Unfractionated heparin forms a complex with and alters the conformation of antithrombin III;

this complex can then inactivate thrombin and factors IXa, Xa, XIa and XIIa. LMWH
interacts with antithrombin III in a different manner to unfractionated heparin, and the
LMWHantithrombin complexes have a more selective anticoagulant action, mainly inhibiting
factor Xa. Also act by promotion of tissue factor pathway inhibitor (TFPI) release from the
vascular wall. TFPI inhibits formation of factor Xa. Also acts by inhibition of platelet aggregation
through binding to platelet factor 4 (mainly unfractionated heparin). Finally, acts by activation
of lipoprotein lipase, which in addition to promoting lipolysis also reduces platelet adhesiveness.
Unfractionated heparin - This is extracted from porcine intestinal mucosa or bovine lung. It has
dose-dependent pharmacokinetics: the half-life is very short (about 30min) at low doses,
increasing some five-fold at higher doses (30 mins to 2.5 hrs). Low-dose subcutaneous
injections are used for prophylaxis against venous thrombosis, although bioavailability by this
route is only about 30%.
Low-molecular-weight heparins - They are almost completely absorbed after subcutaneous
administration. LMWHs have a low affinity for plasma protein binding sites and for endothelial
cell heparin receptors (where unfractionated heparin is metabolized). They have two routes of
elimination: a rapid, saturable liver uptake and slower renal excretion. The different LMWHs
have half-lives in the range 26h. Lovenox is 4.5 hours. The anticoagulant effect of
LMWHs can be monitored by the degree of factor Xa inhibition, but this is not carried out
routinely since their effect is much more predictable than that of unfractionated heparin.
The effect of unfractionated heparin can be rapidly reversed by intravenous injection of
protamine sulphate, a basic peptide which binds strongly to the acidic heparin components.
Protamine binds poorly to LMWHs and only partially reverses their action.
Heparin-induced thrombocytopenia (HIT) usually occurs 515 days after starting intravenous
heparin in about 2% of people, and arises from the development of antibodies to the heparin
platelet factor 4 complex. This causes platelet activation, aggregation and thrombosis.
LMWHs are much less likely to cause HIT.
Platelets are critical components of the blood for initiating thrombus formation, and have a
lifespan in the circulation of 810 days, with about 1012% being replaced each day.

warfarin, acenocoumarol (especially in Europe)

Mechanism of action
These drugs inhibit hepatic vitamin K epoxide reductase, which is
the enzyme that converts vitamin K to its active (hydroquinone)
form. As a result, the hepatic synthesis of the vitamin Kdependent clotting factors II (prothrombin), VII, IX and X is
impaired ( Fig. 11.3 ). There is a delay in the onset of the
anticoagulant effect, due to the presence of previously synthesised
clotting factors, which must be cleared from the circulation.

It is eliminated by cytochrome P450-mediated hepatic

metabolism (CYP2C9) and has a very long half-life of 12
days. Functional CYP2C9 polymorphisms contribute to
considerable inter-individual variability in warfarin
sensitivity. The plasma concentration of warfarin does not
correlate directly with the clinical effect of the drug, which
is determined by the balance between the rates of
synthesis and degradation of clotting factors. The
maximum effect of an individual dose of warfarin is
reflected in the blood coagulation time some 2436h later.

On stopping treatment, the duration of anticoagulant

action is determined largely by the time required to
synthesise new clotting factors.
Control of oral anticoagulant therapy
Factor VII is the clotting factor that is most sensitive to vitamin K
deficiency, since it has the shortest half-life of the vitamin Ksensitive clotting factors. Therefore, a test of the extrinsic
coagulation pathway the prothrombin time is used as a
measure of effectiveness. The degree of prolongation of the
prothrombin time is standardised by comparison with control
plasma from a single source, and referred to as the international
normalised ratio (INR). Therapeutic INR ranges differ according
to the condition being treated:
INR 22.5 for prophylaxis of deep vein thrombosis
(thromboprophylaxis),
INR 23 for thromboprophylaxis in hip surgery and
fractured femur operations, for treatment of deep vein
thrombosis and pulmonary embolism, and for prevention of
thromboembolism in atrial fibrillation,
INR 34.5 for prevention of recurrent deep vein thrombosis
and for preventing thrombosis on mechanical prosthetic
heart valves.

Unwanted effects
Warfarin is an important example of a drug that has a narrow
therapeutic index.
Haemorrhage. The most effective antidote to warfarin is
phytomenadione (vitamin K 1 ). For major bleeding, this is
given intravenously and controls bleeding within 6h. An
immediate coagulant effect is achieved by also giving an
intravenous injection of prothrombin complex concentrate
(vitamin K-dependent clotting factors) or an infusion of
fresh frozen plasma. After giving a large dose of

phytomenadione, it can be difficult to restore therapeutic

anticoagulation with warfarin for up to 3 weeks. If the INR is
>8.0 but there is no bleeding or only minor bleeding, then a
smaller dose of phytomenadione can be given intravenously
or orally with less disturbance to subsequent
anticoagulation.
Alopecia, skin necrosis and hypersensitivity reactions occur
rarely.
Warfarin crosses the placenta and can have undesirable
effects on the fetus. It is teratogenic and should be avoided in
the first trimester of pregnancy, except when essential;
furthermore, it should not be used in the last trimester, as it
increases the risk of intracranial haemorrhage in the baby
during delivery.
Drug interactions are particularly important. The
anticoagulant effect of warfarin can be increased by broadspectrum antibacterial agents that suppress the production
of vitamin K by gut bacteria. Drugs such as amiodarone ( Ch.
8 ) and the histamine H 2 receptor antagonist cimetidine ( Ch.
33 ), which inhibit CYP2C9-mediated metabolism of
warfarin, enhance its effects. Drugs that induce CYP2C9
for example, phenytoin ( Ch. 23 ) and alcohol ( Ch. 54 )
reduce the effect of warfarin by increasing its elimination.

Platelets aggregate following adhesion to an injured blood vessel

and consequent activation. When the integrity of vascular
endothelium is breached, subendothelial proteins such as von
Willebrand factor (vWF) and collagen come into contact with
blood. These proteins interact with a family of platelet-surface
glycoprotein (GP) receptors (integrin receptors), particularly
GPIb (vWF receptor) and GPVI (collagen receptor), resulting in
platelets adhering at the site of injury and to each other (primary
reversible aggregation) and the formation of a platelet plug ( Fig.

