries oxygen in blood
Neuronal protection during hypoxic
conditions (stroke, etc.).

Role in red blood cell

production

Underhypoxicconditions, the kidney will

produce and secrete erythropoietin to increase
the production of red blood cells by
targetingCFU-E, proerythroblastand
basophilic erythroblast subsets in the
differentiation.

It has primary effect on red blood cell

progenitors and precursors by promoting their
survival through protecting these cells
fromapoptosis.

Mechanism of action
Bybinding to theerythropoietin
receptor(EpoR) on the surface of red cell
progenitor
After binding, several intracellular
signaling pathways are activated ( Fliser et
al., 2006).

Binding and activation of JAK2 is essential

for erythropoiesis
Activation of the JAKSTAT pathway
contribute to tissue protection via its
antiapoptotic effects.
Erythropoietin also stimulates the
calcium/PKC pathway and the other
signaling cascades which have novel
protective effects of erythropoietin

Regulation

Erythropoietin levels in blood are quite low

in the absence of anemia

In hypoxic stress
EPO production may increase a 1000-fold

It is synthesized by renal peritubular cells,

with a small amount being produced in the
liver.

Regulation is believed to rely on a feedback

mechanism measuring blood oxygenation

Regulation pathway

Medical uses

Erythropoietins available for use as

therapeutic agents are produced
byrecombinant DNA technology

They are used in treatinganemiaresulting

fromchronic kidney diseaseand the
treatment ofcancer
(chemotherapyandradiation).

Thrombopoietin

known asmegakaryocyte growth and

development factor(MGDF)
Glycoprotein hormone

Sites of production

Liver
Kidneys
Bono marrow

Location
In human, thrombopoeitin is encoded by
theTHPOgene
The thrombopoietin geneis located on the
long arm ofchromosome 3
Mutations in this gene have been shown to
cause familial aplasticanemia

Mechanism of action
This protein is the ligand for
MLP/C_MPL, the product of
myeloproliferative leukemia virus
oncogene
After bindingit acts through JAKSTAT
pathway as erythropoeitin

Regulation
It regulates the differentiationand
production ofplateletsby thebone
marrow

It stimulates the production and

differentiation ofmegakaryocytes, the bone
marrow cells that fragment into large
numbers ofplatelets

Medical use

Administration of thrombopoietin results in

a rapid rise in platelet counts to levels
previously unattainable with other
thrombopoietic cytokines

It is thought as a useful agent for the

prevention and treatment of
thrombocytopenia in cancer patients and
for other disorders of thrombocytopenia

WASEEM ASHRAF
BBC-01093008

Definition of Anemia
Deficiency

in the oxygen-carrying capacity of

the blood due to a diminished erythrocyte
mass.
May be due to:
Erythrocyte loss (bleeding)
Decreased Erythrocyte production
low erythropoietin
Decreased marrow response to erythropoietin
Increased Erythrocyte destruction (hemolysis)

CLASSIFICATION
Morphological classification:
1. Normocytic Normochromic
Anemia
2. Macrocytic Normochromic
Anemia
3. Macrocytic Hpochromic Anemia
4. Microcytic Hypochromic Anemia

Etiologic Classification:
1. Hemorrhagic Anemia.
2. Hemolytic Anemia.
3. Nutrition Deficiency Anemia.
4. Aplastic Anemia.
5. Anemia of Chronic Disease.

Laboratory Definition of Anemia

Hgb:
Women: <12.0

Men: < 13.5

SIGNS & Symptoms of Anemia

SKIN

CARDIOVASCULAR SYSTEM

RESPIRATION

DIGESTION

METABOLISM

KIDNEY

REPRODUCTIVE SYSTEM

NEUROMASCULAR SYSTEM

Echinocytes (burr cells)

Anemia due to Decreased

Response to Erythropoietin
Iron-Deficiency
Vitamin B12 Deficiency
Folate Deficiency
Anemia of Chronic Disease

Anemia due to Decreased

Response to Erythropoietin

Iron Deficiency
Can result from:

Pregnancy/lactation
Normal growth
Blood loss
Intravascular hemolysis
Gastric bypass
Malabsorption

Iron Deficiency Anemia

Iron Deficiency Anemia koilonychia

Treatment of Iron Deficiency

Anemia

Oral iron salts

Ferrous sulfate 325 mg po Q Day
Side effects: constipation, black stools,
Vitamin C can facilitate iron absorption.

Vitamin B12 Deficiency

Treatment of Vitamin B12

Deficiency

Vitamin B12

1000 micrograms intramuscularly

monthly

-OR

Vitamin B12

1000-2000 micrograms po QDaily

Anemia due to Decreased

Response to Erythropoietin

Anemia of Chronic Disease

Usually normocytic, normochromic (but can
become hypochromic, microcytic over time)
Occurs in people with inflammatory conditions such
as collage vascular disease, malignancy or chronic
infection.
Iron replacement is not necessary
May benefit from erythropoietin supplementation.

