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52 Chapter 4 Haemostasis and thromboembolic disorders
Thrombus formation:
Fibrinogen
Fibrin-bound plasminogen
(incorporated into the clot as it is formed)
Plasminogen activators
Endogenous e.g. tPA
or drugs e.g.
alteplase, reteplase
Fibrin fragments
Clot/thrombus
dissolution
Figure 4.3 Clots/thrombi remove themselves by digestion from within.
As the thrombus (clot) is formed, fibrinogen is converted to fibrin. Plasminogen is
brought into the thrombus by binding to the fibrin. Plasminogen activators can then
convert this fibrin-bound plasminogen into plasmin, a proteolytic enzyme capable of
breaking up the fibrin, causing the thrombus to fall apart.
ensure that plasmin is only active within clots, and that it
does not circulate throughout the body.
Plasmin is formed from its inactive precursor
plasminogen. is is a circulating plasma protein which
accumulates within the developing thrombus by binding
to brin formed by the coagulation cascade. e brinbound plasminogen is a good substrate for tissue
plasminogen activator (tPA). is enzyme is released from
damaged blood vessels and also binds to brin to cleave
the local plasminogen into active plasmin (Figure 4.3). is
locally formed plasmin then breaks the brin into soluble
fragments, causing the clot to dissolve. In the absence of
streptokinase,
Thrombin
(Factor IIa)
Cross-linked fibrin mesh
with plasminogen
Plasmin—digests
fibrin mesh
brin, tPA is only a weak enzyme. is brin-dependent
nature of tPA action prevents formation of plasmin from
circulating plasminogen. Plasmin activity outside the
thrombus is further attenuated by plasminogen activator
inhibitors 1 and 2 (PAI-1 and PAI-2).
In Monique’s case, all of these mechanisms will have
been set in place as her deep vein thrombosis (DVT)
became established. e drugs she was prescribed
reduced the thrombogenic processes in her leg and lungs,
leaving removal of the original thrombus to the
endogenous mechanisms just described.
4.2 Drugs used in the treatment of thromboembolic disorders
While we understand the involvement of platelets and
coagulation as a single process in thrombus formation, it
is conventional to classify clinically useful antithrombotic
agents as (1) drugs interfering with the coagulation
cascades (anticoagulant drugs), (2) drugs which reduce
platelet activation (antiplatelet drugs), and (3) drugs
which promote clot dissolution (brinolytic drugs, also
called thrombolytics). is is a valuable approach
because it relates clearly to their clinical patterns of use.
In each case, if you understand the mechanism of action
of the drugs and their pharmacokinetics, you will be able
to understand how they are used to benet patients. e
workbooks (both in this chapter and later) provide a way
of developing your understanding of the relationship
between the mechanisms of drug action and the
treatment of individual patients.
4.2.1 Anticoagulant drugs
e clinical use of drugs that attenuate coagulation is
dominated by warfarin and the heparin group of
preparations. eir mechanisms of action and resulting
clinical use are explored below. In addition, some more
recent drugs now used in anticoagulant therapy are
introduced.
4.2 Drugs used in the treatment of thromboembolic disorders 53
Heparins
Heparin sulphate is secreted by endothelial cells, providing
an anticoagulant surface to blood vessel linings. Along with
the antiplatelet mediators released by endothelial cells
(Box 4.3), endothelium-derived heparin contributes to the
free ow of blood through healthy vessels.
Heparin is a naturally occurring polymer of sugars. For
use as a drug it is extracted from animal tissues. In clinical
preparations it comes in two size ranges. e activity of
unfractionated heparin (UFH), also referred to as
standard heparin, depends on larger forms of 18 or more
saccharide (sugar) units, while smaller fractionated/low
molecular weight heparin (LMWH) preparations
require a minimum pentasaccharide (ve units) size for
their clinical eect.
In Workbook 1, Monique has developed a thrombus in a
vein in her leg; she has a deep vein thrombosis (DVT).
Her clotting factors have been activated as part of the
thrombotic process, generating abnormally large
quantities of thrombin. Since this leaves her at risk of
complications, it is important that antithrombotic
therapy works very quickly. Although LMWH would be
the rst-line choice in most DVT patients, UFH was
used in Monique’s case because she developed multiple
pulmonary emboli (PEs) and became
haemodynamically unstable. When UFH is used, a large
initial dose is administered intravenously to quickly
achieve therapeutic levels and a rapid response (see
Box 4.4).
Mechanism of action of heparin preparations Both
clinically available forms of heparin depend for their
action on increasing the inhibitory action of AT-III on the
activated coagulation factors; AT-III is one of the natural
anticoagulant mechanisms introduced above.
