Anaemia is defined as a below normal plasma haemoglobin

concentration resulting from decreased number of

circulating red blood cells or an abnormally low total

haemoglobin content per unit of blood volume.

Types of anaemia
According to the cause:

Anaemias caused by deficiency of factors

necessary for erythropoiesis such as: Iron, Folic
acid,Vitamin B12.
:
Anaemia caused by excessive destruction of red
blood cells.
 Anaemia caused by depression of the bone marrow:

This may affect the formation and development of

the red cells, leucocytes or platelets.

Due to mutation/ exchange of amino acids

Others like
 Hypochromic microcytic
Iron is essential in the formation of haemoglobin
Factors affecting absorption of iron:
A. Diet:
Tannic acid, phosphates form relatively insoluble and
consequently unabsorbable complexes with iron.
 Reducing substances in food e.g. ascorbic acid and certain
fatty acids such as succinates and the -SH groups of amino
acids, help reduction of ferric salt (non absorbable) to
the ferrous iron (absorbable).
Meat increases absorption of iron through stimulating
production of gastric acid .
The iron in meat protein is more available for absorption
and can be more efficiently absorbed, since haem iron in
meat haemoglobin and myoglobin can be absorbed intact
as haemin without first being broken down into free iron.
 B. Diseases
Absorption of iron is hindered in cases of achlorohydria,
coeliac disease,malabsorption syndrome

Tetracycline, ofloxacilin, norfloxacilin, ciprofloxacilin,

penicillamine, thyroxin, bisphosphonate, antacid, captopril
and desferroxamine, all hinder iron absorption.
Factors regulating absorption of iron:
Serum iron.
Iron stores.
 Daily excretion

Only 1-2 mg of the total iron is lost per day from

normal man.

Two thirds of the iron is excreted from the

gastrointestinal tract as extravasated red cells, iron
in the bile & iron in exfoliated mucosal cells.

The other third of iron is lost in desquamated skin

& in the urine
Causes of iron deficiency anaemia
Decreased intake.

Decreased absorption
(e.g. malabsorption syndrome)

Increased requirement:
Baby: premature (not well developed iron stores).

Child: During rapid growth period.

Pregnant women:
The fetus takes up 600 mg of iron from his mother even if she is
deficient. Iron must be given from the fourth month of pregnancy
 Increased loss
Menstruating women
Occult blood loss (piles, peptic ulcer)

Laboratory and clinical manifestations

Iron deficiency leads to hypochromic microcytic

anaemia i.e.the red cells are deficient in haemoglobin&
smaller in size
 Iron therapy
Indications of iron therapy:
Prevention of iron deficiency anaemia.

Treatment of iron deficiency anaemia

During treatment of severe pernicious anaemia with

cyanocoblamin as the iron stores occasionally become
exhausted by the sudden increase in RBCs formation
 Iron preparations
According to their route of administration,
two types of iron preparations are available:
1- Oral preparations.
2- Parentral preparations.
 ORAL IRON PREPARATIONS:
These preparations should be given after meals to avoid G.I.T irritations
Soluble ferrous salts
Side effects of oral iron preparations
G.I.T irritation

Black coloured stools, which may obscure diagnosis of

continued G.I.T, blood loss

Acute oral iron toxicity

Symptoms of acute oral iron poisoning:

The symptoms are due to acute necrotizing
gastroenteritis, t hey include:
Abdominal pain.
Grey / black vomiting.
Bloody diarrhoea.
 Treatment/antidote
Treatment is urgent and immediate efforts must be made to
chelate iron in the blood and in the stomach and intestine.
Raw egg and milk help to bind iron until a chelating agent is
available
Chelating agent:
desferroxamine 1-2 g i.m

Symptomatic treatment:
Intravenous fluids to treat collapse and dehydration.
Sodium bicarbonate for metabolic acidosis
Barbiturates to counteract convulsions
Indications:
These are indicated only in emergencies or when oral
therapy is impractical

e.g. owing to malabsorption or gastrointestinal sensitivity

Severe oral iron intolerance.

