CLINICAL PHARMACOLOGY 2003 (PART 29)

SECTION 6

BLOOD AND
NEOPLASTIC
DISEASE


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28
Drugs andhaemostasis

SYNOPSIS
Occlusive vascular disease is a major cause of
morbidity and mortality.There is now better
understanding of the mechanisms by which the
haemostatic system ensures blood remains
fluid within vessels, yet forms a solid plug when
a vessel is breached, and of the ways in which
haemostasis may be altered by drugs to
prevent or reverse (lyse) pathological
thrombosis.
• Coagulation system: the mode of action of
drugs that promote coagulation and that
prevent it (anticoagulants) and their uses
• Fibrinolytic system: the mode of action of
drugs that promote fibrinolysis (fibrinolytics)
and their uses to lyse arterial and venous
thrombi (thrombolysis)
• Platelets: the ways that drugs that inhibit

platelet activity are used to treat arterial
disease

The haemostatic system is complex but can be
separated into the following major components:
• Formation of fibrin (coagulation), which
stabilises the platelet plug
• Dissolution of fibrin (fibrinolysis)
• Platelets, which form the haemostatic plug
• Bloodvessels.
Drugs that interfere with the haemostatic system

(anticoagulants, thrombolytics, antiplatelet agents)
are valuable in the management of pathological
thrombus formation within blood vessels, or of
pathological bleeding. They are classified according
to which component of the system they affect.

Coagulation system
The blood coagulation system is shown in simplified
form in Figure 28.1. It consists of glycoprotein
components that circulate in (necessarily inactive)
pro-enzyme or pro-cofactor (factors V and VIII)
form. The activated enzymes are serine proteases.
Physiological coagulation (the 'extrinsic' pathway)
begins when tissue factor (TF, tissue thromboplastin),
exposed by vascular injury, activates and complexes
with factor VII to activate factors IX and X which
complex with Villa and Va respectively on membrane surfaces (which provide phospholipid, PL).
The Xa/Va complex converts prothrombin to

thrombin which converts fibrinogen to fibrin and
also activates factors XI, VIII, V and XIII, both
accelerating coagulation and cross-linking fibrin
(-F-F-F-).
The 'intrinsic' pathway refers to coagulation in
vitro. It is initiated when factor XII with the cofactor
high molecular weight kininogen (HMWK) comes
into contact with a foreign surface, e.g. glass,
kaolin. Thus it has no physiological role (and
patients lacking factor XII do not have a bleeding
disorder).
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28

DRUGS AND

HAEMOSTASIS

The prothrombin time (FT), which is usually
expressed as the International Normalised Ratio
(INR) for control of oral anticoagulant therapy,
primarily evaluates the extrinsic system.
The activated partial thromboplastin time (APTT),
also known as the kaolin-cephalin clotting time
(KCCT), primarily evaluates the intrinsic system.
In-vitro coagulation of plasma is initiated by the
addition of negatively charged particles such as
kaolin with phospholipid, and calcium and exogenous thromboplastin.

Each of these tests is also affected by the final
common pathway, the endpoint of which is tested by
the thrombin time. This tests the formation of a fibrin
clot by the addition of exogenous thrombin and
calcium. It is sensitive to the level of endogenous
fibrinogen and to the presence of inhibitors of
thrombin (heparin, FDPs).

VITAMIN K:A CRITICAL CO-FACTOR

Fig. 28.1 Blood coagulation system (see text)

The classical separation of the intrinsic and extrinsic
pathways is a simplification but remains a useful
in-vitro phenomenon for monitoring coagulation.
Both in vivo and in vitro the systems are dependent
on the presence of Ca++ ions and key in-vivo steps
involve the formation of macromolecular complexes
on membrane surfaces, usually those of platelets.
Cascade reactions culminate in the generation of
fibrin and its polymerisation by factor XIII to form a
fibrin clot.
568

Vitamin K (Koagulation vitamin) is essential to
normal haemostatic and antithrombotic mechanisms.
This vitamin occurs naturally in two forms. Vitamin
Kj (phylloquinone) is widely distributed in plants and
K2 includes vitamin synthesised in the alimentary
tract by bacteria, e.g. Escherichia coli (menaquinones).

Bile is required for the absorption of the natural
vitamins K, which are fat-soluble. Leafy green
vegetables are a good source of vitamin Kr The
storage pool of vitamin K is modest and can be
exhausted in one week, though gut flora will maintain
suboptimal production of vitamin K dependent
proteins. A synthetic analogue, menadione, (K3)
(below) of the natural vitamins also has biological
activity in vivo; it is water-soluble.
Vitamin K is necessary for the final stage of the
synthesis of six coagulation-related proteins in the
liver by y-carboxylation of glutamic acid residues on
the molecule. The y-carboxyglutamic acid residues
permit calcium to bind to the molecule which in
turn mediates binding to negatively charged phospholipid surfaces. The vitamin K-dependent proteins
are coagulation factors II (prothrombin), VII, IX and
X, and the anticoagulant (regulatory) proteins,
proteins C and S. During y-carboxylation of the
proteins by the vitamin K dependent carboxylase,
the reduced form of vitamin K is converted to an


COAGULATION SYSTEM

28

epoxide, an oxidation product, which is subsequently
reduced again enzymatically to the active vitamin
K, i.e. there exists an interconversion cycle (the
vitamin K cycle) between vitamin K epoxide and

reduced and active vitamin K (KH2). When the
vitamin is deficient or where its action is inhibited
by drugs, coagulation proteins which cannot bind
Ca++ result; their physiologically critical binding
to membrane surfaces fails to occur, and this
impairs the coagulation mechanism. This non- ordescarboxylated protein is called 'protein induced
in vitamin K absence' or PIVKA.

Menadiol sodium phosphate in moderate doses
causes haemolytic anaemia and for this reason it
should not be given to neonates, especially those that
are deficient in glucose-6-phosphate dehydrogenase;
their immature livers are unable to cope with the
heavy bilirubin load and there is danger of
kernicterus.
Fat-soluble analogues of vitamin K which are
available in some countries include acetomenaphthone and menaphthone.