Anemia due to Decreased

marrow response

Thalassemia
Microcytic anemia
Defects in either the alpha or beta chains of
hemoglobin, leading to ineffective erythropoiesis and
hemolysis
-thalassemia:
Prevalent in Africa, Mediterranean, Middle East, Asia

-thalassemia:
Prevalent in Mediterranean, South East Asia, India,
Pakistan

Smear shows microcytosis with target cells

Thalassemia

Anemia due to Destruction of

Red Blood Cells

Hemoglobinopathies
Sickle Cell Anemia

Aplastic Anemia
Decrease in all lines of cells hemoglobin,
hematocrit, WBC, platelets
Parvovirus B19, EBV, CMV
Acquired aplastic anemia

Hemolytic Anemia

Sickle Cell Anemia

Evaluating the Patient with

Anemia

Is the patient bleeding?!

Any bright red blood per rectum (hematochezia)
or black tarry stools (melena)?
Check stool guaiac, may consider sigmoidoscopy or
colonoscopy

Any abdominal pain, or recent femoral vein/artery

manipulation?
Consider retroperitoneal hematoma

Evaluating the Patient with

Anemia

Any jaundice, elevated bilirubin, suspicious

for hemolysis?

Check for increased indirect bilirubin, increased

LDH, decreased haptoglobin, increased
reticulocyte count.

theraputis for anemia

Iron therapy

Iron is absorbed best from the duodenum and

proximal jejunum

Enteric coated or sustained release capsules may be

counterproductive

Iron salts should not be given with food because the

phosphates, phytates, and tannates in food bind the
iron and impair its absorption

Iron is best absorbed as the ferrous (Fe2+) salt

Acidic environment favors ferrous over ferric state

Ascorbic acid can enhance iron absorption

antacids impair absorption

Treatment therapies

Hydroxocobalamin dose of 1000 g (1 mg) IM every

day for one week, followed by 1 mg every week for
four weeks and then, if the underlying disorder
persists, as in PA, 1 mg every 3 months for life

high dose oral cobalamin is an alternative but requires

much greater patient compliance

THANK YOU

Polycythemia

Polycythemia
Polycythemia:
PolycythaemiaorPolyglobulia) is a
disease state in which the proportion of
blood volume that is occupied by red
blood cells increases.
Blood volume proportions can be
measured ashematocritlevel.

Types
Absolute polycythemia
Primary polycythemia
Secondary polycythemia

Polycythemia and
erythrocytosis

Polycythemia refers to any increase in

red blood cells, whereas erythrocytosis
only refers to a documented increase of
red cell mass.

Polycythemia Vera
P. vera is a rare disease
Median age 60 - 65 years
Clinical features

Attributed to increased blood viscosity and

poor oxygen delivery to organs (brain)
Poor O2 delivery leads to ischemia and
thrombosis
Expanded blood volume and viscosity leads to
increased cardiac work load

P. Vera - Symptoms

Symptoms

Headache
Weakness
Pruritis (aquagenic)
Dizziness
Diaphoresis
Visual disturbance
Weight loss

P. vera - Bone Marrow

Biopsy

Therapeutic Agents

Phlebotomy
Removal of 0.5 L of blood
Goal is to reduce viscosity, reduce HCT to
<45.

Hydroxyurea
Acts by non-alkalating mechanism to inhibit
the enzyme ribonucleotide diphosphate
reductase involved in DNA synthesis
Reduced incidence of thrombosis compared
to phlebotomy
Effective in reducing blood counts although
transient cytopenia may occur

Imatinib (Gleevec)
Tyrosine kinase inhibitor which inhibits
tyrosine kinase activity of BCR-ABL
(remember CML)
In vitro it inhibits autonomous growth of
erythroid colonies in PCV

JAK2 mutation

Janus Kinase 2 (JAK2) has tyrosine

kinase activity and is involved in signal
transduction from EPOR (erythropoietin
receptor) to nucleus for gene
expression

Single nucleotide JAK2 mutation (JAK2 V617F)

Valine to phenylalanine substition at codon 617

Mutation occurs in pseudokinase (normally negative

regulator of kinase activity) domain of JAK2 gene
resulting in constitutively activated tyrosine kinase
Exclusive to disorders of myeloid lineage and not
observed in lymphoid neoplasms or solid tumors
Mutation prevalence: PCV (60-90%), ET and
Idiopathic Myelofibrosis (30-50%)

Antiplatelet therapy

Aspirin is preferred antiplatelet drug in

polycythmia for different reasons. An
increased biosynthesis of thromboxane
has been reported in PV, and 1 of the
cellular effects of aspirin on platelet
aggregation is the reduction of
thromboxane biosynthesis.