Patients with extensive chronic blood loss, who cannot be

controlled with oral iron alone.

Preparation
Iron dextran
Iron content 50 mg/ml can be used i.m or i.v. It is a
complex of ferric hydroxide in low molecular weight
dextran. It is the least toxic preparation for parental
use

Iron sorbitol
50 mg/ml given by deep i.m.i. It is a complex of low
molecular weight sorbitolt hat can be rapidly
absorbed from the site of injection
 VITAMIN B12 (CYANOCOBALAMIN)
DEFICIENCY ANAEMIA
Normochromic Macrocytic

Functions

Cyanocobalamin is essential for nucleoprotein synthesis, so it

is required for the normal maturation of epithelial cells and

for normal haemopoiesis

Its deficiency leads to pernicious anaemia characterized by

the formation of erythroblasts which are somewhat irregular

in shape and larger in size (i-e megaloblastic or macrocytic).

 Cyanocobalamin is also essential for proper functioning of
the nervous tissue and for the formation of myelin
sheath.

It has a lipotropic action

Absorption, transport, &storage
Dietary vitamin B12 in the presence of gastric acid and
pancreatic proteases, is released from proteins to which it
is bound and then it is immediately bound to the
intrinsic factor.

The vit B12 - intrinsic factor complex then reaches

the ileum, where it interacts with a specific receptor on
ileal mucosal cells and is transported to the circulation
 The specific defect in pernicious anaemia is the
failure to absorb vit B12 due to lack of the intrinsic
factor

(e.g. when the gastric mucosa is atrophied or

damaged after gastrectomy and in many cases of
cancer of the stomach).

In this case vit B12 must be given by injection.

It is non-irritant and completely absorbed when

injected subcutaneously or intramuscularly.
 Preparations and dosage

A solution containing 100 or 1000 g/ml given by intamuscular

or deep subcutaneous injection.
It should not be given by intravenous route
Treatment is started with 100-1000 g every day or every other
day for two weeks.
Then maintenance therapy (100-1000 g every month) must be
given for life.
In cases of presence of neurological manifestations
we start with the same initial doses for two weeks, then give
100-1000 g / week for six months, followed by the same
maintenance dose for life.
 Hydroxycobolamin:
Given by intramuscular injection. It is highly bound to
plasma protein so it is retained in the body in greater
amounts than cyanocobalamin and for longer periods

It is slowly excreted and so requires less frequent

injections
(Normochromic-Macrocytic)

Folic acid is a water-soluble member of B complex

group of vitamins.

It occurs in a conjugated form mainly in yeast, liver, fresh

green vegetables and fruits
 Absorption, transport, &
storage
Folic acid is readily and completely absorbed in the proximal
jejunum.

Folates present in food are largely in the form of reduced

polyglutamates.

Before absorption, the polyglutamates are deconjugated to

monoglutamates, then methylated and reduced to methyl
tetrahydrofolate CH3 H4PteGlu by dihydrofolate reductase.
 Once absorbed, folate is rapidly transported as CH3 H4 Pte
Glu, to the tissues.

Following uptake into cells,CH3 H4Pte Glu acts as a methyl

donor for the formation of methyl cobalamin and as a
source of other folate congeners, which are essential for
nucleoprotein synthesis .
Deficiency of folic acid
Folic acid deficiency leads to megaloblastic anaemia
with haematological manifestations and without
neurological manifestations
Causes of deficiency of folic acid:
Nutritional deficiency
Decreased absorption
Abnormally increased requirements
Pregnancy
Lactation
Proliferative diseases.
Haemolytic diseases
Drugs
Drugs reducing the level of folic acid
Folic acid antagonists
 Therapeutic uses
Treatment of folic acid deficiency

Dose:

Adults: 1 mg two or three times daily.