Deficiency may arise from:

• Haemorrhage or threatened bleeding due to the
coumarin or indandione anticoagulants.
Phytomenadione is preferred for its more rapid
action; dosage regimens vary according to the
degree of urgency and the original indication for
anticoagulation, as described on page 576.
• Haemorrhagic disease of the newborn which
develops during the first week of life, usually
between days 2-7 (and also late haemorrhagic
disease which presents at 6-7 months).

Prophylaxis is recommended1 during the period
of vulnerability with vitamin K
(phytomenadione, as Konakion) 1 mg by single
i.m. injection at birth. Alternatively, vitamin K
may be given by mouth as two doses of a
colloidal (mixed micelle) preparation of
phytomenadione in the first week. Breast-fed
babies should receive a further 2 mg at one
month of age. Formula-fed babies do not need
this last supplement as the formula contains
vitamin K. Fears that i.m. vitamin K might cause
childhood cancer have been allayed.
• Hypoprothrombinaemia due to intestinal
malabsorption syndromes. Menadiol sodium
phosphate should be used as it is water-soluble.

• bile failing to enter the intestine, e.g. obstructive
jaundice or biliary fistula
• certain malabsorption syndromes, e.g. coeliac
disease, or after extensive small intestinal
resection
• reduced alimentary tract flora, e.g. in newborn
infants and rarely after broad-spectrum
antimicrobials.
The following preparations of vitamin K are
available:
Phytomenadione (phytonadione, Konakion), the
naturally occurring fat-soluble vitamin K1 acts
within about 12 h and should correct the INK
within 24-48 h. The i.v. formulation is used in

emergency and must be administered slowly as an
anaphylactoid reaction with facial flushing, sweating,
fever, chest tightness, cyanosis and peripheral
vascular collapse may occur. Patients with chronic
liver disease and those using histamine H2-receptor
antagonists seem to be especially likely to react.
Otherwise phytomenadione may be given i.m., s.c.
or orally. The preferred route depends on the
urgency of correcting the haemorrhagic tendency.
The i.m. route should be avoided if the INK is
significantly prolonged as local intramuscular haemorrhage may be induced; s.c. absorption is variable
and despite the risk of allergic reaction, the intravenous route ensures rapid delivery.
Menadiol sodium phosphate (vitamin K3, Synkavit),
the synthetic analogue of vitamin K, being watersoluble, is preferred in malabsorption or in states in
which bile flow is deficient. The main disadvantage
is that it takes 24 h to act, but its effect lasts for
several days. The dose is 5-40 mg daily, orally.

Indications for vitamin K or its analogues

DRUGSTHAT PREVENT
COAGULATION: ANTICOAGULANTS
There are two types of anticoagulant:
Indirect-acting: coumarin2 and indandione drugs
take about 72 h to become fully effective, act for
several days, are given orally and can be antagonised
(see below) by vitamin K.
1

British National Formulary.

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28

DRUGS AND

HAEMOSTASIS

Direct-acting: heparin, hirudin, bivalirudin and
argatroban are rapidly effective, act for only a few
hours and must be given parenterally.
Indirect-acting anticoagulants
Coumarins include warfarin and acenocoumarol
(nicoumalone). The vitamin K antagonists were
discovered as a result of investigation of a haemorrhagic disease of cattle that plagued farmers in the
Great Plains of the USA during the 1920s. The
disorder which was due to hypoprothrombinaemia
was caused by ingestion of spoiled sweet clover hay
contaminated by specific toxins. The compound 3, 3'methylene-bis-4-hydroxycoumarin was purified from
bacterial contaminants in the spoiled hay and was
found to produce a syndrome similar to vitamin K
deficiency.3 Bishydroxycoumarin (dicoumarol) was
introduced into clinical practice as an anticoagulant in
the 1940s and other structurally related vitamin K
antagonists followed; all share a common ring
structure with vitamin K. Warfarin is the most
widely used.

Warfarin
Mode of action. During the y-carboxylation of the
coagulant factors II (prothrombin), VII, IX and X
(and also the anticoagulant regulatory proteins C
and S) in the liver, active vitamin K (KH2) is
oxidised to an epoxide and must be reduced by the
enzymes vitamin K epoxide reductase and vitamin
K reductase to become active again (the vitamin K
cycle). Coumarins are structurally similar to vitamin
K and competitively inhibit vitamin K epoxide
reductase and vitamin K reductase, so limiting
availability of the active reduced form of the vitamin
to form coagulant (and anticoagulant) proteins. The
overall result is a shift in haemostatic balance in
favour of anticoagulation because of the accumulation
of clotting proteins with absent or decreased y2

Coumarins are present in many plants and are important in
the perfume industry; the smell of new mown hay and grass
is due to coumarins.
3
Campbell H A, Link K P 1941 Studies on the haemorrhagic
sweet clover disease IV: the isolation and crystallisation of
the haemorrhagic agent. Journal of Biological Chemistry
138: 21.
570

carboxylation sites (PIVKAs). This shift does not
take place until functional vitamin K-dependent
proteins made before the drug was administered

are cleared from the circulation. The process occurs
at different rates for individual coagulation factors
(VII tl/2 6 h, IX and X tl/2 24 h, prothrombin tl/2 72 h).
Moreover, the anticoagulant proteins C and S have
a shorter tl/2 than the procoagulant proteins and
their more rapid decline in concentration creates a
transient hypercoagulable state. This can be serious in
those who have inherited protein S and C
deficiency who may develop skin necrosis and
justifies initiating anticoagulation with heparin
until the effect of warfarin is well established. Thus
the anticoagulant effect of warfarin is delayed and
indeed the drug must be administered for 4-5 days
before the effect is properly therapeutic. Furthermore, the INR does not reliably reflect
anticoagulant protection during this initial phase,
because the vitamin K-dependent factors diminish
at different rates.
The great advantage of warfarin over heparin is
that it can be given orally. Its chief disadvantage is
the time lag before it exerts its effect, which is due to
its indirect mode of action. A similar time lag is found
when the warfarin dose is altered or discontinued
as the tl/2 of the nonfunctioning proteins is
approximately that of functioning proteins.
Pharmacokinetics. Warfarin is readily absorbed
from the gastrointestinal tract and like all the oral
anticoagulants, is more than 90% bound to plasma
proteins. Its action is terminated by metabolism in
the liver. Warfarin (t l / 2 36 h) is a racemic mixture of
approximately equal amounts of two isomers S (tl/2

