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One of
the most remarkable properties of blood is its ability to
clot, or coagulate. Normally, within the blood vessels,
blood remains in a fluid condition. Within the body, blood
may clot in response to tissue injury, such as a muscle
tear, a cut, or a sharp blow. When exposed to air, blood
becomes sticky and sets into a firm, jellylike mass. This
mass then separates into two portions: a firm red clot
floating free in a transparent, straw-colored fluid called
serum.
A clot
consists almost entirely of red blood cells
entangled in a network of fine fibrils, or threads,
composed of a substance called fibrin. Fibrin does
not exist as such in blood but is created by the action of
thrombin, an enzyme that promotes the conversion of
fibrinogen, one of the plasma proteins, to fibrin
in the clotting process. Thrombin is not present in
circulating blood; it is formed from prothrombin,
another of the plasma proteins, by a complex process
involving blood platelets, certain calcium salts,
substances produced by injured tissue, and contact with
rough surfaces. If any of these factors is
deficient, clot formation is defective. The
addition of sodium citrate removes calcium ions
from the blood and thus prevents a clot from forming. Lack
of Vitamin k makes impossible the maintenance of
the proper amount of prothrombin in the blood. Certain
diseases may lower the concentration of the various
clotting proteins or of the platelets of the blood.
Although
clot formation is a normal process, it sometimes occurs
inappropriately and constitutes a threat to life. In
people who are hospitalized for a long time, for example,
clots sometimes form in the large veins of the legs .If
these clots, or thrombi, travel to the lungs, they
can cause death Such venous thrombi are dissolved in many
cases with a combination of drugs that prevent coagulation
and break down clots. Anticoagulants include the natural
compound heparin, prepared from the lungs and
livers of animals, and the synthetic chemicals
dicumarol and warfarin. Clot-dissolving drugs,
called thrombolytics, include two enzymes,
urokinase and streptokinase, approved for
medical use in 1979, and tissue plasminogen
activator (TPA), a product of genetic
engineering.
Interaction of thrombocytes with the fatty deposits
found in atherosclerotic heart disease is thought to
contribute to heart attacks. Compounds such as
aspirin and sulfinpyrazone, which inhibit
platelet activity, may decrease heart attacks in persons
with atherosclerotic disease.
Definition of Anticoagulants: It is a drug to prevent and treat abnormal blood clotting.
Anticoagulants are sometimes called “blood thinners”, but
this name is misleading. These drugs do not “thin the
blood”-they make your blood less likely to clot .
Some Pathological definitions related to anticoagulants:
q
Embolism: obstruction of a blood vessel by
an embolus, or foreign substance, that has been
transported by the CIRCULATORY SYSTEM. The embolus
may be a blood clot.
q
Thrombosis:
differs from embolism in that a thrombus consisting of a
blood clot, or clump of blood cells, forms inside the
affected blood vessel; a fragment of a thrombus becomes an
embolus if it is dislodged and moves through the
bloodstream to create an obstruction, or embolism.
q
Stroke: damage of the brain due to a
blockage in blood flow, or to a hemorrhage of blood
vessels in the brain. Without blood, sections of brain
tissue quickly deteriorate or die, resulting in
paralysis of limbs or organs controlled by the
affected brain area. The majority of stroke cases are due
to arterial blockage caused by either thrombosis or
embolism.
About anticoagulants
Indications:
Among the the main indications for anticoagulant therapy
comes Atrial fibrillation (AF) which is a recognized risk
factor for thromboembolic events. This is due to the
disturbance of blood flow in the left atrium of the heart.
Recently, trials have shown the benefit of anticoagulation
in patients with AF. A reduction in the incidence of
strokes, systemic embolism and mortality have been
demonstrated. There is also an increased risk of
thromboembolism in patients with prosthetic heart valves,
because the valve acts as a focus for thrombi formation.
The risk is also affected by the type of valve, its
location and other patient factors. In brief words ,Anticoagulants
are used for atrial fibrillation because irregularly
beating heart chambers cause pooling of blood. Pooled
blood is more likely to develop blood clots, which can
travel from the heart to the brain and cause a stroke.
Anticoagulants help prevent the blood clots from forming
and reduce the risk of stroke caused by atrial
fibrillation.
Mode of action
The two most commonly
used anticoagulant agents are heparin and the
coumarin warfarin. Both of these agents exert their
effect by acting on the clotting cascade.
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Warfarin and other coumarins Warfarin and other
coumarins inhibit the formation of factors II, VII, IX,
and X which are all dependent on Vitamin K. The
coumarins are chemically related to Vitamin K and so
competitively inhibit the synthesis of the above
clotting factors.
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Heparin Heparin exerts its main action by binding
to antithrombin III. Antithrombin III is an inhibitor of
thrombin, and heparin potentiates this effect.