Children: 1 mg daily.

Adverse effects:

Folic acid in large amounts may counteract the antiepileptic

effect of phenobarbital, phenytoin, and primidone and
increase the frequency of seizures in susceptible children.
 HAEMOLYTIC ANAEMIA
(Normochromic-Normocytic)
This is due to excessive blood destruction, which may
be due to
Congenital anomalies of RBCs; e.g. congenital
spherocytosis.
Infective or toxic factors.
Haemolysis which occurs in haemolytic diseases of
the new born e.g. erythroblastosis foetalis.
Causative agents
It may occur as an adverse action of some drugs
(idiosyncrasy due to genetic deficiency of the enzyme
glucose -6- phosphate dehydrogenase in the red cells)
such as
sulphonamide,
nalidixic acid,
some antimalarials (primaquine),
analgesics (acetylsalicylic acid in high dose)

-It may also be due to an allergic reaction

 Treatment
Immediate withdrawal of the causative drug (if any).
Blood transfusion
Corticosteroids: e.g. prednisone, tend to abolish the
production of haemolysins.
Splenectomy may be indicated in cases of hereditary
spherocytosis (congenital haemolytic anaemia)
Coagulation
Platelets and clotting factors are responsible for initiating
coagulation.
When an injury occurs, platelets (thrombocytes) immediately
migrate to the damaged area. Because platelets stick to each
other (aggregation) and to the vessel walls (adhesion), they
form a plug around the injured tissue.
Plasma clotting factors reach the platelet plug and interact
with each other to form a stable blood clot.
Hemostasis is the balance between clot formation and
clot breakdown that occurs throughout the day.
 INITIATION OF BLOOD COAGULATION
Extrinsic Pathway Intrinsic Pathway
Blood trauma/ contact with collagen
Tissue trauma

Leakage of Tissue Factor Activation of factor

Ca+2, factor VII XII, IX, VIII

X Xa X Xa
Ca+2 Ca+2

Prothrombin activator
Prothrombin
Ca+2 activator
Prothrombin Thrombin Prothrombin Thrombin
(factor II) (factor II)

Activation of certain factors (VII, II, X and protein C and S) is essential for
coagulation. This activation requires vit K (reduced form)
1-36
 The coagulation of blood may be interfered with
due to

, which may be due to deficiency of one or

more of the clotting factors e.g. haemophilia.

Missing clotting factors can be supplied by giving fresh

blood or plasma.

, e.g. liver disease, vitamin K

deficiency and ingestion of oral anticoagulant drugs. These
cases require treatment with vitamin K
 SYSTEMIC COAGULANTS
Vitamin K:
It is useful only in cases of hypo-prothrombinaemia due to
deficiency of vitamin K, which may occur due to faulty
absorption, as in cases of obstructive jaundice since the
presence of bile is essential for the absorption of this fat soluble
vitamin
In cases of bleeding due to overdosage with drugs, which act by
competitive antagonism to vitamin K, like oral anticoagulants and
salicylates.
Vitamin K can be administered orally, s.c, i.m or i.v 5-20 mg
Vitamin K1 comes from dietary sources while vitamin K2 is
synthesized by intestinal bacteria
 Thromboplastin
Preparations containing thromboplastin are
usually obtained from mammalian tissues or
blood.
They may be used by local application to
stop bleeding from oozing surfaces, or may
be given by i.m. injection.
Anti haemophilic globulin
(AHG):
Haemophilia is a hereditary disease that occurs in males
only, but is transmitted by females.

It is characterized by deficiency of circulating

antihaemophilic globulin, leading to excessive haemorrhage
from minor injuries.