35 h) and R (tl/2 50 h) warfarin, i.e. it is in effect two
drugs. S warfarin is four times more potent than R
warfarin. Drugs which interact with warfarin affect
these isomers differently.
Uses. Warfarin is the oral anticoagulant of choice,
for it is reliably effective and has the lowest incidence
of adverse effects. Monitoring of therapy is by the
prothrombin time. Usually the test is carried out
with a standardised thromboplastin and the result
is expressed as the International Normalised Ratio
(INR), which is the ratio of the prothrombin time in
the patient to that in a normal (non-anticoagulated)
person—taking account of the sensitivity of the


COAGULATION SYSTEM

thromboplastin used. Oral anticoagulation is
commonly undertaken in patients who are already
receiving heparin. The INR reliably reflects the
degree of prothrombin activity provided that the
activated partial thromboplastin time (APTT, a
measure of the anticoagulant effect of heparin, see
below) is within the therapeutic range (1.5-2.5
times control). Warfarin therapy with an INR in the
therapeutic range does not prolong the APTT.
Dose. There is much inter-individual variation in
dose requirements. It is usual to initiate therapy
with 10 mg daily for 2 days, with the maintenance
dose then adjusted according to the INR using an

established protocol.4
The level of anticoagulation should be adjusted
to match the perceived risk of thrombosis, by the
following guidelines:5
• INR 2.0-2.5 Prophylaxis of deep vein thrombosis
including surgery on high-risk patients (2.0-3.0
for hip surgery and fractured femur operations).
• INR 2.0-3.0 Treatment of deep vein thrombosis;
pulmonary embolism; systemic embolism;
prevention of venous thromboembolism in
myocardial infarction; mitral stenosis with
embolism; transient ischaemic attacks; atrial
fibrillation.
• INR 3.0-4.5 Recurrent deep vein thrombosis and
pulmonary embolism; arterial disease including
myocardial infarction; mechanical prosthetic
heart valves.
Adverse effects. Bleeding is the commonest complication of warfarin therapy. The incidence of major
haemorrhage is about 5% per year6 and an identifiable risk factor is often present, e.g. thrombocytopenia, liver disease or vitamin K deficiency, an
endogenous disturbance of coagulation, cancer or
recent surgery. Naturally, poor anticoagulant control
or drug interaction with warfarin increase the risk.
Haemorrhage is most likely to occur in the alimentary
and renal tracts, and in the brain in those with
cerebrovascular disease.

28

Cutaneous reactions, apart from purpura and
ecchymoses in those who are excessively anticoagulated, include hypersensitivity, rash and alopecia.

Skin necrosis due to a mixture of haemorrhage and
thrombosis occurs rarely where induction of warfarin
therapy is over-abrupt and/or the patient has a
genetically determined or acquired deficiency of
the anticoagulant protein C or its cofactor protein S;
it can be very serious.
Warfarin used in early pregnancy may injure the
fetus (other than by bleeding). It causes skeletal
disorders (5%) (bossed forehead, sunken nose, foci
of calcification in the epiphyses) and absence of the
spleen. Women on long-term warfarin should be
advised not to become pregnant while taking the
drug. Heparin should be substituted prior to
conception and continued through the first trimester,
after which warfarin should replace heparin, as
continued exposure to heparin may cause osteoporosis. Warfarin should be discontinued near term
as it exacerbates neonatal hypoprothrombinaemia
and its control is too imprecise to be safe in labour;
heparin may be substituted at this stage for it can be
discontinued just before labour and its anticoagulant
effect wears off in about 6 h.
CNS abnormalities (microcephaly, cranial nerve
palsies) are reported with warfarin used at any
stage of pregnancy and are presumed to be due to
intracranial haemorrhage.
Management of bleeding or over-anticoagulation
is guided by the clinical state and the INR:7
• Haemorrhage threatening life or major organs. In
addition to blood replacement, rapid reversal of
anticoagulation is achieved with prothrombin

complex concentrate (containing factors II, IX
and X, and given i.v. as 50 units per kg of factor
IX) or fresh frozen plasma. If full reversal of
anticoagulation is judged necessary,
phytomenadione 5 mg is then given by slow i.v.
injection. This renders the patient refractory to
oral anticoagulant (but not to heparin) for about
2 weeks. The thrombotic risk so created must be
assessed for each patient and may be judged

4

Fennerty A et al 1988 British Medical Journal 297:
1285-1288.
5
British Society for Haematology 1990 Guidelines on oral
anticoagulants, 2nd edn. Journal of Clinical Pathology 43:
177-183 (Reproduced with permission).

6

A study of 261 patients who received warfarin for 221
patient-years reported major haemorrhage in 5.3% after 1
year and 10.6% after 2 years. Gitter M J et al 1995 Mayo
Clinic Proceedings 70: 725-733.
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28

DRUGS AND

HAEMOSTASIS

unacceptable in some, e.g. those with prosthetic
heart valves. For less severe haemorrhage,
warfarin should be withheld and
phytomenadione 0.5-2 mg may be given by slow
i.v. injection if rapid correction of the INR is
necessary.
• INR > 7 but without bleeding. Correct by
withholding warfarin, and giving
phytomenadione 0.5 mg by slow i.v. injection if
judged appropriate.
• INR 4.5-7.0. Manage by withholding warfarin
for 1-2 days and then reviewing the INR.
• INR 2.0-4.5 (the therapeutic range). Bleeding,
e.g. from the nose, alimentary or renal tract,
should be fully investigated as a local cause
frequently exists.
Withdrawal of oral anticoagulant. The balance of
evidence is that abrupt, as opposed to gradual
withdrawal of therapy does not of itself add to the
risk of thromboembolism, for renewed synthesis of
functional vitamin K dependent clotting factors
takes several days.
Interactions. Oral anticoagulant control must be
precise both for safety and efficacy. If a drug that
alters the action of warfarin must be used, the INR
should be monitored frequently and the dose of

warfarin adjusted during the period of institution
of the new drug until a new stable therapeutic dose
of warfarin is identified; careful monitoring is also
needed on withdrawal of the interacting drug.
The following list, although not comprehensive,
identifies medicines that should be avoided and
those which may safely be used with warfarin.
• Analgesics. Avoid if possible, all NSAIDs
including aspirin (but see p. 576, myocardial
infarction)because of their irritant effect on
gastric mucosa and action on platelets.
Paracetamol is acceptable but doses over 1.5 g/d
may raise the INR. Dextropropoxyphene inhibits
warfarin metabolism and compounds that
contain it, e.g. co-proxamol, should be avoided.
Codeine, dihydrocodeine and combinations with
paracetamol, e.g. co-dydramol, are preferred.
7

Based on recommendations of the British Society for
Haematology.