11.1 ). Platelet adhesion then initiates a process known as platelet

activation.

Fig. 11.1
Platelets and platelet aggregation.
Subendothelial macromolecules such as von Willebrand factor and
collagen interact with glycoprotein receptors (GPVI and GPIb) on platelets,
causing activation of platelets and upregulation of GPIIb/IIIa receptors,
which are crosslinked by fibrinogen, resulting in aggregation. During the

initial processes of aggregation, stimulation of the synthesis and release of

a number of platelet-derived substances, such as thromboxane A 2 (TXA 2 )
synthesised from arachidonic acid (AA) by cyclo-oxygenase-1 (COX-1),
ADP, and other factors (see text) further promote aggregation by
upregulation of GPIIb/IIIa receptors. Conversely, prostacyclin (PGI 2 ) from
endothelial cells inhibits activation and upregulation of GPIIb/IIIa receptors.
Thrombin is generated by the action of factor Xa on prothrombin (see Fig.
11.3 ).

Extension of the platelet plug requires activation of platelets and

their subsequent aggregation together (homotypic aggregation).
Platelets are initially activated by exposure to soluble agonists,
such as thrombin generated by local coagulation, ADP released
from endothelial cells and collagen. These activators lead to an
increase in intracellular Ca 2 + and activation of (MLCK). MLCK
phosphorylates myosin light chains in the platelet which interact
with actin, disrupt the platelet cytoskeleton and change the shape
of the platelet.
The increase in platelet intracellular Ca 2+ activates phospholipase
A 2 , which liberates arachidonic acid (AA) from membrane
phospholipids. AA is then converted by cyclo-oxygenase type 1
(COX-1) in the platelet to thromboxane A 2 , the most potent
naturally occurring pro-aggregating agent, which diffuses from
the platelet. Significant disruption of the platelet cytoskeleton as
the platelet changes shape also initiates a platelet release reaction,
which expels mediators in platelet dense storage granules from
the cell. Fusion of dense granules with the platelet cell membrane
releases platelet factor 4, adrenaline, ADP and serotonin. Outside
the platelet ADP, thrombin and thromboxane A 2 interact with
specific platelet surface receptors and trigger intracellular
pathways that express and activate GPIIb/IIIa collagen receptors
on the surface of the platelets ( Figs 11.1 and 11.2 ). Therefore, ADP
released from platelets acts as a mediator for initiators of platelet
activation, such as collagen and thrombin. Secondary irreversible
homotypic plateletplatelet aggregation follows platelet activation

when the activated GPIIb/IIIa receptors on the surface of the

platelets are crosslinked by fibrinogen in the plasma.

Fig. 11.2
Sites of action of major drugs used in haemostasis.
Drugs act directly or indirectly to inhibit activation of platelets or to block or
reduce upregulation of the glycoprotein GPIIb/IIIa receptors (integrin
receptor family), which are necessary for aggregation of platelets.
Abciximab is an antibody, tirofiban a non-peptide inhibitor and eptifibatide a
peptide inhibitor of these glycoprotein receptors. Epoprostenol and
dipyridamole inhibit activation of platelets and downregulate the
glycoprotein receptors by increasing cAMP. Clopidogrel inhibits ADP

receptors and prevents ADP-induced upregulation of the glycoprotein

GPIIb/IIIa receptors and platelet aggregation. Aspirin inhibits the generation
of thromboxane A 2 (TXA 2 ) by cyclo-oxygenase-1 (COX-1), which otherwise
causes activation of platelets and upregulation of GPIIb/IIIa receptors. AA,
arachidonic acid. For direct and indirect inhibitors of thrombin, see Fig. 11.3
.

The substances released from platelet dense granules also

facilitate haemostasis by:
reducing prostacyclin (prostaglandin I 2 , PGI 2 ) synthesis by
vascular endothelium; prostacyclin is a vasodilator and a
potent inhibitor of platelet aggregation,
inhibiting the action of heparin sulphate produced by
vascular endothelium; this enhances activity of the
coagulation cascade.
Expression of platelet GPIIb/IIIa surface receptors can be
inhibited by an increase in the concentration of cyclic nucleotides
(cAMP, cGMP) in the platelet. This is the mechanism by which
prostacyclin (PGI 2 ) inhibits platelet aggregation ( Figs 11.1 and
11.2 ).
Polyunsaturated (omega-3) fatty acids in fish oils are precursors
for thromboxane A 3 , which causes less platelet aggregation than
thromboxane A 2 ; they also increase production of a modified
form of prostacyclin (PGI 3 ) by vascular endothelium which has
equal anti-aggregatory activity to PGI 2 . Therefore, a high intake
of fish oils creates a state in which platelets are less able to
aggregate.
Heterotypic platelet aggregation can also arise when platelets
aggregate with leucocytes (and particularly monocytes) in
circulating blood. This process has been detected close to
atherosclerotic lesions but also in a variety of inflammatory
conditions, and may follow initial activation of platelets by
vascular damage. Heterotypic aggregation results from expression
of P-selectin on the surface of the platelet. P-selectin is one of
several molecules found in platelet alpha-granules, which are

released when the platelet cytoskeleton is only minimally

disrupted by thrombin- or ADP-mediated activation of the cell.
Heterotypic platelet aggregation is not inhibited by some
antiplatelet drugs (such as aspirin) to the same extent as
homotypic aggregation
end ngRepeat: item in XocsCtrl.sections

Blood coagulation and the coagulation cascade

Both coagulant and anticoagulant factors regulate haemostasis.
Activation of the coagulation cascade is divided into extrinsic and
intrinsic pathways ( Fig. 11.3 ). The factors involved in these
cascades amplify the coagulation response and work together to
produce a thrombus. The extrinsic pathway accounts for most of
the coagulation in vivo , but both coagulation pathways respond
to breaches in endothelial integrity much more slowly than
platelet aggregation. The following description of the pathways is
simplified to identify the key steps at which drugs can modulate
coagulation.