Understanding the pattern of clinical use of UFH and
LMWH depends on understanding dierences in their
manner of binding to AT-III, as well as the way in which
the pharmacokinetics of the two preparations varies.
Heparins have their eect by vastly increasing the rate
of inhibition of coagulation factors by AT-III. ey
achieve this by bringing about a conformational change
in AT-III which increases its anity for the factors.
ere is a signicant dierence, though, in the action of
UFH compared with LMWH which relates to the
dierent requirements for eective inhibition of
thrombin compared with the other factors. is is
illustrated in Figure 4.4. Specically, for thrombin to be
eectively inhibited, both thrombin and AT-III must
bind directly to heparin. is is achieved by the long
unfractionated form of heparin, but not by the shorter
LMWH which is unable to bind thrombin directly. In
contrast, other factors, crucially factor Xa, can be
inhibited by the AT-III–heparin complex in the absence
of their direct binding to the heparin molecule. In
summary then, both forms of heparin can inhibit
(A)
ThrombinAT–III
(B)
AT–III
Unfractionated heparin
Figure 4.4 Action of heparins on AT-III and clotting factors.
This figure shows both short (panel C) (fractionated/LMWH) and long (panel B) (unfractionated) heparin molecules (in brown)
binding to AT-III (green), creating an effective inhibitor of factor Xa (dark blue). However, only unfractionated heparin can also
bind thrombin (panel A) (light blue), necessary for its inhibition by AT-III.
Factor Xa
(C)
AT–III
LMWH
Factor Xa
54 Chapter 4 Haemostasis and thromboembolic disorders
factor Xa, but only UFH can additionally inhibit
thrombin.
Several points of therapeutic signicance follow from this
account of the mechanisms of action of heparins.
• Considering that factor Xa activates prothrombin to
thrombin (factor IIa), and that the AT-III–heparin
complex eectively inhibits factor Xa, it is not
surprising that both UFH and LMWH are very eective
anticoagulants.
• Both types of heparin act quickly: AT-III is already in the
plasma and inhibits clotting factors immediately the
heparin levels in the blood are raised. e speed of
inhibition depends on the route of administration.
Neither drug can be absorbed from the gut because of
their large size and charge, and therefore cannot be given
orally. If subcutaneous injection is used, eective action
is delayed by about 30 minutes, but an intravenous
injection will have an almost immediate eect.
• Both heparins can have an antiplatelet eect, greater
for UFH than for LMWH. is is not unwelcome and
occurs because, as mentioned above, thrombin
activates platelets directly.
Pharmacokinetics of heparin Most UFH binds to AT-III.
However, a signicant remainder (about a third) binds to
other sites such as plasma proteins and endothelial cells,
and is therefore not pharmacologically active. is
contributes to its dose-dependent pharmacokinetic prole.
Almost all bound LMWH is complexed with AT-III. ere
is little or no binding to plasma proteins, endothelial cells,
etc., leading to a more predictable dose response, and
better-sustained clinical eect.
Other properties of UFH and LMWH are compared in
Table 4.3.
How are heparins used in hospital? Heparins are
given either intravenously or by subcutaneous injection.
e clinical use of UFH is more complicated than that of
many drugs. e complexities arise for a number of
reasons, including unpredictable pharmacokinetics and
a variable antithrombotic response from one patient to
the next. It is important that the anticoagulant response
is sucient to protect the patient, but not so overeective that the patient is left vulnerable to severe
bleeding. Working out the correct dose for the
continuous infusion is guided by testing each patient’s
blood by measurement of the activated partial
thromboplastin time (aPTT), which reects the
alterations by heparin to the clotting cascade. (aPTT is
the time it takes for plasma to clot following addition of
an activator of the intrinsic pathway.)
Use of LMWH is more straightforward, with predictable
pharmacokinetics and little inter-patient variability in
response, meaning that monitoring is not routinely
required. Also, with a longer half-life, it requires less
frequent dosing. For these reasons, LMWH (or
fondaparinux, see below), given by subcutaneous
injection, is preferred in most cases. e use of UFH is
generally reserved for those patients who are
haemodynamically unstable (like Monique), at increased
risk of bleeding (see below), or in renal failure.