572

• Antimicrobials. Aztreonam, cefamandole,
chloramphenicol, ciprofloxacin, co-trimoxazole,
erythromycin, fluconazole, itraconazole,
ketoconazole, metronidazole, miconazole,
ofloxacin and sulphonamides (including cotrimoxazole) increase anticoagulant effect by
mechanisms that include interference with

warfarin or vitamin K metabolism. Rifampicin
and griseofulvin accelerate warfarin metabolism
(enzyme induction) and reduce its effect.
Intensive broad-spectrum antimicrobials, e.g.
eradication regimens for Helicobacter pylori (see
p. 630), may increase sensitivity to warfarin by
reducing the intestinal flora that produce
vitamin K.
• Anticonvulsants. Carbamazepine, phenobarbital
and primidone accelerate warfarin metabolism
(enzyme induction); the effect of phenytoin is
variable. Clonazepam and sodium valproate are
safe.
• Cardiac antiarrhythmics. Amiodarone,
propafenone and possibly quinidine potentiate
the effect of warfarin and dose adjustment is
required, but atropine, disopyramide and
lignocaine do not interfere.
• Antidepressants. Serotonin reuptake inhibitors
may enhance the effect of warfarin but tricyclics
may be used.
• Gastrointestinal drugs. Avoid cimetidine and
omeprazole which inhibit the clearance of R
warfarin, and sucralfate which may impair its
absorption. Ranitidine may be used but INR
should be checked if the dose is high. Most
antacids are safe.
• Lipid-lowering drugs. Fibrates, and some statins,
enhance anticoagulant effect. Colestyramine is
best avoided for it may impair the absorption of

both warfarin and vitamin K.
• Sex hormones and hormone antagonists. Oestrogens
increase the synthesis of some vitamin K
dependent clotting factors and progestogen-only
contraceptives are preferred. The hormone
antagonists danazol, flutamide and tamoxifen
enhance the effect of warfarin.
• Sedatives and anxiolytics. Benzodiazepines may
be used.
Other vitamin K antagonists. Acenocoumarol
(nicoumalone) is similar to warfarin but seldom


COAGULATION SYSTEM

used; it is eliminated in the urine mainly in unchanged form (t l / 2 24 h). Indandione anticoagulants
are practically obsolete because of allergic adverse
reactions unrelated to coagulation; phenindione (tl/2
5 h) is still available but also seldom used.

Direct-acting anticoagulants: heparin
Heparin was discovered by a medical student, J.
McLean, working at Johns Hopkins Medical School
in 1916. Seeking to devote one year to physiological
research he was set to study 'the thromboplastic
(clotting) substance in the body'. He found that
extracts of brain, heart and liver accelerated clotting
but that activity deteriorated during storage. To his
surprise, the extract of liver which he had kept
longest not only failed to accelerate but actually

retarded clotting. His personal account proceeds:
After more tests and the preparation of other
batches of heparophosphatide, I went one morning
to the door of Dr. Howell's office, and standing
there (he was seated at his desk), I said 'Dr.
Howell, I have discovered antithrombin'. He was
most skeptical. So I had the Deiner, John
Schweinhant, bleed a cat. Into a small beaker full of
its blood, I stirred all of a proven batch of
heparophosphatides, and I placed this on Dr.
Howell's laboratory table and asked him to call me
when it clotted. It never did clot. [It was heparin.]8
Heparin is a sulphated mucopolysaccharide
which occurs in the secretory granules of mast cells
and is prepared commercially from a variety of
animal tissues (generally porcine intestinal mucosa
or bovine lung) to give preparations that vary in
molecular weight from 3000 to 30000 (average
15 000). It is the strongest organic acid in the body
and in solution carries an electronegative charge.
The low molecular weight (LMW) heparins (mean
MW 4000-6500) are prepared from standard heparin
by a variety of chemical techniques and commercial
preparations (dalteparin, enoxaprin, tinzaparin)
contain different fractions and display different
pharmacokinetics.
Mode of action. Heparin depends for its anticoagulant action on the presence in plasma of a
single chain glycoprotein, antithrombin (formerly
antithrombin III), a naturally-occurring inhibitor of

28

activated coagulation factors of the intrinsic and
common pathways including thrombin, factor Xa
and factor IXa (Fig. 28.1). Antithrombin is
homologous to members of the a-antitrypsin
family of serine protease inhibitors (serpins). On
intravenous administration heparin binds to
antithrombin and this leads to rapid inhibition of
the proteases of the coagulation pathway. In the
presence of heparin antithrombin becomes vastly
more active (approximately 1000-fold) and
inhibition is essentially instantaneous. Heparin
binding to antithrombin induces a conformational
change in antithrombin that locks the heparin in
place and is followed by rapid reaction with a target
protease. This reaction in turn reduces the affinity
of antithrombin for heparin, allowing the heparin to
dissociate from the antithrombin/protease complex
and to catalyse further antithrombin/protease
interactions.
The importance of inhibition of factor Xa is that
this factor is a critical step in both the intrinsic and
extrinsic coagulation systems and heparin is effective
in small quantities. This provides the rationale for
giving low dose subcutaneous heparin to prevent
thrombus formation. At a molecular level the capacity
of heparin to inhibit factor Xa has been found to
depend on a specific pentasaccharide sequence
which can be isolated in fragments of average MW