Antithrombin III also inhibits the activated factors
XIIa, XIa and Xa, which results in less fibrin
formation, so there is a reduced incidence of thrombus.
Heparin also has a slight inhibitory effect on platelet
function.
It should be remembered
that anticoagulants do not dissolve any existing clots.
The body's own hermostatic mechanisms do this.
Anticoagulants prevent any new clot formation while this
process is taking place.
Heparin
Initial therapy
Choice of therapy is
primarily determined by the indication for treatment. If
it is for the treatment of AF, immediate anticoagulation
is not necessary. But, in the treatment of a
thromboembolic event, anticoagulation is required
immediately to prevent further life-threatening embolism.
For immediate
initiation, heparin is the drug of choice it has a rapid
onset of action and a short half-life (0.5-2hr).
Initially, a loading
dose of between 5,000 and 100,000u (or 50-75u/kg) is given
intravenously over five minutes to neutralise the high
level of clotting factors in the blood. This is then
followed by a maintenance dose which may be given as an IV
infusion of 20,000-40,000u over 24 hrs (or 25u/kg/hr).
Alternatively, heparin
can be given subcutaneously every 12 hrs. The dose needs
to be slightly higher at around 15,000-20,000u every 12
hrs. The injection acts as a depot, with the heparin being
released over the next 12 hrs.
Subcutaneous heparin is
available as both the sodium and calcium salt. There seems
to be little difference between the two as regards
efficacy or adverse effects. IV heparin is always given as
the sodium salt.
N.B:
The anticoagulant drug heparin has proved valuable
in vascular surgery and cerebral thrombosis.
Monitoring of
heparin
The clotting status of
the patient is measured by the Activated Partial
Thromboplastin Time (APTT). An equivalent measure
sometimes used is the Kaolin Cephalin Clotting Time
(KCCT). The normal (control) value for APTT is between
24 and 36 seconds. If possible, this should be measured
for the patient before any anticoagulation is started, to
ensure the patient's coagulation status is normal. The
APTT is then measured six hours after the infusion has
started and the rate adjusted to maintain the APTT at
1.5-2.5 the normal value. If the result is <1.5, the
patient is still at risk of further thrombi forming. If it
is >2.5 the patient may be at risk of haemorrhage. The
APTT should be checked at least daily while the heparin
infusion continues.
Low molecular
weight heparins
These include
enoxaparin, tinzaparin, dalteparin and certoparin.
Evidence suggests they are as effective as unfractionated
heparin in the treatment of thromboembolic events and are
now being used for initial treatment. They have a longer
duration of action than unfractionated heparin and do not
need any monitoring. This means patients could be
discharged from hospital earlier.
Warfarin
Once the diagnosis has
been confirmed, oral anticoagulation is initiated. Heparin
treatment is maintained until the activity of the oral
coagulant is therapeutic. This may take up to 5 days to
allow any existing clotting factors to be cleared from the
blood.
Warfarin is usually
used for oral anticoagulation. Other agents include
nicoumalone and phenindione but these are
seldom used.
There are several ways
of initiating warfarin. Commonly, patients are loaded
using 10mg on day one, 10mg on day two and 5mg on day
three. In many cases, though, subsequent measurement of
the clotting status shows these doses to be excessive.
An alternative method
is shown in Table 2. No single method will be accurate for
all patients and daily monitoring is essential to
establish a safe and effective dose.
Monitoring of
warfarin
The clotting status of
a patient on warfarin is established by measuring their
Prothrombin Time (PT), expressed as a ratio of a
normal control sample the International Normalised
Ratio (INR). The normal control PT is roughly 12-16
seconds.
The INR range aimed for
depends on the indication for treatment. Different centres
may use slightly differing ranges, but the common ones are
illustrated in Table 3. However, an individual patient's
circumstances must always be taken into consideration when
deciding on a suitable INR range.
As a patient
stabilises, and successive INR measurements remain within
the therapeutic range, the patient's clotting status can
be monitored less frequently. This should be a gradual
process and most clinics see even their most stable
patients at least every three months. If a stable patient
presents with an INR outside their range, they should then
be seen more regularly until they stabilise again.
Several computer
programmes are now available to assist in dosing
alterations in response to a change in INR. These may also
suggest appropriate appointment intervals depending on a
patient's previous results and history.
Duration of
treatment
This will vary
according to indication. Patients being treated for AF
will require lifelong therapy, as will those with
prosthetic valves. Those receiving warfarin for recurrent
deep vein thrombosis or pulmonary embolism will also need
long-term therapy.
Treatment of first
thromboembolic event is more complicated as
recommendations vary depending on whether a specific cause
is identified.
Three months is the
standard treatment length, although some references now
suggest six weeks.