Table 4.3 Comparison of unfractionated heparin and low molecular weight heparin
Unfractionated heparin Low molecular weight heparin
Molecular weight 3000–30,000 1000–10,000
Fraction bound to AT-III ~2/3 Almost all
Fraction bound to plasma protein ~1/3 Almost none
Inhibition of platelet function
Increases vascular permeability Ye s No
Dose-dependent clearance Ye s No
Elimination half-life 30–150 minutes 60–750 minutes
Endothelial cell binding
Primary route of elimination Saturable binding processes
Activated partial thromboplastin time
monitoring required
Reversibility with protamine
+ + + + + +
+ + + +
Renal
Yes (complex binds to thrombin) No (complex does not bind to
+ + + +
–
Renal
thrombin)
4.2 Drugs used in the treatment of thromboembolic disorders 55
Fondaparinux is a synthetic pentasaccharide which
selectively inhibits factor Xa. It is similar in ecacy to
LMWH and has a rapid onset of action and a half-life that
allows once-daily dosing. Like LMWH, its use does not
require monitoring. is drug is the rst-line choice in
many hospitals for the treatment of acute coronary
syndrome (i.e. unstable angina, non-ST-segment
elevation myocardial infarction ((UA/NSTEMI) or
ST-segment elevation myocardial infarction (STEMI);
Chapter 6), and is also used in the prevention of VTE. It is
administered by intravenous or, more usually,
subcutaneous injection.
Adverse eects of heparin Haemorrhage (bleeding) is
the most common side eect of heparins. Factors that
inuence this are length of therapy, advanced age of
patient, comorbidity (patient with other disease states),
concomitant antiplatelet treatment (e.g. aspirin), and
where the dose of heparin is too high (raised aPTT).
Bleeding as a result of heparin use should be managed by:
• discontinuing heparin
• uid infusion to maintain volume if bleeding
• blood/plasma/clotting factor infusion
• protamine may be administered intravenously to
neutralize heparin by forming an inactive protamine–
heparin complex. Protamine has a rapid onset of action
and its eect lasts 2 hours. It is more eective against
UFH than LMWH because the longer half-life of LMWH
exceeds that of protamine. It is ineective against
fondaparinux.
rombocytopenia (low platelet count in the blood) can
be caused by heparin. is is known as heparin-induced
thrombocytopenia (HIT). ere are two types.
• Type I HIT occurs 2–3 days after the start of heparin
treatment. It is a direct result of the interaction between
heparin and circulating platelets, resulting in platelet
clumping and signicant reduction in platelet count. It
is reversible; patients remain asymptomatic and
platelet counts return to normal around day 4, even if
heparin is continued. Type I HIT occurs in 10–20% of
patients receiving heparin.
• Type II HIT occurs in 1–3% of patients receiving
prolonged treatment with heparin. It can develop 5–10
days after the start of treatment, and is a much more
serious condition than type I, with a greater fall in
platelet number. It is an immunological response to
heparin which involves binding of heparin to a platelet
protein, called platelet factor 4, to form a complex
against which antibodies are raised. e antibodies
bind heparin and the resulting complex binds to, and
activates, platelets which clump together giving a
reduced platelet count. Consequently, and
paradoxically, the patient is now at risk of thrombosis,
which can occur in limbs and requires amputation in
25% of cases. Stroke, myocardial infarction, skin
necrosis, and thrombosis of other major organs can
also occur; mortality can be as high as 30%. Monique,
our patient in Workbook 1, only received heparin for
5 days and therefore was at minimal risk.
In cases of type II HIT, heparin must be discontinued. e
antibodies formed, however, can persist for weeks or
months. LMWH and fondaparinux bind less well to
platelet factor 4, and are therefore less likely to lead to
antibody generation and so present less of a risk of
thrombocytopenia. However, if antibodies to the heparin
complex remain, it is also possible for LMWH to cause
type II HIT and caution is required; cross-reactivity has
been reported to be as high as 90%. Danaparoid is a
LMWH-related preparation with high anity for factor
Xa; it can be administered intravenously to patients with
type II HIT. Argatroban, a direct thrombin inhibitor
which is given by intravenous infusion, can also be used
in this situation.
Warfarin
Warfarin is the most commonly prescribed anticoagulant.
In Monique’s case in Workbook 1, treatment begins with
both heparin and warfarin before heparin is
discontinued, and warfarin is continued long-term. Why
are both drugs given initially? As discussed above,
heparins have a very rapid anticoagulant action (within
minutes). Warfarin, on the other hand, is an
anticoagulant with a very slow onset of action (days).