5000 (LMW heparins). LMW heparins inhibit factor
Xa at a dose similar to standard heparin but have
much less antithrombin activity. These fragments
are too short to inhibit thrombin which is the
principal action of conventional heparin (average
MW 15 000). Fibrin formed in the circulation binds
to thrombin and protects it from inactivation by the
heparin-antithrombin complex, which may provide
a further explanation for the higher doses of
heparin needed to stop extension of a thrombus
than to prevent its formation. Heparin also inhibits
thrombin through other inhibitors and, at higher
concentrations, accelerates plasminogen activation
and inhibits platelet aggregation.
Apart from its anticoagulant properties, heparin
inhibits the proliferation of vascular smooth muscle
cells and is involved in angiogenesis. Heparin also
8

McLean gives a fascinating account of his struggles to pay
his way through medical school, as well as his discovery of
heparin in: McLean J 1959 Circulation XIX: 75.
573


28

DRUGS AND

HAEMOSTASIS

inhibits certain aspects of the inflammatory response;
this is evident in the rapid resolution of inflammation that accompanies deep vein thrombosis
when heparin is given.
Pharmacokinetics. Heparin is poorly absorbed
from the gastrointestinal tract and is given i.v. or
s.c.; once in the blood its effect is immediate.
Heparin binds to several plasma proteins and to
sites on endothelial cells; it is also taken up by cells
of the reticuloendothelial system and some is
cleared by the kidney. Due to these factors,
elimination of heparin from the plasma appears to
involve a combination of zero-order and first-order
processes, the effect of which is that the plasma
biological effect tl/2 alters disproportionately with
dose, being 60 min after 75 units per kg and 150 min
after 400 units per kg.
LMW heparins are less protein bound and have
a predictable dose-response profile when administered s.c. or i.v. They also have a longer tl/2 than
standard heparin preparations.
Monitoring heparin therapy. Control of standard
heparin therapy is by the activated partial thromboplastin time (APTT), the optimum therapeutic
range being 1.5-2.5 times the control (which is
preferably the patient's own pretreatment APTT).
An alternative method is to measure the plasma
concentration of heparin using an anti-Xa assay
aiming for a therapeutic concentration of 0.1-1.0
U/ml. Therapeutic doses of LMW heparin do not
prolong the APTT and, having predictable pharmacokinetics, they can be administered using a bodyweight adjusted algorithm without laboratory
monitoring. If necessary an anti-Xa assay can be

used to measure the heparin level.
Dose Treatment of established thrombosis. The
traditional intravenous regimen of standard unfractionated heparin is a bolus i.v. injection of 5000
units (or 10 000 units in severe pulmonary embolism)
followed by a constant rate i.v. infusion of 1000-2000
units per hour. Alternatively 15 000 units may be
given s.c. every 12 h but control is less even. The
APTT should be measured 6 h after starting therapy
and the administration rate adjusted to keep it in
the optimum therapeutic ratio of 1.5-2.5; this usually
requires daily measurements of APTT preferably
574

between 0900 h and 1200 h (noon) as the anticoagulant effect of heparin exhibits circadian
changes.
The convenience (and cost-effectiveness) of LMW
heparin therapy has resulted in widespread changes
in practice. Patients with acute venous thromboembolism can be treated safely and effectively with
LMW heparin as outpatients. Large-scale studies
have demonstrated that outpatient treatment of
acute deep vein thrombosis (DVT) with unmonitored
body-weight adjusted LMW heparin is as safe and
effective as inpatient treatment with adjusted dose
intravenous standard heparin.9, 10, 11 Further trials
have confirmed the safety and efficacy of LMW
heparin therapy in acute pulmonary embolism12
and that 80% of unselected patients with acute
thromboembolism can be safely treated as
outpatients.13
Prevention of thrombosis. Postoperatively or after

myocardial infarction 5000 units of unfractionated
heparin should be given s.c. every 8 or 12 h without
monitoring (this dose does not prolong the APPT),
or in pregnancy 5000-10 000 units s.c. every 12 h
with monitoring (except for pregnant women with
prosthetic heart valves for whom specialist monitoring is needed).
LMW heparins have become the preferred drugs
for perioperative prophylaxis because of their convenience. They are as effective and safe as unfractionated heparin at preventing venous thrombosis
(see above). Once-daily s.c. administration suffices,
as their duration of action is longer than that of
conventional heparin and no laboratory monitoring
is required. LMW heparins are at least as effective
as standard heparin for unstable angina, in
combination with aspirin.
Adverse effects Bleeding is the principal acute
complication of heparin therapy. It is uncommon,
9

Levine M et al 1996 New England Journal of Medicine 334:
677-681.
10
Koopman M M W et al 1996 New England Journal of
Medicine 334: 682-687.
11
The Columbus Investigators 1997 New England Journal of
Medicine 337: 657-662.
12
Simonneau G et al 1997 New England Journal of Medicine
337: 663-669.
13

Lindmarker P, Holmstrom M 1996 Journal of Internal
Medicine 240: 395-401.


COAGULATION SYSTEM

but patients with impaired hepatic or renal function,
with carcinoma, and those over 60 years appear to
be most at risk. An APPT ratio > 3 is associated with
an 8-fold increased chance of bleeding.
Heparin-induced thrombocytopenia (HIT), characterised by arterial thromboemboli and haemorrhage,
occurs in about 2-3% of patients who receive standard
heparin for a week or more (less in patients on
LMW heparins). It is due to an autoantibody
directed against heparin in association with platelet
factor 4, causing platelet activation, and occurs
most commonly with heparin derived from bovine
lung. HIT should be suspected in any patient in
whom the platelet count falls by 50% or more after
starting heparin, and usually occurs 5 or more days
after starting therapy (or sooner if the patient has
previously been exposed to heparin). Up to 30% of
patients may require amputation or may die.
In patients with HIT and evidence of thrombosis,
danaparoid sodium, hirudin or argatroban (see p.
577) should be substituted. Warfarin should not be
started until adequate anticoagulation has been
achieved with one of these agents and the platelet
count has returned to normal as skin necrosis or
worsening thromboembolism may result. LMW

heparins are unsuitable as the antibody may be
cross-reactive.
Osteoporosis may occur, it is dose-related and
may be expected with 15 000-30 000 units/day for
about 6 months. It is most frequently seen in
pregnancy. The relative risk with LMW heparin is
not yet established.
Hypersensitivity reactions and skin necrosis
(similar to that seen with warfarin) occur but are
rare. Transient alopecia has been ascribed to heparin
but in fact may be due to the severity of the
thromboembolic disease for which the drug was
given.
Heparin antagonism. Heparin effects wear off so
rapidly that an antagonist is seldom required except
after extracorporeal perfusion for heart surgery.
Protamine, a protein obtained from fish sperm,
reverses the anticoagulant action of heparin, when
antagonism is needed. It is as strongly basic as
heparin is acidic, which explains its immediate
action. Protamine sulphate, 1 mg by slow i.v. injection,
neutralises about 100 units of heparin derived from
mucosa (mucous) or 80 units of heparin from lung;