Fig. 11.3
The coagulation cascade and action of anticoagulants.
The complex cascade of clotting factor synthesis is initiated extrinsically by
tissue damage. Activation of the clotting factors after damage depends
upon platelet factors, tissue factor, phospholipids, Ca 2+ and vitamin K. The
provision of platelet products is further enhanced by the formation of
thrombin, which then activates further platelets as well as causing fibrin
formation. Heparin acts at various sites in the cascade by complexing with
the anticlotting factor antithrombin III (AT) and inhibiting thrombin (IIa) and
the other activated clotting factors shown. Low-molecular-weight heparin
(LMWH) complexes with AT but in a different manner to unfractionated
heparin and inhibits only factor Xa. Bivalirudin and dabigatran etexilate
inhibit thrombin (IIa) action. Warfarin inhibits the synthesis of the vitamin Kdependent clotting factors VII, IX, X and II (prothrombin). Roman numerals
indicate the individual clotting factors; PL, phospholipid; TF, tissue factor.

The extrinsic coagulation pathway is initiated by exposure of

blood to tissue factor (TF) on the surface of subendothelial cells
after vascular injury, and is activated rapidly within minutes of
endothelial disruption. Formation of complexes of TF with factor
VIIa, and the presence of phospholipids and Ca 2+ , result in the
conversion of inactive factor X to active Xa.
The intrinsic pathway is triggered by contact of blood with a
negatively charged surface such as subendothelial collagen, and
its activation is delayed by more than 10min after tissue
disruption. The intrinsic coagulation pathway comprises a series
of enzyme-mediated reactions involving activation of several
clotting factors and eventually activation of factor X.
Activation of factor X, which mediates the hydrolysis of
prothrombin to thrombin (factor IIa), is the point at which the
two pathways of coagulation converge ( Fig. 11.3 ). The actions of
thrombin (factor IIa) and several other activated coagulation
factors ( Fig 11.3 ) are inhibited by circulating antithrombin.
Antithrombin inhibits coagulation factors after forming
complexes with heparin-like molecules that are produced by
intact endothelial cells, and with heparin released from mast cells.
Once sufficient thrombin has been produced to overcome the
effect of circulating antithrombin, the soluble protein fibrinogen
is converted to an insoluble fibrin gel. Thrombin also activates
factor XIII, which crosslinks the fibrin polymers and forms a
fibrin mesh that traps circulating platelets, leucocytes and red
blood cells.
Each activated clotting factor is inactivated extremely rapidly so
that the coagulation process remains localised at the site of the
initiating event. However, in some circumstances, aggregates of
platelets combined with fibrin thrombi can embolise and occlude
more distal parts of the circulation.

Arterial and venous thrombosis

There are differences in the composition of an arterial or venous

thrombus. Arterial thrombosis occurs in the setting of high flow
and high shear stress, and platelets play a prominent role in the

initiation and growth of the thrombus. In contrast, venous

thrombi form in a low-flow, low-shear stress environment.
Venous thrombus usually forms initially in the valve pockets of
deep veins, and consists mainly of fibrin and red cells with few
platelets.
end ngRepeat: item in XocsCtrl.sections

Antiplatelet drugs
Cyclo-oxygenase inhibitors
Examples

aspirin

Mechanism of action on platelets

The highly potent platelet-aggregating agent thromboxane A 2 is
formed in platelets from AA by the enzyme COX-1. After release
from the platelet, thromboxane A 2 acts via TP receptors on the
surface of the platelet to generate the intracellular second
messengers inositol triphosphate (IP 3 ) and diacylglycerol (DAG).
These lead to Ca 2+ release in the cell and expression and activation
of GPIIb/IIIa receptors.
Inhibition of COX-1 by aspirin reduces platelet thromboxane A 2
synthesis and inhibits platelet aggregation, but does not eliminate
it completely because other pathways for platelet activation still
function ( Figs 11.1 and 11.2 ). Aspirin (acetylsalicylic acid)
irreversibly inhibits COX-1 by acetylation ( Ch. 29 ) and since
platelets lack a nucleus and cannot synthesise new enzyme, their
ability to aggregate will be reduced throughout the lifespan of the
platelet. The antiplatelet action of aspirin occurs at very low doses
that have little analgesic or anti-inflammatory actions. At higher
doses, aspirin also inhibits the production of prostacyclin by
vascular endothelium which may offset some of the beneficial
effects on platelets. Details of the pharmacology of aspirin can be
found in Chapter 29 .

Phosphodiesterase inhibitors

Example

dipyridamole

Mechanism of action
Dipyridamole has multiple mechanisms of action; the most
important is probably inhibition of the reuptake of adenosine by
cells. The increased plasma concentration of adenosine promotes
vasodilation and inhibits platelet aggregation by stimulation of
intracellular adenylyl cyclase and production of the intracellular
cyclic nucleotides cGMP and cAMP. Dipyridamole also inhibits
phosphodiesterase types 3 and 5, which degrade cyclic
nucleotides. High intracellular cyclic nucleotide concentrations
inhibit activation of cell surface GPIIb/IIIa receptors, leading to
reduced platelet activation ( Fig. 11.2 ). Dipyridamole has a
number of other actions that are of uncertain significance,
including antioxidant properties.

Pharmacokinetics
Dipyridamole is incompletely absorbed from the gut and is
metabolised in the liver. It has a half-life of 12h. A modifiedrelease formulation is better tolerated than the standard
formulation.

Unwanted effects

Gastrointestinal effects.
Myalgia.
Dizziness, headache.
Flushing, hypotension, tachycardia.
Hypersensitivity reactions, including rash, urticaria,
bronchospasm and angioedema.

ADP receptor antagonists

Examples

clopidogrel, prasugrel, ticagrelor

Mechanism of action
ADP activates platelets via two purinergic surface receptors, P2Y 1
and P2Y 12 . P2Y 1 receptors increase intracellular Ca 2+ and initiate
platelet shape change. Activation of P2Y 12 receptors inhibits
adenylyl cyclase, and reduces generation of the intracellular cyclic
nucleotides that inhibit activation of GPIIb/IIIa receptors.
ADP receptor antagonists inhibit platelet aggregation by binding
selectively to P2Y 12 receptors ( Fig. 11.2 ). Inhibition of P2Y 12
receptors also reduces the production of thromboxane A 2 by the
platelet. Clopidogrel and prasugrel are irreversible receptor
inhibitors, while ticagrelor binds to a different site on the receptor
and produces reversible inhibition. There is considerable interindividual variability in the degree of platelet inhibition by
clopidogrel, and it has a slow onset of action (about 5 days for full
effect) without a loading dose. Both prasugrel and ticagrelor are
more predictable inhibitors of platelet activation than clopidogrel
and have a more rapid onset of action.