Heparins are given by injection, while warfarin is
administered orally. ese dierences dene the clinical
use of these two compounds. Typically, heparins are used
where it is necessary to rapidly establish an
antithrombotic state, as in Monique’s case. Warfarin
therapy is normally started on the same day, so for the
initial few days both drugs are given. Overlap of this
nature ensures that heparin secures the antithrombotic
status of the patient during the few days before warfarin
has its anticoagulant eect. In addition, it avoids harm
from a pro-coagulant eect that warfarin may have when
rst used. is is due to its inhibitory eect on the natural
56 Chapter 4 Haemostasis and thromboembolic disorders
Synthesis of protein chain
γ-carboxylation
Mature inactive clotting factor
Preceding factor in cascade
Active clotting factor
Thrombin activity
Figure 4.5 Sequential maturation and activation of clotting factors.
The sequence starts with the synthesis in the liver of the protein chain which
forms the immature clotting factor. This must then be -carboxylated to
produce the mature factor which enters the circulation. This -carboxylation
process is inhibited by warfarin (see also Figure 4.2). Mature precursor factors
(inactive) already present in the blood have to be cleared from the body before
warfarin administration results in an antithrombotic effect. Heparin
preparations, on the other hand, block the proteolytic activity of the activated
factors (Figure 4.4) which are participating in the coagulation cascade as the
clot/thrombus is forming; therefore their effects are essentially immediate.
*Both LMWH and unfractionated heparin can inhibit the action of factors IXa–XIIa, but
only unfractionated heparin can block the action of thrombin (factor IIa).
Blocked by WARFARIN
Blocked by HEPARINS*
Blocked by UNFRACTIONATED HEPARIN
anticoagulant, protein C, which is also a vitamin-Kdependent factor (see below), that occurs ahead of the
eect on clotting factors. When warfarin becomes
eective, heparin is discontinued. e length of time a
patient remains on warfarin depends on their relative risk
of venous thromboembolic disorders; however, many will
continue to take the drug for years and even for life,
facilitated by its oral administration.
Why is the onset of warfarin action so slow? Warfarin
acts by preventing the maturation of clotting factors. e
mature factors are already present in the blood in the
form of a circulating pool of inactive precursor factors
(e.g. factors II, VII, IX, and X) ready to be converted on
initiation of the coagulation cascade into the active form
(e.g. factor IIa etc.). e anticoagulant eects of warfarin
are only seen when these precursor factors are cleared
from the circulation and a reduced level of mature factors
is established; this takes a few days. is delay in the
pharmacological eect of warfarin explains why Monique
was given both warfarin and heparin for several days. As
noted earlier, warfarin also reduces the synthesis of the
natural anticoagulant protein C. e lifespan in the blood
of this protein is shorter than that of the clotting factors,
and therefore its levels decrease before the benecial
reduction of mature factors is established. is leaves the
patient transiently (and paradoxically) at risk of
coagulation at the start of warfarin therapy; the overlap
between warfarin and heparin will additionally protect
the patient during this period.
Figure 4.5 shows the relationship between the maturation
and activation of clotting factors, and illustrates the point
of action of warfarin and heparin in these processes.
How can the eect of warfarin be reduced by vitamin K
administration? Warfarin acts by competing directly
with vitamin K at its binding site on the vitamin K
reductase enzyme (Figure 4.2). is means that it prevents
vitamin K having access to the reductase enzyme,
resulting in the depletion of reduced vitamin K and the
consequent inhibition of -carboxylation. Eventually, over
several days, this leads to a reduction of mature clotting
factors in the blood. Since warfarin is a competitive
antagonist, its binding to the reductase enzyme can be
overcome by an elevated vitamin K concentration. is
explains why warfarin overdose is eectively treated by
administration of intravenous vitamin K.
Pharmacokinetics of warfarin Warfarin exists 99% bound
to plasma albumin and has a mean half-life in the body of
approximately 36 hours. It is metabolized in the liver by
cytochrome P450 enzymes, with the subsequent
4.2 Drugs used in the treatment of thromboembolic disorders 57
production of inactive metabolites that are excreted in the
urine and stool. e rate of metabolism diers a lot between
individuals, giving rise to variable half-lives. In addition, the
rate of metabolism of warfarin is aected by many drugs;
some cause it to increase, whilst others lead to a decrease.
Drug interactions can therefore have an important eect on
the correct dosage for the individual patient.
Drugs which inhibit warfarin breakdown, thereby
increasing its eectiveness, include macrolide antibiotics,
azole antifungal agents, and the H2 receptor antagonist
cimetidine used in the treatment of gastric ulcers
(Chapter 12). e anticoagulant eect of warfarin can also
be increased by many broad-spectrum antibiotics which
kill the gut ora that synthesize vitamin K, although this is
usually only a problem where dietary deciency is also
present. Non-steroidal anti-inammatory drugs
(NSAIDs) potentiate the eect of warfarin, increasing the
risk of gastrointestinal bleeding associated with NSAIDs;
care should be exercised, particularly in elderly patients
(see Chapter 9, Section 9.3.1).
e eectiveness of warfarin is decreased by drugs which
increase the rate of metabolism by inducing P450
enzymes. ese include the antiepileptic drugs phenytoin
and phenobarbital (Chapter 16), and the antibiotic
rifampicin; such interactions could therefore leave the
patient at risk of thrombosis.