28

but if the heparin was given more than 15 min
previously, the dose must be scaled down. Protamine
itself has some anticoagulant effect and overdosage
must be avoided. The maximum dose must not

exceed 50 mg. Its effectiveness in patients treated
with LMW heparins is unknown.
Heparinoids. Danaparinoid sodium is a mixture of
several types of non-heparin glycosaminoglycans
extracted from pig intestinal mucosa (84% heparan
sulphate). It is an effective anticoagulant for the
treatment of deep vein thrombosis (DVT) prophylaxis
in high-risk patients and treatment of patients with
heparin-associated thrombocytopenia.

USES OF ANTICOAGULANTS
Venous disease
Established venous thromboembolism. An anticoagulant is used to prevent extension of an
existing thrombus while its size is reduced by
natural thrombolytic activity. Effective anticoagulation
prevents formation of fresh thrombus, which is
more likely to detach and embolise, particularly if it
is in large proximal veins; it also helps to recanalise
veins and to clear vein valves of thrombus and
should thus prevent long-term consequences such
as swelling of the leg and stasis ulceration. The site
and extent of thrombosis should be established by
venous ultrasound. The majority of patients with
proximal vein thrombosis or calf vein thrombosis
can be treated with outpatient low molecular
weight heparin, weight-adjusted and administered
once or twice daily according to manufacturer's
recommendations. It should be continued for a total
of 4-7 days and until the signs of thrombosis (heat,
swelling of the limb) have settled. Warfarin should

be started at the same time as the heparin. Patients
with a symptomatic pulmonary embolism should
be treated in hospital with LMW heparin or highdose intravenous unfractionated heparin (above).
In patients with an uncomplicated DVT following
a precipitating event (e.g. orthopaedic surgery),
warfarin may be necessary for only 6 weeks if the
patient has returned to normal mobility and the
precipitating factor(s) have been eliminated. The
patient should wear a well-fitting compression
575


28

DRUGS AND

HAEMOSTASIS

stocking to increase flow in deep veins, should
exercise the leg and should be encouraged to
mobilise as soon as the discomfort has settled. The
risk of recurrence reduces with passage of time after
the initial event. In cases of DVT uncomplicated by
pulmonary embolus, 3 months of anticoagulant
therapy appears adequate. Where there is evidence
of pulmonary embolus it is common practice to
continue therapy for 6 to 12 months.
Thrombolytic therapy with streptokinase or
urokinase i.v. may be used for life-threatening
thrombosis, e.g. major pulmonary embolism with

compromised haemodynamics (see p. 580).
Anticoagulant therapy may be life-saving in
thromboembolic pulmonary hypertension.

Long-term anticoagulation with warfarin to prevent
arterial thromboembolism should be considered for
any patient who has a large left atrium or a low
cardiac output or paroxysmal or established atrial
fibrillation (with or without cardiac valvular disease).
Where warfarin is considered unsuitable, aspirin
may be substituted, for it prevents stroke in patients
with atrial fibrillation, though less effectively. The
combination of warfarin and aspirin, once regarded
as contraindicated, may yet be most effective in
patients at high risk of embolism. Heparin is given
for 2 h to patients after undergoing angioplasty.
Heparin, aspirin or both are used to prevent
myocardial infarction in the acute phase of unstable
angina.

Prevention of venous thrombosis. Oral anticoagulant reduces the risk of thromboembolism in
conditions in which there is special hazard, e.g.
after surgery. Partly because of the danger of bleeding
and partly because of the effort of maintaining
control, oral anticoagulants have not been widely
adopted. Numerous trials, however, have shown
the protective effect of low doses of unfractionated
heparin (5000 units every 8-12 h s.c.) and more
recently LMW heparin (dose adjusted for bodyweight and/or risk) against deep leg vein thrombosis.
The significant fact is that it takes a lot less heparin

to prevent thrombosis than it does to treat
established thrombosis, because heparin acts in low
concentration at an early stage in the cascade of
coagulation factors which leads to fibrin formation
(see above).
Low-dose unfractionated heparin or LMW heparin
can be used to prevent venous thromboembolism in
other high-risk patients, e.g. those confined to bed
and immobilised with strokes, cardiac failure or
malignant disease. Spontaneous bleeding has not
been a problem with this form of anticoagulant
treatment.
Low MW dextrans (see later).

Peripheral arterial occlusion. Heparin may prevent
extension of a thrombus and hasten its recanalisation;
it is commonly used in the acute phase following
thrombosis or embolism. There is no case for treating
ischaemic peripheral vascular disease with an oral
anticoagulant (for prevention, see Antiplatelet drugs).

Cardiovascular disease
Acute myocardial infarction. Anticoagulation with
heparin is used to reduce the risk of venous
thromboembolism, and the risk and size of emboli
from mural thrombi following acute myocardial
infarction.
576

Long-term anticoagulant prophylaxis

The decision to use warfarin long-term must take
into account nondrug factors. The patient should be
told of the risks of haemorrhage, including those
introduced by taking other drugs, and of the signs
of bleeding into the alimentary or urinary tracts. All
patients should carry a card stating that they are
receiving an oral anticoagulant. Such therapy should
be withheld from a patient who is considered to be
unlikely or unable to comply with the requirements
of regular medication and blood testing. The
incidence of haemorrhagic complications is directly
related to the level of anticoagulation; safety and
good results can be obtained only by close attention
to detail. The INR should be monitored at a
maximum interval of 8 weeks in patients on a stable
maintenance dose and more frequently in patients
with an unstable INR.