Pharmacokinetics
Clopidogrel is a prodrug. It is well absorbed from the gut, and is
activated by metabolism in the liver to a derivative that has a halflife of 7h. Prasugrel is also a prodrug that is well absorbed from
the gut and metabolised rapidly in the liver to an active metabolite
which has a long half-life of 8 days. Ticagrelor is active as the
parent drug, and also has an active metabolite. The offset of action
of ticagrelor over 3 days is much slower than would be predicted
from the short half-life.

Unwanted effects

Bleeding; a greater risk with prasugrel and ticagrelor than

clopidogrel.
Gastrointestinal upset, especially dyspepsia, abdominal
pain and diarrhoea with clopidogrel.

Dyspnoea with ticagrelor.

Glycoprotein IIb/IIIa receptor antagonists

Examples

abciximab, eptifibatide

Mechanism of action
Abciximab is a murine/human chimaeric monoclonal antibody to
the GPIIb/IIIa receptors with the Fc fragment removed to prevent
clearance of antibody-bound platelets from the circulation.
Abciximab binds irreversibly to the GPIIb/IIIa receptors and
blocks the binding of fibrinogen ( Fig. 11.2 ). Abciximab can reduce
platelet aggregation by more than 90%.
Eptifibatide is a synthetic peptide that binds reversibly to and
blocks the GPIIb/IIIa receptor.

Pharmacokinetics
All GPIIb/IIIa antagonists are given intravenously, usually as an
initial bolus to achieve rapid inhibition of platelets followed by
continuous infusion. The duration of receptor blockade with
abciximab is longer than predicted from its very short half-life of
30min due to slow dissociation from the receptor over several
hours. After stopping abciximab, platelet aggregation largely
recovers by 48h as new platelets are synthesised.
Eptifibatide has a short half-life of about 2.5h, and is eliminated
by the kidney. Platelet aggregation recovers more rapidly after
treatment than with abciximab, due to rapid dissociation of the
drug from the receptor after a few seconds.

Unwanted effects

Bleeding, especially in the elderly and those of low body

weight; the risk is reduced if the dose is adjusted for body
weight.
Thrombocytopenia.

Abciximab can cause nausea, vomiting, hypotension,

bradycardia, headache and, occasionally, hypersensitivity
reactions.

Epoprostenol
Mechanism of action
Epoprostenol (PGI 2 ) increases platelet cAMP, which at low
concentrations inhibits platelet aggregation and at higher
concentrations reduces platelet adhesion. Epoprostenol is also a
peripheral arterial vasodilator.

Pharmacokinetics
Epoprostenol is given by intravenous infusion. Unlike most other
prostaglandins it is not significantly metabolised in the lung, as it
is rapidly metabolised by hydrolysis in plasma and peripheral
tissues, giving a very short half-life of about 3min.

Unwanted effects
These can be reduced by starting the infusion with a low dose and
include:
facial flushing,
headache,
hypotension,
gastrointestinal disturbances.
end ngRepeat: item in XocsCtrl.sections

Clinical uses of antiplatelet drugs

Aspirin has often been used as the sole antiplatelet drug in a
variety of clinical settings. However, there are some situations
where clopidogrel is more effective, or where combinations of
aspirin and an ADP receptor antagonist give better outcomes than
aspirin alone. The suppression of thromboxane A 2 production by
ADP receptor antagonists has called into question whether the
concurrent use of aspirin is necessary to achieve optimal clinical
outcomes, but this issue is unresolved. A combination of

antiplatelet drugs inevitably carries a greater risk of bleeding than

a single agent. Main uses of antiplatelet drugs are listed here.
Secondary prevention of embolic stroke and
transient cerebral ischaemic attacks (aspirin,
clopidogrel, dipyridamole). Clopidogrel alone is more
effective than aspirin alone for the secondary prevention of
stroke, while the combination has no further advantage
despite a higher risk of bleeding. Dipyridamole combined
with aspirin is better than aspirin alone for prevention of
recurrent transient ischaemic attacks, and is equally effective
as clopidogrel after stroke ( Ch. 9 ).
Secondary prevention after acute coronary
syndrome (aspirin, clopidogrel, prasugrel, ticagrelor,
eptifibitide, tirofiban). The combination of aspirin and
clopidogrel is better than aspirin alone for reducing further
vascular events after myocardial infarction. Prasugrel and
ticagrelor may have advantages over clopidogrel in some
situations ( Ch. 5 ).
Reduction of ischaemic complications produced by
stent thrombosis following percutaneous coronary
intervention (PCI) with stent insertion ; these
complications include non-fatal myocardial infarction, death
and the need for emergency surgical revascularisation.
Aspirin with clopidogrel or prasugrel are given for up to a
year, often with abciximab or eptifibatide added at the time
of the procedure when PCI is carried out following
myocardial infarction.
Secondary prevention of myocardial infarction in
stable angina or peripheral vascular disease (aspirin,
clopidogrel): either aspirin or clopidogrel alone is effective,
and there is no evidence to support combination therapy (
Chs 5 and 10 ).
Primary prevention of ischaemic heart disease
(aspirin). This is a controversial area, with the potential for
serious haemorrhage offsetting much of the potential

benefit. Use of aspirin should be confined to people at very

high risk of developing cardiovascular disease.
Anticoagulation in extracorporeal circulations ; for
example, cardiopulmonary bypass and renal haemodialysis
(epoprostenol).
Symptom relief in Raynaud's phenomenon
(epoprostenol) ( Ch. 10 ).
Dipyridamole is used as a pharmacological stress
for the coronary circulation to detect myocardial
ischaemia in people who are unable to exercise . This
is related to its ability to block the cellular uptake of
adenosine. In the heart, adenosine acts on specific receptors
in the small resistance coronary arteries to produce
vasodilation. Dipyridamole can divert blood away from
myocardium supplied by stenosed coronary arteries by
preferentially dilating healthy vascular beds (vascular steal).

end ngRepeat: item in XocsCtrl.sections

Anticoagulant drugs
Anticoagulation can be achieved with either injectable or oral
drug therapy. Increasingly, oral anticoagulant therapy with newer
agents is likely to supersede the long-established use of heparin
followed by warfarin to initiate anticoagulation.