How is the eect of warfarin monitored? Warfarin is
taken orally, facilitating its use for long-term
maintenance therapy at home. is enhances the need
for good patient education (see Box 4.4). However, even
with prolonged home use, warfarin therapy needs to be
monitored to ensure that the best dose is used. As with
heparin, the dose needs to be optimized to provide
eective protection against thrombus formation while
minimizing bleeding problems. is is achieved using a
simple measurement of the time taken for a sample of
the patient’s blood to clot following addition of tissue
factor to activate factor VII. is is then compared with a
standard to generate an International Normalized Ratio
(INR) value. e INR is used to monitor the eect of
warfarin on the levels of vitamin-K-dependent factors
(see Workbook 1), reected in the time taken for a clot to
form. For a healthy individual not receiving medication,
this test will yield an INR value of around 1.
Anticoagulant medication aims to raise the INR,
meaning that the blood clots more slowly; the exact INR
target value will depend on the clinical situation, but for
a patient such as Monique an INR target of 2.5 is usual.
is target is achieved by adjusting the warfarin dose
according to INR values. Administration and dosage of
warfarin are further explored in Box 4.4.
Adverse eects of warfarin e most common adverse
eects of warfarin are bleeding and skin necrosis. ere
are several factors that inuence the risk of bleeding
which mostly occurs in the nose, pharynx,
gastrointestinal tract, and urinary tract. Bleeding tends to
be dose dependent and can be controlled by withdrawal
or suspension of warfarin therapy and/or vitamin K
administration. Bleeding occurred in Monique’s case
because of the interaction of warfarin with antibiotics,
increasing the eectiveness of warfarin (see above), and
raising her INR value well above her target value.
Other anticoagulants
ere is interest in clinically useful anticoagulants that
directly inhibit thrombin or other factors, independently
of AT-III. Some are derived from hirudin, the
anticoagulant present in the saliva of medicinal leeches
which ensures a free ow of blood. Bivalirudin is an
analogue of hirudin which reversibly inhibits thrombin. It
is administered intravenously and is in use clinically in
the management of VTE in patients with acute coronary
syndrome (Chapter 6).
Novel oral anticoagulants (NOACs)
Of particular interest is the development of novel oral
anticoagulants which in the future could replace warfarin,
with its many associated drawbacks as outlined above.
Ximelagatran was the rst of the class of direct (i.e. not
AT-III mediated) thrombin inhibitors. It was an oral drug
with a xed dose, and would have resolved the problems
of dosing, interaction, and monitoring but had to be
withdrawn in 2006 after reports of hepatotoxicity.
Recently, however, dabigatran has been introduced as an
acceptable direct thrombin inhibitor. It is administered in
the form of a pro-drug, dabigatran etexilate, and has a
rapid onset of action. Acting at a dierent point in the
coagulation cascade rivaroxaban and apixaban are
direct factor Xa inhibitors. All three drugs have
advantages in terms of xed dosing, rapid onset of action,
and few drug interactions compared with warfarin. In
addition, their anticoagulant eects are predictable,
removing the need for monitoring to maintain INR. ese
drugs are used in the treatment and prevention of VTE.
However, they suer from one major disadvantage: unlike
warfarin their eect can neither be reversed nor reduced.
Box 4.4
How heparins and warfarin are used in the clinic
When wishing to anticoagulate a patient it is
commonplace for heparin to be used to give an
immediate eect because of its fast onset of action. At
the same time, long-term treatment with warfarin is
initiated. Because of the long delay before warfarin
therapy becomes eective, both drugs are
administered for several days. Heparin is
administered intravenously or subcutaneously in
clinic, while warfarin, being orally available, is suitable
for long-term home use.
HEPARIN
Heparin is available as unfractioned (UFH) or puried
low molecular weight fragments (LMWHs).
Dierences between these preparations are set out in
Table 4.3 and Figure 4.4.
Heparin administration, aPTT tests, and
dosage ree modes of administration of heparins
are available.