Surgery in patients receiving
anticoagulant therapy
For elective surgery warfarin may be withdrawn
about 5 days before the operation and resumed
about 3 days later if conditions seem appropriate;
heparin may be used in the intervening period. In


COAGULATION SYSTEM

patients with mechanical prosthetic valves, heparin
is substituted at full dosage 4 days before surgery,

and restarted 12-24 h after the operation. Warfarin
is restarted when the patient resumes oral intake.
Emergency surgery: proceed as for bleeding (p. 571).
For dental extractions: omission of warfarin for 1-2
days to adjust the INR to the lower limit of the
therapeutic range is adequate (INR should be tested
just prior to the procedure). The usual dose of
warfarin can be resumed the day after extraction.
Aspirin, taken prophylactically for thromboembolic disorders (see below), is commonly discontinued
2 weeks before elective procedures and restarted
when oral intake permits.

Contraindications to anticoagulant
therapy
Contraindications relate mostly to conditions in
which there is a tendency to bleed, and are relative
rather than absolute, the dangers being balanced
against the possible benefits. They include:
• Behavioural: inability or unwillingness to
cooperate, dependency on alcohol
• Neurological: stroke within 3 weeks, or surgery to
the brain or eye
• Alimentary: active peptic ulcer, active
inflammatory bowel disease, oesophageal
varices, uncompensated hepatic cirrhosis
• Cardiovascular: severe uncontrolled hypertension
• Renal: if function is severely impaired
• Pregnancy: in early pregnancy the fetal warfarin
syndrome is a hazard and bleeding may cause
fetal death in late pregnancy

• Haematological: pre-existing bleeding disorder.

Emerging anticoagulant drugs
Recent strategies have sought to develop substances
that act at different sites in the coagulation cascade
and agents that inhibit thrombin, or prevent thrombin
generation, or block initiation of the coagulation
process or enhance endogenous anticoagulation
have reached the clinical arena.
Novel delivery systems, using synthetic amino
acids (e.g. SNAC) to facilitate absorption, allow the
oral administration of unfractionated or LMW
heparins sufficient to prolong the APTT. These are
being evaluated.

28

Direct inhibitors of thrombin inactivate fibrinbound thrombin which may promote thrombus
extension (as opposed to heparin which acts
indirectly through antithrombin) as follows:
Hirudin, a polypeptide originally isolated from
the salivary glands of the medicinal leech Hirudo
medicalis, is now produced by recombinant technology. It is a potent and specific inhibitor of thrombin
with which it forms an almost irreversible complex.
It is cleared predominantly by the kidneys and has
a t l / 2 of 40 minutes after i.v. administration. No
antidote is available for a bleeding patient. It has
been used successfully in patients with heparininduced thrombocytopenia (HIT), thromboprophylaxis in elective hip arthroplasty, unstable
angina and myocardial infarction.
Bivalirudin is a semisynthetic bivalent thrombin

inhibitor which contains an analogue of the Cterminal of hirudin; this binds to thrombin but having
a lower affinity, produces only transient inhibition
and hence may be safer. It has been used in patients
undergoing coronary angioplasty.
Argatroban, a carboxylic acid derivative, binds
noncovalently to the active site of thrombin and is an
effective alternative to heparin in patients with HIT.
Other highly selective agents in clinical development include blockers of:
factor IXa, an essential factor for amplification of
the coagulation cascade (by active-site-blocked
factor IXa or monoclonal antibodies against the
factor),
the factor Vila/tissue factor pathway, the initiating
step of coagulation [with recombinant tissue factor
pathway inhibitor (TFPI) the analogue of the natural
inhibitor], and
factor X or factor Xa and inhibition of factor VIIa
within the factor Vila/tissue factor complex (by
NAPc2, a recombinant nematode anticoagulant
peptide).

Fibrinolytic
(thrombolytic) system
The preservation of an intact vascular system requires
not only that blood be capable of coagulating but
577


28

DRUGS AND

HAEMOSTASIS

also that there should be a mechanism for removing
the products of coagulation when they have served
their purpose of stopping a vascular leak. This is
the function of the fibrinolytic system, the essential
features of which are shown in Figure 28.2.
The system depends on the formation of the
fibrinolytic enzyme plasmin from its precursor protein,
plasminogen, in the blood. During the coagulation
process, plasminogen binds to specific sites on
fibrin. Simultaneously the natural activators of
plasminogen, i.e. tissue plasminogen activator (tPA) and
urokinase, are released from endothelial and other
tissue cells and act on plasminogen to form plasmin.
The result is that plasmin formation only takes place
locally on the fibrin surface but not generally within
the circulation where widespread defibrination
would occur and the whole coagulation mechanism
would be compromised. Since fibrin is the framework
of the thrombus, its dissolution clears the clot away.
Fibrinolytics (thrombolytics) can remove established thrombi and emboli. Inhibitors of the
fibrinolytic system (antifibrinolytics) can be of value
in certain haemorrhagic states notably those
characterised by excessive fibrinolysis.

DRUGSTHAT PROMOTE FIBRINOLYSIS
An important application of fibrinolytic drugs has

been to dissolve thrombi in acutely occluded
coronary arteries, thereby to restore blood supply to
ischaemic myocardium, to limit necrosis and to
improve prognosis. The approach is to give a
plasminogen activator intravenously by infusion or
by bolus injection in order to increase the formation
of the fibrinolytic enzyme plasmin. Those currently
available include:
Streptokinase is a protein derived from (3-haemolytic
streptococci: it forms a complex with plasminogen
(bound loosely to fibrin) where it converts plasminogen to plasmin. Too rapid administration
causes abrupt fall in blood pressure. The t l / 2 is
20 min.
Anistreplase (anisoylated plasminogen Streptokinase
activator complex, APSAC), is the plasminogenstreptokinase complex (above) in which the enzyme
centre that converts plasminogen to plasmin is
protected from deactivation, so prolonging its action.
578