It is prepared from pooled human plasma and is given by

i.v. injection
 Transfusion of fresh whole blood
It is necessary for all cases of uncontrollable haemorrhage
Calcium,Vitamin C, Rutin
May be used especially in cases of abnormal capillary
fragility
Local haemostatics or styptics:
These are substances which are used to stop bleeding from
localized areas.
1) Physical methods:
e.g. application of pressure, cold or heat coagulation
2) Vasoconstrictor drugs:
e.g. adrenaline may be used locally.
3) Astringents:
They act by precipitating blood proteins at the site of application,
e.g. tannic acid, alum, ferric chloride, ethyl alcohol,... etc,
 These are drugs which interfere with the coagulation of blood
either in vivo or in vitro

They are used clinically to prevent the extension of an existing

thrombus (therapy) and

stop formation of new thrombi in the vascular bed (prophylaxis)

Venous thromboembolism: anticoagulants are useful in
therapy and prophylaxis.
Arterial thrombosis: anticoagulants are less useful as therapy ,
and have only a limited place in prophylaxis.
Properties of an ideal anticoagulant
It should have a high therapeutic index
The therapeutic dose should be standardized and should be
easily measured by simple laboratory tests.
It should be effective by oral or parentral administration
It should have a rapid onset of action for use in emergencies and
long duration
Its action should be quickly antagonized by non-toxic agents, in
case of overdosage
There is no anticoagulant which possesses all these properties
 Classification of anticoagulants
Parenteral anticoagulants
Substansces which inhibit conversion of prothrombin
to thrombin and interfere with the action of thrombin
on fibrinogen
They include:
1- Heparin.
2- Low molecular weight heparin.
3- Heparin-like agents : e.g. Dextran sulphate
 Oral anticoagulants
Substances which interfere with synthesis of
prothrombin and factors VII, IX and X.
Vitamin K dependent coagulation factors
These agents comprise two subgroups
These agents comprise two subgroups:
1. Coumarins
Warfarin Sodium
Dicoumarol (Bishydroxycoumarin)
Tromexan
Cyclocoumarol
2. Indanedione Derivatives
Phenindione (Dindevan
III. Substances which remove ionic
calcium
Ca precipitants

oxalate of potassium or sodium may be used to prevent blood

clotting in vitro but they can not be used in vivo

Drugs which diminish ionizable Ca but do not precipitate it

These drugs are active in vitro.

They include sodium citrate and edetate, which form soluble but
non-ionizable chelates with calcium. 3.8% sodium citrate may be
used to maintain the fluidity of blood for tranfusion processes
 Parenteral Anticoagulants
HEPARIN
Heparin was originally obtained from the liver, but is also present in the
lungs and other tissues and in the mast cells.

It is prepared commercially from beef lung or hog intestinal mucosa.

Heparin is a mucopolysaccharide composed of sulphated D-

glucosamine and D-glucuronic acid.

Its molecule has a large molecular size and strong

electronegative charge and due to this charge it has an anticoagulant
activity.

It is normally present in the blood and is one of the main factors which
maintains its normal fluidity.
 Mechanism of action of heparin
Heparin prevents fibrin formation in the process of
coagulation as follows:

1. It acts indirectly by markedly increasing the activity of a

heparin cofactor (antithrombin-III).

[The heparin co-factor or antithrombin III is an -globulin

and a protease inhibitor that inactivates several activated
clotting cofactors, namely Xlla, Xla, Xa, lla and Xllla].
2. Antithrombin III then inhibits the conversion of
prothrombin to thrombin by thromboplastin.

3. Antithrombin III also directly inactivates thrombin.

Absorption, fate and excretion
Heparin is not absorbed when given orally because
of its highly negative charge and large molecular size
It is given by IV or SC injection. It has a rapid and
transient action, it must be given every 2-4 hours
Rapid onset and short duration of action
Heparin is metabolized by a liver enzyme called heparinase
to uroheparin.
It is excreted in urine partly as uroheparin and partly
unchanged
 Dosage
Intravenous administration:

Intermittently: 5000 units every 2-4 hours.