Injectable anticoagulants
Heparins
Heparins are a family of highly sulphated acidic
mucopolysaccharides (glycosaminoglycans) that are found in
mast cells, basophils and endothelium. Heparins have a variable
molecular weight of between 3000 and 30000Da according to
the numbers of polysaccharide subunits.

Mechanism of action and effects

Heparin is available as an unfractionated preparation, or as lowmolecular-weight heparins (LMWHs), which consist of the

heparin subfractions that have molecular weights of less than

7000Da.
Unfractionated heparin forms a complex with and alters the
conformation of antithrombin III; this complex can then
inactivate thrombin and factors IXa, Xa, XIa and XIIa ( Fig. 11.3 ).
LMWH interacts with antithrombin III in a different manner to
unfractionated heparin, and the LMWHantithrombin complexes
have a more selective anticoagulant action, mainly inhibiting
factor Xa ( Fig. 11.3 ).
Additional actions of the heparins are as follows.
Promotion of tissue factor pathway inhibitor (TFPI) release
from the vascular wall contributes to the antithrombotic
effects of heparin. TFPI inhibits formation of factor Xa.
Inhibition of platelet aggregation through binding to
platelet factor 4 (mainly unfractionated heparin).
Activation of lipoprotein lipase, which in addition to
promoting lipolysis also reduces platelet adhesiveness.

Pharmacokinetics
Heparins are inactive orally and are given intravenously or by
subcutaneous injection. They have a rapid onset of action.
Heparins do not cross the placenta or enter breast milk. The two
principal forms of heparin have different pharmacokinetic
properties.

Unfractionated heparin
This is extracted from porcine intestinal mucosa or bovine lung,
and consists of a mean of 45 polysaccharide units. It has dosedependent pharmacokinetics: the half-life is very short (about
30min) at low doses, increasing some five-fold at higher doses.
Variable binding to plasma proteins contributes to interindividual variation in the dose required to achieve target levels of
anticoagulation. Most heparin is metabolised in endothelial cells
after binding to cell surface receptors. Unfractionated heparin is
usually given by continuous intravenous infusion for full

anticoagulation. Low-dose subcutaneous injections are used for

prophylaxis against venous thrombosis, although bioavailability
by this route is only about 30%.

Low-molecular-weight heparins
LMWHs have a mean of 15 polysaccharide units. They are almost
completely absorbed after subcutaneous administration and only
need to be given once or twice daily by subcutaneous injection for
full anticoagulation. LMWHs have a low affinity for plasma
protein binding sites and for endothelial cell heparin receptors.
They have two routes of elimination: a rapid, saturable liver
uptake and slower renal excretion. The different LMWHs have
half-lives in the range 26h. When the dose of a LMWH is based
on body weight they produce a more predictable anticoagulant
effect compared with unfractionated heparin.

Control of heparin therapy

The therapeutic index for heparin is low. The degree of
anticoagulation with unfractionated heparin is usually monitored
with the activated partial thromboplastin time (APTT; a global
test of the intrinsic coagulation pathway), which should be
prolonged by 1.52.0 times the control value for full
anticoagulation. Monitoring is not required when unfractionated
heparin is used subcutaneously for prophylaxis. The anticoagulant
effect of LMWHs can be monitored by the degree of factor Xa
inhibition, but this is not carried out routinely since their effect is
much more predictable than that of unfractionated heparin.

Unwanted effects

Haemorrhage is the most common problem. The risk is

greater in the elderly, especially if there is a history of heavy
alcohol intake. The effect of unfractionated heparin can be
rapidly reversed by intravenous injection of protamine
sulphate, a basic peptide which binds strongly to the acidic
heparin components. Protamine binds poorly to LMWHs
and only partially reverses their action.

Osteoporosis is a rare complication which can occur when

heparin is given for several weeks; heparin binds to
osteoblasts, and inhibits their activity. The risk is less with
LMWH.
Heparin-induced thrombocytopenia (HIT) usually occurs
515 days after starting intravenous heparin in about 2% of
people, and arises from the development of antibodies to the
heparinplatelet factor 4 complex. This causes platelet
activation, aggregation and thrombosis. LMWHs are much
less likely to cause HIT, since they have much less affinity for
platelet factor 4 and their lower binding to endothelium also
reduces interference with plateletvessel wall interaction.
Danaparoid (see the Compendium at the end of this chapter)
is often used if continued parenteral anticoagulation is
necessary.
Hyperkalaemia by inhibition of aldosterone secretion. This
is most likely to occur after at least 7 days of treatment.
Hypersensitivity reactions.

Fondaparinux
Mechanism of action
Fondaparinux is a synthetic pentasaccharide almost identical to
the natural pentasaccharide sequence of heparin that binds to
antithrombin. Like LMWH, it enhances the innate ability of
antithrombin to inhibit factor Xa.

Pharmacokinetics
Fondaparinux is given by subcutaneous injection. It is predictably
absorbed from the injection site, is eliminated unchanged by the
kidney and has a long half-life (18h).

Unwanted effects

Haemorrhage.
Thrombocytopenia.
Oedema.

Gastrointestinal upset.

Oral anticoagulants
Vitamin K antagonists
Examples

warfarin, acenocoumarol (especially in Europe)

Mechanism of action
These drugs inhibit hepatic vitamin K epoxide reductase, which is
the enzyme that converts vitamin K to its active (hydroquinone)
form. As a result, the hepatic synthesis of the vitamin Kdependent clotting factors II (prothrombin), VII, IX and X is
impaired ( Fig. 11.3 ). There is a delay in the onset of the
anticoagulant effect, due to the presence of previously synthesised
clotting factors, which must be cleared from the circulation.

Pharmacokinetics
Warfarin is the most widely used vitamin K antagonist. It is
almost completely absorbed from the gut and is highly bound to
plasma albumin. It is eliminated by cytochrome P450-mediated
hepatic metabolism (CYP2C9) and has a very long half-life of 12
days. Functional CYP2C9 polymorphisms contribute to
considerable inter-individual variability in warfarin sensitivity.
The plasma concentration of warfarin does not correlate directly
with the clinical effect of the drug, which is determined by the
balance between the rates of synthesis and degradation of clotting
factors. The maximum effect of an individual dose of warfarin is
reflected in the blood coagulation time some 2436h later. On
stopping treatment, the duration of anticoagulant action is
determined largely by the time required to synthesise new clotting
factors.