1. Loading dose followed by continuous infusion In
patients with acute PE who are compromised
haemodynamically, such as Monique, it is
important that eective anticoagulation is achieved
very quickly. UFH should be used because the
ecacy of LMWH in this situation is unknown. To
achieve a rapid result it is common to give an initial
high dose (loading dose) followed by continuous
infusion (intravenous) to maintain the desired
anticoagulant eect. A loading dose is usually
required in an emergency such as
haemodynamically compromised pulmonary
embolism because it ensures rapid achievement of
therapeutic levels, and because there is resistance
to anticoagulation within the thrombus while there
are ongoing clotting processes. So the
concentration required to shut the thrombotic
process down is higher than that required to
prevent it starting up again.
Working out the correct dose for continuous
infusion is guided by measurement of the activated
partial prothrombin time (aPTT) which reects the
alterations in the intrinsic pathway of the clotting
cascade. Using a heparin dose which prolongs the
aPTT to between 1.5 and 2.5 times the mean
normal value is considered adequate to prevent
extension of the thrombus.
2. Subcutaneous unfractionated heparin Twicedaily subcutaneous injection of heparin has been
shown to be as safe and ecacious as continuous
infusion for the initial period of treatment of DVT,
although there is a slight delay in onset of action
(around 30 min). It has some advantages over the
infusion technique:
• itisanalternativeinpatientswithoutIVaccess
• moremobilityforpatientswhoarenothooked
up continuously to infusion
• reducednursingtime
• moreeasilyreversiblethanLMWHs
• cheaper.
is could have been an alternative for Monique if she
had been more stable. Note that aPTT measurement is
still required for dosing (in contrast with
subcutaneous LMWHs below).
3. Subcutaneous LMWH is has been shown to be
as eective as and safer than UFH in most
situations.
Advantages of LMWH are:
• noaPTTmonitoringrequired
• easycalculationofcorrectdosebasedonthe
weight of the patient
• longerhalf-livesallowonce-dailyadministration
• canbeusedathome
• althoughthesedrugsareusuallymore
expensive, the overall cost is lower for the
reasons stated above.
LMWH preparations Examples of LMWHs used in the
treatment and prophylaxis of VTE are dalteparin,
enoxaparin, and tinzaparin. ere are signicant
dierences in their molecular weight and their
pharmacokinetic and pharmacodynamic
characteristics. Monique was treated with dalteparin,
which was chosen because it was the rst-line LMWH
for VTE on the formulary in Monique’s hospital.
Box 4.4 How heparins and warfarin are used in the clinic
WARFARIN
e method used for initiating warfarin therapy depends
upon the need for rapid or slow anticoagulation.
a) For patients requiring rapid anticoagulation, for
instance those with acute DVT/PE (like
Monique), an induction dose of 5–10 mg is given.
INR is monitored daily and the dose adjusted
accordingly to establish a maintenance dose. e
initial dose is reduced in patients with risk factors
for increased sensitivity to warfarin. ese factors
include: age >70, congestive heart failure,
malignancy, renal and hepatic disease, and
concurrent use of interacting medication. is
rapid-loading protocol presents more of a
transient risk of hypercoagulation due to
decreases in protein C levels. It is generally
reserved for use in hospital.
b) A slow-loading regimen achieves therapeutic
anticoagulation within 3–4 weeks in the majority of
patients; it is deemed to be safer and avoids risk of
haemorrhage due to over-anticoagulation. A daily
dose of 1–3 mg is prescribed, and INR levels are
checked on day 5. Subsequently the dose is
adjusted in small increments, informed by INR
measurements, until the desired INR is attained
and a maintenance dose established. Whichever
method of initiation is used, continuing with
warfarin therapy necessitates regular attendance at
clinic to monitor INR.
Patient education for those on warfarin is essential for
many reasons, including the numerous drug
interactions. Patients must be aware that warfarin
treatment can be aected by alcohol consumption
(see Chapter 21, Section 21.4.4) and alterations in diet,
as introduction of foodstus high in vitamin K (such
as some green vegetables) could reduce the eect of a
given warfarin dose. Patients should additionally be
encouraged to take their medication at the same time
of the day to minimize uctuations in levels of mature
factors. Warfarin should not be taken in pregnancy as
it poses a risk to the developing fetus, particularly in
the early stages. Patients are issued with an
anticoagulant book at the start of therapy which alerts
them to these issues.
is would delay eective management of a patient on
such drugs who presents with a major bleed or requires
emergency surgery.
It is likely that drugs of this type will be developed and
become the major oral anticoagulants of the future,
displacing warfarin in many clinical settings and reducing
the burden of regular attendance at anticoagulant clinics.
Summary of clinical uses of anticoagulants
Heparins are used acutely where rapid anticoagulation is
necessary, such as in the treatment of myocardial
infarction and of DVT and PE, as in Monique’s case.