Continuous infusion: initial bolus of 5000-10.000 units, then 20.000

units in one liter of saline (0.9%) or dextrose (5%) at a rate of 15-20
drops/min

Subcutaneous administration:

Can be used for long term management of patients in whom warfarin

is contraindicated e.g. in pregnancy.

Dose:

a total daily dose of about 35.000 U is administered as divided doses

every 8-12 hours.
 Low dose heparin therapy is sometimes used prophylactically to
prevent deep vein thrombosis and thromboembolism in
susceptible patients
N.B: Intramuscular injection is contraindicated because it
causes painful haematoma.
Control of therapy:
Heparin therapy is monitored by the partial thromboplastin time
(PTT):
The test is done at any time during continuous infusion therapy
If the heparin is given intermittently, PTT is measured prior to an
injection .
During therapy the PTT should be twice the control value.
Side effects
These are mainly caused by overdosage
It leads to spontaneous haemorrhages with
haematuria and bleeding from mucous
membranes.
Thrombocytopenia
heparin-induced platelet aggregation( mild)
formation of heparin dependent antiplatelet
antibodies (Sever)
Hypersensitivity reactions
Transient alopecia
 Mild anticoagulant side effects of heparin is treated by
discontinuation of the drug.
If the effects are severe and bleeding occurs, administration of a
specific antagonist is indicated.
The specific heparin antagonist is , a
strongly basic protein which forms an inactive complex with
heparin
Protamine sulphate carries a positive charge that neautralizes
the negative charge of heparin
1 mg I.V. is required to antagonise each 100 units of heparin
Transfusion of fresh whole blood
Low Molecular Weight Heparin
(LMWH)
Low molecular weight heparin, e.g. enoxaparin, is
synthesized by depolymerization of heparin.

Most LMWHs have a molecular weight of about one third

that of heparin.
Mechanism of action
Antithrombotic activity: Both heparin and LMWHs exert
their anticoagulant activity by activating antithrombin III.

But unlike heparin which has equivalent activity against

factor Xa and thrombin, LMWHs have greater activity
against factor Xa.
Oral anticoagulants
General characteristics
These drugs are produced synthetically.

They are structurally similar to vitamin K.

They are only active in vivo (indirect anticoagulants).

They are given orally as they are absorbed from the gut
There are two main groups:
a) Coumarin derivatives:
Warfarin(prototype)
Dicoumarol

They are the safest and most commoly used preparations especially
warfarin which has the lowest incidence of adverse effects

b) Indandione derivatives:
Phenandione(Dindevan)
Diphenadione.

They are obsolete because of adverse reactions unrelated to

coagulation
 They interfere with the production of prothrombin and
clotting factors VII, IX and X by the liver leading to an
anticoagulant effect

During the formation of these clotting factors in the liver,

vitamin K is converted to a biologically inactive metabolite
(epoxide form), that is then reduced back to the active
vitamin by the enzyme epoxide reductase
 The oral anticoagulants (e.g warfarin) which are structurally
similar to vitamin K are believed to act as competitive
inhibitors of this enzyme and thus limit the availability of the
active form of the vitamin to form the clotting factors.

A latent period is always present before their anticoagulant

action is manifested, this is due to the slow removal of
prothrombin and factors VII & IX already present in the
circulation and also the rate of drug action in the liver
Doses
Warfarin sodium
Initial dose:10-15 mg/daily for 3-5 days followed by a
maintenance dose:2-15 mg daily

It should be noted that the maintenance dose varies

from one patient to another depending on the effect

of the drug on the prothrombin time.

Control of therapy
Prothrombin time (PT) adjusted to be
double the normal value
INR (International Normalized Ratio
Toxicity
Main toxic manifestation is spontaneous haemorrhage

Anorexia, nausea, vomiting and diarrhoea.

Skin rashes may occur

They are contraindicated during pregnancy

Reversal of action
Stopping the drug.

The antidote is Vitamin K1 i.v. 50-100 mg (phytondione).

Transfusion of fresh whole blood