Control of oral anticoagulant therapy

Factor VII is the clotting factor that is most sensitive to vitamin K
deficiency, since it has the shortest half-life of the vitamin K-

sensitive clotting factors. Therefore, a test of the extrinsic

coagulation pathway the prothrombin time is used as a
measure of effectiveness. The degree of prolongation of the
prothrombin time is standardised by comparison with control
plasma from a single source, and referred to as the international
normalised ratio (INR). Therapeutic INR ranges differ according
to the condition being treated:
INR 22.5 for prophylaxis of deep vein thrombosis
(thromboprophylaxis),
INR 23 for thromboprophylaxis in hip surgery and
fractured femur operations, for treatment of deep vein
thrombosis and pulmonary embolism, and for prevention of
thromboembolism in atrial fibrillation,
INR 34.5 for prevention of recurrent deep vein thrombosis
and for preventing thrombosis on mechanical prosthetic
heart valves.

Unwanted effects
Warfarin is an important example of a drug that has a narrow
therapeutic index.
Haemorrhage. The most effective antidote to warfarin is
phytomenadione (vitamin K 1 ). For major bleeding, this is
given intravenously and controls bleeding within 6h. An
immediate coagulant effect is achieved by also giving an
intravenous injection of prothrombin complex concentrate
(vitamin K-dependent clotting factors) or an infusion of
fresh frozen plasma. After giving a large dose of
phytomenadione, it can be difficult to restore therapeutic
anticoagulation with warfarin for up to 3 weeks. If the INR is
>8.0 but there is no bleeding or only minor bleeding, then a
smaller dose of phytomenadione can be given intravenously
or orally with less disturbance to subsequent
anticoagulation.

Alopecia, skin necrosis and hypersensitivity reactions occur

rarely.
Warfarin crosses the placenta and can have undesirable
effects on the fetus. It is teratogenic and should be avoided in
the first trimester of pregnancy, except when essential;
furthermore, it should not be used in the last trimester, as it
increases the risk of intracranial haemorrhage in the baby
during delivery.
Drug interactions are particularly important. The
anticoagulant effect of warfarin can be increased by broadspectrum antibacterial agents that suppress the production
of vitamin K by gut bacteria. Drugs such as amiodarone ( Ch.
8 ) and the histamine H 2 receptor antagonist cimetidine ( Ch.
33 ), which inhibit CYP2C9-mediated metabolism of
warfarin, enhance its effects. Drugs that induce CYP2C9
for example, phenytoin ( Ch. 23 ) and alcohol ( Ch. 54 )
reduce the effect of warfarin by increasing its elimination.

Direct factor Xa inhibitors

Examples

apixaban, rivaroxaban

Mechanism of action
Apixaban and rivaroxaban are orally active factor Xa inhibitors
that bind reversibly to the active site of factor Xa. They inhibit
both free factor Xa and that bound to the prothrombinase
complex, and unlike warfarin produce a rapid onset of predictable
anticoagulation.

Pharmacokinetics
Apixaban and rivaroxaban are well absorbed from the gut. They
are partially metabolised in the liver and partially excreted by the
kidneys. Their half-lives are around 10h.

Unwanted effects

Nausea, and less often other gastrointestinal upset.

Haemorrhage. If bleeding occurs, the short half-life means
that stopping treatment may be all that is required. There is
no direct antidote, but serious bleeding can be reduced with
intravenous prothrombin complex concentrates or activated
factor X.
Drug interactions: rivaroxaban is a substrate for Pglycoprotein (P-gp), and its excretion is reduced by drugs
that inhibit P-gp, such as ketoconazole.

Direct thrombin inhibitors

Example

dabigatran etexilate

Mechanism of action
Dabigatran is a selective, direct competitive thrombin inhibitor
that binds to and inhibits both free circulating and thrombusbound thrombin (factor IIa). It produces a rapid onset of
predictable anticoagulation.

Pharmacokinetics
Dabigatran etexilate is a prodrug that has a low oral
bioavailability and undergoes first-pass metabolism to its active
derivative dabigatran. The active metabolite is excreted
unchanged by the kidneys, and has a short half-life of about
40min.

Unwanted effects

Nausea, dyspepsia, diarrhoea, abdominal pain.

Haemorrhage, but with a lower risk than warfarin at
equally effective doses. There is no direct antidote, but
serious bleeding can be treated with intravenous
prothrombin complex concentrates.

end ngRepeat: item in XocsCtrl.sections

Clinical uses of anticoagulants

Until recently, rapid anticoagulation was usually achieved with
LMWH or unfractionated heparin, and warfarin was started
simultaneously for long-term anticoagulation. The heparin is
stopped when the INR reaches the desired therapeutic range. The
newer oral anticoagulants have a rapid onset of action (so heparin
is not needed) and compared to warfarin they have fewer drug
interactions and do not need monitoring of their anticoagulant
effect. In most situations where warfarin is used, they have similar
or greater efficacy compared to warfarin with either similar or
lower risk of bleeding. Therefore, increasing use of drugs such as
rivaroxaban and dabigatran in place of warfarin is likely.

Venous thromboembolism
Acute pulmonary embolism can present with a wide variety of
symptoms. Massive emboli produce shock or sustained
hypotension, while smaller emboli can present with chest pain,
dyspnoea or haemoptysis. Pulmonary embolism is a major cause
of morbidity and death. Most serious pulmonary emboli arise
from deep vein thrombosis in the lower limb, particularly if the
thrombus extends to the larger veins above the calf. Massive
pulmonary emboli causing haemodynamic instability are fatal in
about 60% of cases if untreated. Mortality is much lower in stable
patients. Many episodes of deep vein thrombosis occur in
hospital, particularly in people over 40 years of age following
major illness, trauma or surgery. Pulmonary embolism has been
estimated to be responsible for 10% of all deaths in hospital.
Chronic pulmonary embolic disease can lead to pulmonary
arterial hypertension with progressive dyspnoea ( Ch. 6 ).
Factors predisposing to venous thromboembolism in hospital (
Table 11.1 ) include prolonged immobility and a variety of
coexisting medical conditions such as cancer. Spontaneous
thromboembolism can occur after long journeys, such as by road

or air, and in various inherited or acquired disorders of the

coagulation system. Use of the combined oral contraceptive pill by
older women who smoke (see Ch. 45 ) is also a factor.
Table 11.1
Risk of thromboembolism in people admitted to hospital