Pharmacological prevention of VTE, usually in the form
of LMWH or fondaparinux, is administered to patients
undergoing surgery who are at risk of thrombosis. e use
of heparins is mostly, but not exclusively, restricted to
hospital settings; subcutaneous LMWH/fondaparinux
can be administered at home, for instance in those
patients who cannot tolerate warfarin.
Where long-term therapy is required, warfarin remains
the oral anticoagulant of choice, and is used in a wide
range of clinical conditions that predispose to thrombinrich clots (red clots). It is used in patients who have
suered a DVT or PE for a period of 3–6 months after the
rst clot, and for life if there is a second clot. Warfarin is
also used to prevent an ischaemic stroke in patients with
chronic atrial brillation, because clots that could form in
a brillating heart may dislodge and cause a blockage in
the brain (Chapter 7).
Patients with articial implants (e.g. valves, pacemakers,
and debrillators) are in some cases put on warfarin for 3
months to lifetime, depending on the type of implant and
any concurrent risk factors. In some of these situations
orally available anticoagulants such as dabigatran,
apixaban and rivaroxaban are viable alternatives; there
are, however, considerable cost implications for their use
compared with warfarin, and also the risk associated
with the irreversibility of bleeding when used, should
this occur.
60 Chapter 4 Haemostasis and thromboembolic disorders
Arachidonic acid
4.2.2 Antiplatelet drugs
e inhibition of platelet activation will reduce platelet
plug formation, but will also indirectly attenuate
activation of the coagulation cascade by reducing the
assembly of coagulation factors at the surface of the
activated platelets. Antiplatelet drugs can be
mechanistically divided into two classes: (1) those acting
at an intracellular location to inhibit enzymes, for
example aspirin and dipyridamole, and (2) those acting
at receptors on the surface of platelets, such as
clopidogrel and abciximab.
Aspirin
Aspirin is a drug with diverse signicant applications. In
Workbook 3, for example, we discuss another ctional
patient, Brian, who takes aspirin in connection with his
angina. We will encounter this drug at a number of points
in this book, in a variety of clinical contexts, and in
particular will discuss aspirin and related drugs as
anti-inammatory and analgesic agents. Here, though,
we are considering aspirin as an example of an
antiplatelet drug. In all these applications, aspirin has a
single mode of action at the molecular level as an
inhibitor of the enzyme cyclo-oxygenase (COX) by
irreversible acetylation.
In Box 4.3 various aspects of platelet and endothelial
interactions are discussed, and the local mediators
prostacyclin and TXA2 are introduced. As shown in
Figure 4.6 the initial step in the synthesis of both these
compounds from arachidonic acid is dependent on COX;
this is the step inhibited by aspirin. From this point the
pathway splits, with cyclic endoperoxides being
channelled into either prostacyclin in endothelial cells or
TXA2 in platelets. e inhibition of COX by aspirin will
therefore aect the production of both mediators, and
because they have opposing roles, this presents a
potentially confusing situation:
• TXA2 promotes platelet aggregation and therefore
reducing its production will have an antiplatelet eect
• Prostacyclin inhibits platelet aggregation (Box 4.3,
Figure d). It contributes to the antithrombotic inuence
of endothelial cells by inhibiting the recruitment of
platelets into a thrombus. Decreasing its production
e actions of aspirin on endothelial cells and platelets
could conceivably both increase and decrease platelet
recruitment. In fact, the eect of low-dose aspirin (e.g.
75 mg/day) is predominantly exerted on platelets, leaving
the endothelial prostacyclin pathway unaected. e
result is that aspirin is both antiplatelet and
Aspirin
Prostacyclin
synthase
(endothelial cells)
Effect of aspirin is
to increase
platelet aggregation
Irreversible
inhibition
Prostacyclin
Cyclo-oxygenase (COX)
Cyclic
endoperoxides
Thromboxane
synthase
(platelets)
TXA
2
Effect of aspirin is
to decrease
platelet aggregation
Figure 4.6 Aspirin has different effects on platelets and endothelial cells.
Aspirin acts on the same molecular target in the two cell types, but the
consequences are very different. This is because the enzyme cyclo-oxygenase
inhibited by aspirin leads to prostacyclin synthesis in endothelial cells, but
thromboxane (TXA2) synthesis in platelets. When given at low dose the dominant
effect of aspirin is to reduce TXA2 synthesis in platelets (as shown by the orange
shaded box). As a consequence, low-dose aspirin is antiplatelet.