Adverse effects
The main adverse of all
anticoagulants is haemorrhage. In severe cases, this may
present as intracranial or gastro-intestinal bleeding
which could be life-threatening. Less serious bleeding
includes nose bleeds or haemorrhoid bleeding. All bleeding
should be treated seriously. An immediate INR should be
taken and if raised, intravenous vitamin K should be
administered 1mg is usually sufficient, although in
life-threatening situations 5mg may be given along with
fresh frozen plasma.
Patients with a history
of gastro-intestinal bleeding, or stroke prior to
anticoagulant therapy, should be considered high risk,
treated with caution and monitored closely. Patients with
impaired liver function are particularly sensitive to the
effects of oral anticoagulants and are at a high risk of
bleeding. They should only be treated if absolutely
necessary.
Other adverse
effects of warfarin
include:
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teratogenicity The greatest risk of congenital abnormalities
due to warfarin is in the 6-9th week of gestation. Women
requiring anticoagulation are transferred to heparin
therapy during their first trimester
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rash
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alopecia
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skin necrosis thought to result from a paradoxical
hypercoagulable state following initiation of warfarin
and causing extensive capillary thrombosis.
Other adverse
effects of heparin include:
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thrombocytopenia
occurs usually after 6-12 days of treatment. The
Committee on Safety of Medicines recommends platelet
counts for patients receiving heparin for longer than
five days
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osteoporosis has been reported after long-term use.
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hypersensitivity
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skin necrosis at the site of injection.
Contraindications
Warfarin
Contraindications
include pregnancy (but see notes above), active
haemorrhage, recent CNS surgery, severe uncontrolled
hypertension, alcoholism/severe liver disease.
Heparin
Contraindications to
heparin include :haemophilia, active haemorrhage,
thrombocytopenia, known hypersensitivity, severe
liver disease, severe uncontrolled hypertension,
recent major trauma or surgery.
Interactions with
warfarin
These can be non-drug
or drug interactions. The two main non-drug interactions
are alcohol and vitamin K. Alcohol can
potentiate the effect of warfarin resulting in an increase
in INR. Vitamin K is found in many green vegetables
and a radical change in diet could effect its dietary
intake. This would affect the action of warfarin and
subsequent INR results.
mechanisms of
interaction are possible including:
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displacement of warfarin from serum albumin
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induction/inhibition of the cytochrome P-450
system in the liver
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effects on vitamin K synthesis
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unknown, idiosyncratic interactions.
Patient counselling
Because of the
potential toxicity and narrow therapeutic index of oral
anticoagulants it is of vital importance that patients
understand the nature of their treatment. All new patients
need counselling to ensure complete compliance with their
treatment. The following points should always be covered
at an initial counselling session.
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Dose: the dose may be the same each day or may differ
throughout the week. It is imperative that the patient
understands the regime and diary cards/compliance charts
should be supplied if needed. Patients should be
encouraged to take the medication at the same time each
day to maintain a stable INR.
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Appearance of tablets:
if possible, the patient should be shown the different
strength tablets to differentiate between them.
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Anticoagulant effects:
the patient needs to know what an anticoagulant is, its
effect on the blood, what the INR result means and why
frequent blood tests are necessary. He or she also needs
to be aware of the risks of non-compliance, ie the risk
of thrombosis/haemorrhage.
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Overcoagulation:
symptoms include any bleeding/bruising problems which
may suggest the INR is higher than desired.
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Missed/extra doses:
there will always be times when a dose is missed. The
patient should either make a note of the discrepancy and
continue as normal the following day, or contact the
clinic/GP for advice if more than one dose is missed. If
an extra dose is taken, the patient should come to the
clinic for an INR check.
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Drug interactions:
these should include both OTC and prescription
medicines. The patient should be encouraged to inform
all health care professionals that he or she is on
warfarin therapy.
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Alcohol: the importance of maintaining a moderate alcohol input
should be expressed to the patient, along with the
danger of marked changes in intake.
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Diet: the patient should be encouraged to continue with their
normal diet. The clinic should be told of any changes.
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Clinic arrangements: these should include location, clinic operation,
appointment times, any transport arrangements and a
contact
telephone number.
Anticoagulants & Pregnancy:
q
Heparin: does not cross the placenta and has no effect on the foetus.
q
Oral anticoagulants:
cross the placenta and have been associated with an
increase in abortion rate in the first trimester. There
may also be an association with foetal cerebral hemorrhage
when given within a few days of vaginal delivery.
q
NSAIDs & Salicylic acid salts:
May
prolong gestation and labour, and result in
premature closure of the ductus arteriosus. Also,
they may be associated
with neonatal hypertension and hemorrhage.
Anticoagulants & Lactation
Individual maternal and infant situations must be taken
into account before any drug is prescribed for the mother.
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In
general, all drugs should be avoided in premature or low
birth weight infants, or in those who have any
underlying conditions.
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If a
drug is prescribed, it should be at the lowest practical
dose and for the shortest time.
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The
table (1) shows the effect of different anticoagulants
on lactation depending on the results of several
experiments.
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