Risk
Procedure
Low
Minor surgery, no other risk factor
Major surgery, age <40 years, no other risk factors
Minor trauma or illness
Moderate
Major surgery, age 40 years or other risk factor
Heart failure, recent myocardial infarction, malignancy,
inflammatory bowel disease
Major trauma or burns
Minor surgery, trauma or illness in patient with previous deep vein
thrombosis or pulmonary embolism
High
Fracture or major orthopaedic surgery of pelvis, hips or lower limb
Major pelvic or abdominal surgery for cancer
Major surgery, trauma or illness in patient with previous deep vein
thrombosis or pulmonary embolism
Lower limb paralysis
Major lower limb amputation
After an initial spontaneous deep vein thrombosis, the risk of
recurrence is about 25% after 4 years, but is much lower after
postoperative thrombosis. Following a deep vein thrombosis,
chronic post-phlebitic syndrome can develop, with pain, swelling
and ulceration of the affected leg.

Prevention of deep vein thrombosis

In hospitalised people, the most appropriate method to prevent
deep vein thrombosis will depend on the degree of risk.

Mechanical methods

These are used for people in hospital who are at moderate risk of
thromboembolism and include graduated elastic compression
stockings and intermittent pneumatic compression devices to
improve venous flow and limit stasis in venous valve pockets.
They can also be used to supplement pharmacological prophylaxis
in people at high risk.

Low-dose subcutaneous heparin

This is the treatment of choice for many people in hospital who
are at high or moderate risk of thromboembolism. Heparin
reduces both initiation and extension of fibrin-rich thrombi at
doses that have little effect on other measurements of blood
coagulation; therefore, laboratory monitoring is unnecessary.
Low-dose unfractionated heparin reduces deep venous
thrombosis and fatal pulmonary emboli by about two-thirds, with
minimal risk of serious bleeding, although minor bleeding is
increased. LMWHs or fondaparinux are more effective than
unfractionated heparin for those at highest risk.

Oral anticoagulants
Low-dose dabigatran, apixaban and rivaroxaban are at least as
effective as LMWHs for thromboprophylaxis in people
undergoing hip and knee orthopaedic surgery. Bleeding rates with
dabigatran, apixaban and LMWH are similar, but may be higher
with rivaroxaban. Prophylaxis should be started before surgery.
Warfarin may be more effective than heparin for prophylaxis in
people at highest risk of thromboembolism, but is not widely
used. Although a meta-analysis of several studies suggests that
low-dose aspirin reduces deep venous thrombosis, it is less
effective than heparin.

Treatment of established venous thromboembolism

The goals of treatment for deep vein thrombosis are to prevent
pulmonary emboli and to restore patency of the occluded vessel,
with preservation of the function of venous valves. In about 50%
of people with deep venous thrombosis, the vessel will recanalise
within 3 months if appropriately treated. Use of compression

stockings in the first few weeks after a deep venous thrombosis of

the leg reduces the incidence of post-phlebitic syndrome.

Therapeutic anticoagulation
This is the treatment of choice for deep vein thrombosis and for
most pulmonary emboli since anticoagulation substantially
reduces mortality. Heparin is still the most widely used initial
treatment for its rapid onset of effect. LMWH or fondaparinux
given subcutaneously are preferred to unfractionated heparin,
except in people with significant renal impairment. Heparin is
usually given for 35 days, with concurrent initiation of treatment
with warfarin. Heparin can be stopped once warfarin has
produced adequate anticoagulation (i.e. the INR is within the
therapeutic range; see above). When deep vein thrombosis occurs
in someone with cancer there is a high risk of both bleeding and
recurrence during treatment with warfarin. In this situation,
prolonged treatment with LMWH (6 months, or lifelong if
remission is not achieved) is usually advocated. The optimal
duration of anticoagulant therapy is not well defined, but
suggested periods are shown in Table 11.2 .
Table 11.2
Suggested duration of anticoagulant therapy for venous thromboembolism

Risk of recurrence
Clinical setting
Duration
Low
Temporary risk factors for thromboembolism
3 months
Intermediate
Continuing medical risk factors for thromboembolism
36 months
High
Recurrent thromboembolism; inherited thrombophilic tendency
Indefinite

Oral anticoagulants such as rivaroxaban can be used instead of

sequential heparin and warfarin, and have equal efficacy. At
present there is only evidence for the efficacy of dabigatran after
initial treatment with LMWH.

Surgical venous thrombectomy

This may be required for massive iliofemoral thrombosis if it
threatens the viability of the limb. Pulmonary embolectomy is
occasionally carried out for large pulmonary emboli.

Thrombolysis and percutaneous thrombectomy

Pharmacological thrombolysis (see below) has no advantage over
warfarin in uncomplicated deep venous thrombosis. However, it
is used to disintegrate massive pulmonary emboli, and reduces
mortality in haemodynamically unstable patients. Percutaneous
mechanical thrombectomy (fragmentation and removal of the
thrombus) and surgical embolectomy are occasionally used if
there are contraindications to thrombolysis.

Other treatments
When pulmonary emboli recur despite adequate anticoagulation,
or when anticoagulation is contraindicated, inferior vena caval
plication or insertion of a filter device to trap emboli in the
inferior vena cava can be considered.

Arterial thromboembolism
Warfarin is used long term for the prevention of thrombosis on
prosthetic heart valves. Atrial fibrillation and mural thrombus in
the left ventricle following a myocardial infarction predispose to
arterial embolism and are indications for anticoagulation with
warfarin. Dabigatran, apixaban and rivaroxaban are at least as
effective as warfarin for prevention of thromboembolism in atrial
fibrillation and may have a lower risk of haemorrhage ( Ch. 8 ).
When combined with antiplatelet therapy, apixaban reduces the
composite endpoint of mortality, reinfarction and ischaemic
stroke after an acute coronary syndrome ( Ch. 5 ).
end ngRepeat: item in XocsCtrl.sections

The fibrinolytic system

Fibrinolysis is the physiological mechanism for dissolving the

fibrin meshwork in a thrombus. The process is initiated by
activation of plasminogen, a circulating 2 -globulin ( Fig. 11.4 ).
Tissue plasminogen activator (t-PA) is released from damaged
vessels and cleaves plasminogen to the active enzyme plasmin. In
the circulation, plasminogen activator inhibitors 1 and 2 rapidly
inactivate t-PA. However, t-PA binds to fibrin locally at the site of
release, and converts fibrin-bound plasminogen to plasmin.
Plasmin splits both fibrinogen and fibrin into degradation
products, and if this occurs at the site of a thrombus it produces
lysis of the clot matrix. Fibrinolytic therapy (also called
thrombolytic therapy) is achieved by using a plasminogen
activator in such large quantities that the inhibitory controls are
overwhelmed.