4.2 Drugs used in the treatment of thromboembolic disorders 61
antithrombotic. is selective action of low-dose aspirin
is explained (in part) by the irreversible nature of the
inhibition of COX. Individual platelets cannot recover
since they have no nucleus and therefore cannot make
new enzyme. Recovery of platelet COX activity in the
patient depends therefore on the natural turnover of
platelets (7–10 days). By contrast, the endothelial cells
continually make more COX protein, and so with
low-dose aspirin an equilibrium is reached which
preserves prostacyclin production.
Another reason why aspirin has a greater eect on
platelets than endothelial cells is that it is subject to
considerable rst-pass metabolism. is means that
while aspirin inuences the blood (and therefore
platelets) as it passes through the intestines and liver, its
distribution around the body remains limited, restricting
its contact with endothelial cells.
Clinical use of aspirin as an antiplatelet drug Clinical
use of aspirin is essentially summarized by noting that it
is most eective at preventing or limiting arterial
occlusions in which platelet involvement is high, and
where anticoagulants have a limited eect. is contrasts
with venous thromboembolism (VTE), where
anticoagulants are most eective. is explains why
Monique in Workbook 1 is not treated with aspirin, while
Brian in Workbook 3, with his arterial occlusion, is. In
these cases, it is common to prescribe an initial dose of
150–300 mg immediately after the ischaemic event,
followed by the low-maintenance dose of 75 mg/per day
to prevent further events. Aspirin may also be used
following heart surgery and in the management of atrial
arrhythmias (Chapter 7).
Adverse eects of aspirin are discussed elsewhere
(Chapter 9, Section 9.3.1). However, it is important to
note here that aspirin should not usually be used in
patients with bleeding disorders. It is also important to
note that the antiplatelet action of aspirin is reduced by
widely used NSAIDs, particularly ibuprofen. Such drugs
protect platelet COX from acetylation by aspirin,
presumably by blocking the enzyme’s active site. Aspirin
is contraindicated for those under the age of 16 because
of its association with Reye’s syndrome, a potentially fatal
condition that aects many organs of the body, but
principally the brain and liver.
Other antiplatelet drugs
Other COX inhibitors have been produced for clinical use
by the pharmaceutical industry, but aspirin remains the
only one used for its antiplatelet eect. Other antiplatelet
drugs act by dierent mechanisms.
Clopidogrel is an orally available pro-drug, meaning that
it acts after conversion within the body to an active
metabolite, which in this case is an antagonist at platelet
P2Y12 receptors. e stimulation of these receptors by
ADP is central to the aggregation process, as set out in Box
4.2. e clopidogrel metabolite irreversibly inhibits ADP
binding to P2Y12 receptors and so reduces aggregation
stimulated by ADP. Like aspirin, it is useful in the
prevention of recurrence of arterial ischaemic disease,
and in most cases of acute coronary syndrome. It is also
used in patients who have coronary stents. e eects of
aspirin may be additive with those of clopidogrel; in some
cases an improved clinical outcome is seen when both
drugs are administered together. Based on evidence from
clinical trials, this combination is used in acute coronary
syndrome to reduce risk of further thrombotic events. It
should be noted, however, that not surprisingly,
combining these drugs increases the risk of haemorrhage.
Clopidogrel is also licensed for the prevention of stroke in
some patients with atrial brillation (again given with
aspirin) and for those who cannot tolerate warfarin.
Prasugrel acts in the same way as clopidogrel to inhibit
ADP stimulation of P2Y12 receptors, so blocking platelet
aggregation. It too is used in combination with aspirin
and is an option, instead of clopidogrel, for prevention of
atherothrombotic events in adult patients.
Ticagrelor is another oral antiplatelet, a member of the
chemical class of cyclopentyltriazolopyrimidines. It acts
directly (i.e. it is not a pro-drug) to reversibly inhibit P2Y12
receptors, thereby reducing ADP-mediated platelet
aggregation. Unlike clopidogrel and prasugrel, which
block ADP from binding, ticagrelor binds to a part of the
receptor distinct from the ADP binding site and noncompetitively inhibits ADP-induced P2Y12 receptor
activation. It is used in combination with low-dose
aspirin, and provides an alternative to clopidogrel for the
prevention of atherothrombotic events in adult patients
with acute coronary syndrome.
Dipyridamole acts to increase the level of cyclic AMP in
platelets by inhibition of phosphodiesterase (see Chapter
2, Section 2.2.4), thereby stabilizing platelets and
reducing their activation. In patients with a history of
occlusion of blood vessels in the brain (cerebral
ischaemic events, such as stroke), dipyridamole may be
useful to prevent recurrence. It is routinely administered
together with aspirin. Notably, bleeding is not one of this