Fig. 11.4
The fibrinolytic system.
The fibrinolytic system is linked intimately with the coagulation cascade and
platelet function. When a clot is formed via the prothrombotic system,
activation of plasminogen to the fibrinolytically active plasmin is initiated by
several tissue plasminogen activators, thus lysing the clot. The drugs
promoting this act as plasminogen activators (alteplase (recombinant
tissue-type plasminogen activator, rt-PA) and derivatives) or bind to
plasminogen (streptokinase), promoting plasmin activity. The antifibrinolytic
drug tranexamic acid inhibits plasminogen activation.

Fibrinolytic (thrombolytic) agents

Examples

alteplase (recombinant tissue-type plasminogen activator, rt-PA),

streptokinase, tenecteplase

Mechanism of action
Fibrinolytic drugs enhance fibrinolysis by substituting for the
naturally occurring t-PA. They bind to and activate plasminogen,
which degrades fibrin thrombi. Alteplase is a genetically
engineered copy of the naturally occurring t-PA that binds directly
to fibrinogen and fibrin. It has a wide range of clinical uses.
Tenecteplase is a genetically engineered modified form of t-PA
with increased fibrin specificity, less sensitivity to plasminogen
activator inhibitors and a longer duration of action than alteplase.
Tenecteplase is only licensed for treatment of myocardial
infarction
Streptokinase is obtained from haemolytic streptococci, and is
inactive until it forms a complex with circulating plasminogen; the
resultant streptokinaseplasminogen activator complex
substitutes for t-PA in the fibrinolytic cascade, causing
plasminogen activation. Streptokinase is now used less frequently
than other fibrinolytic drugs.
The effectiveness of any fibrinolytic agent is greatest with fresh
thrombus and if a large surface area of thrombus is exposed to the
drug.

Pharmacokinetics
All fibrinolytic agents are given intravenously or intra-arterially.
Alteplase and related compounds are metabolised in the liver. The
streptokinaseplasminogen activator complex is degraded
enzymatically in the circulation. Some streptokinase is cleared
from the plasma before it forms an active complex, by combining
with circulating neutralising antibody formed during previous
exposure to streptokinase. After the use of streptokinase, or
following a streptococcal infection, neutralising antibodies can
persist in high titre for several years and substantially reduce the

effectiveness of subsequent therapy with streptokinase. For this

reason, repeat use of streptokinase is not recommended.
Alteplase and its derivatives have a more rapid onset of action
than streptokinase and consequently the reperfusion of occluded
vessels is faster. Infusions of alteplase are given over 13h,
depending on the condition being treated. Tenecteplase is given as
a single bolus. Because of a short duration of action, when
alteplase or its derivatives have been used to lyse coronary artery
thrombus, subsequent anticoagulation with heparin for 48h is
necessary to reduce the risk of reocclusion. Streptokinase is
usually given as a short (1h) infusion for the treatment of
coronary artery occlusion, although longer infusions are usual for
peripheral arterial occlusions or pulmonary embolism. The long
duration of action means that heparin is not necessary after
streptokinase has been given.

Unwanted effects

Nausea and vomiting.

Haemorrhage is usually minor, but serious bleeding, for
example intracerebral haemorrhage, occurs in about 1% of
those treated. Bleeding can be stopped by antifibrinolytic
drugs (see below) or by transfusion of fresh frozen plasma.
Hypotension: this is dose-related and more common with
streptokinase. It may be caused by enzymatic release of the
vasodilator bradykinin from its circulating precursor. If the
infusion of the fibrinolytic is stopped for a brief period, the
blood pressure usually recovers rapidly and treatment can be
continued.
Allergic reactions: these are rare but can occur with
streptokinase, as a consequence of its bacterial origin.

Clinical uses of fibrinolytic agents

Fibrinolytic agents are used to treat the following:

acute myocardial infarction (although this use is rapidly

declining with the greater availability of primary coronary
angioplasty) ( Ch. 5 ),
ischaemic stroke (alteplase only) ( Ch. 9 ),
pulmonary embolism or deep venous thrombosis, in a
minority of cases (see above),
peripheral arterial thromboembolism ( Ch. 10 ),
central venous catheters occluded by clot (alteplase): this is
particularly useful to restore patency of long lines inserted
for intravenous nutrition or administration of cytotoxic
drugs.

Antifibrinolytic and haemostatic agents

Antifibrinolytic agents
Example

tranexamic acid

Mechanisms of action
Tranexamic acid competitively inhibits the activation of
plasminogen, so fibrinolysis is inhibited. The theoretical risk of
creating a thrombotic tendency does not appear to be a clinical
problem.

Pharmacokinetics
Tranexamic acid is a synthetic amino acid that is incompletely
absorbed from the gut and can also be given intravenously. It is
excreted unchanged by the kidney and has a short half-life (1
2h).

Unwanted effects

Nausea, vomiting, diarrhoea.

Desmopressin

Desmopressin ( Ch. 43 ) briefly increases the plasma

concentrations of clotting factor VIII and von Willebrand factor,
an adhesion protein in blood vessel walls. Factor VIII accelerates
the process of fibrin formation and von Willebrand factor
enhances platelet adhesion to subendothelial tissue.

Clinical uses of antifibrinolytic and haemostatic

agents
The use of haemostatic agents is limited, but includes the
following.
Tranexamic acid is used to prevent bleeding after surgery,
for example prostatectomy or bladder surgery, or after dental
extraction in individuals with haemophilia.
Desmopressin is used in mild congenital bleeding disorders
such as haemophilia A or von Willebrand's disease; it is
given to reduce spontaneous or traumatic bleeding, or as a
prophylactic before surgery.
Tranexamic acid is used for the treatment of menorrhagia
and epistaxis, or for bleeding following overdose of a
fibrinolytic drug.
Tranexamic acid is used for treatment of hereditary
angioedema.
end ngRepeat: item in XocsCtrl.sections

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