Fig. 28.2 Blood fibrinolytic system

The tl/2 is 70 min. It is not available in some
countries.
Urokinase made from human fetal kidney cells in
tissue culture, is a direct activator of plasminogen.
The tl/2 is 15 min.
Streptokinase, anistreplase and urokinase are not
well absorbed by fibrin thrombi and are called nonfibrin-selective. They convert plasminogen to plasmin
in the circulation, which depletes plasma fibrinogen
and induces a general hypocoagulant state. This

does not reduce their local thrombolytic potential
but increases the risk of bleeding.
Recombinant prourokinase, as the name suggests,
is produced by recombinant DNA technology; on
binding to fibrin it converts to urokinase. The tl/2 is
7 min.
Alteplase (rt-PA) (tl/2 5 min) is tissue type
plasminogen activator produced by recombinant


F I BRI N O L Y T I C ( T H R O M B O LY T I C ) S Y S T E M

DNA technology. Reteplase (tl/2 15 min) is another
recombinant human protein.
Recombinant prourokinase and alteplase are
termed fibrin-selective, for they bind strongly to
fibrin, and are capable of dissolving aging or lysisresistant thrombi better than nonfibrin-selective
agents. These drugs are less likely to produce a
coagulation disturbance in the plasma, i.e. they are
selective for thrombi.

USES OFTHROMBOLYTIC DRUGS
Coronary artery thrombolysis
(See also Ch. 23)
Timing of administration. The earlier thrombolysis
is given the better the outcome. Treatment commencing within the first 3 h of onset is a realistic
aim but thrombolysis up to 12 h is still worthwhile.
Benefit is most striking in patients with anterior
myocardial infarction treated within 4 h of onset.
Anistreplase can be given i.v. over 4-5 min (and

so more easily out of hospital); its effect persists for
6-9 h. Other agents are normally infused i.v. over
1-3 h with most of the dose being given early in that
period. Retelpase is given as a double bolus 30 min
apart.
Reduction in mortality (see also Myocardial infarction,
p. 485). There is now compelling evidence that
streptokinase, anistreplase, alteplase and retelpase
reduce mortality with an acceptable frequency of
adverse effects.14 Comparisons between these drugs
show no apparent survival advantage of one over
the others in respect of survival.15,16 Both streptokinase
and t-PA decrease mortality by about 25% when
used alone but by 40-50% when either agent is used
with aspirin17 which reduces the incidence of reinfarction. Those under 75 years appeared to gain
most from thrombus dispersal but 'physiological'
age is more important than chronological age.
Stroke may complicate myocardial infarction
and is considered usually to be embolic, for its
incidence correlates with the extent of myocardial
infarction. Evidence18 indicates that the combination
of thrombolysis plus aspirin lowers the overall risk
of stroke, possibly by limiting the size of the infarct,

28

or by reducing thromboembolic episodes, or by
both.
Thrombolysis may also be valuable in persistent
unstable angina and especially where arteriography

demonstrates substantial thrombus in coronary
arteries.
Adverse effects. Bleeding is the most important
complication and usually occurs at a vascular lesion,
e.g. the site of injection, for fibrinolytic therapy does
not distinguish between an undesired thrombus
and a useful haemostatic plug. If the contraindications
are followed, the incidence of bleeding severe
enough to require transfusion is < 1%. Nausea and
vomiting may occur.
Multiple microemboli from disintegration of preexisting thrombus anywhere in the vascular system
may endanger life; these commonly originate in an
enlarged left atrium, or a ventricular or aortic
aneurysm.
Cardiac arrhythmias result from reperfusion of
ischaemic tissue. These vary in type and are often
transient, a factor which may influence the decision
whether or not to treat.
Allergy. Streptokinase and anistreplase are antigenie and anaphylactic reactions with rash, urticaria
and hypotension may occur for most people have
circulating antibodies to streptococci. Antibodies
persist after exposure to these drugs and their reuse should be avoided between 5 days and 12
months as the recommended dose may not overcome
immune resistance to plasminogen activation.
Contraindications to thrombolytic drug use (see
Myocardial infarction, p. 485).

Noncoronary thrombolysis
Pulmonary embolism. Thrombolysis is superior to
heparin at relieving obstructed veins demonstrated

radiologically. While a reduction in mortality is thus
implied, the numbers of cases reported in clinical
trials of thrombolytics have been insufficient to
14

Carins J A et al 1992 Chest 102 (Suppl): 482S-507S.
The International Study Group 1990 Lancet 336: 71-75.
16
ISIS-3 Collaborative Group 1992 Lancet 339: 753-770.
17
Carins J A et al 1998 Chest 114: 634S-657S
18
ISIS-2 Collaborative Group 1988 Lancet 2: 349-360.
15

579


28

DRUGS AND

HAEMOSTASIS

provide conclusive statistical proof. There is,
nevertheless, a strong impression that thrombolysis
is beneficial where pulmonary embolism is accompanied by signs of haemodynamic decompensation (raised jugular venous pressure, pulse
rate > 100 beats/min, systolic pressure < 100 mmHg,
arterial oxygen desaturation). Alteplase 100 mg may
be infused over 2 h, followed by an i.v. infusion of

heparin.
Deep vein thrombosis. Thrombolysis may be
justified where the affected vessels are proximal
and the risk of pulmonary embolism is high.
Complete lysis may be achieved in 50% of cases
treated within 7 days of onset.
Arterial occlusion Systemic or local thrombolysis
may be considered for arterial occlusions distal to
the popliteal artery (thrombectomy being the usual
therapeutic approach for occlusion of < 24 h duration
proximal to this site). Intravenous streptokinase
will lyse 80% of occlusions if infusion begins within
12 h, and 60% if it is delayed for up to 3 days.
Ischaemic stroke. There is little evidence of benefit
and most trials have shown increased short-term
mortality in patients treated with thrombolysis.
Thrombolysis may also be considered for ocular
thrombosis (urokinase) and for thrombosed arteriovenous shunts (streptokinase).

DRUGSTHAT PREVENT FIBRINOLYSIS
Antifibrinolytics are useful in a number of bleeding
disorders.
Tranexamic acid competitively inhibits the binding
of plasminogen and t-PA to fibrin and effectively
blocks conversion of plasminogen to plasmin
(which causes dissolution of fibrin); fibrinolysis is
thus retarded. After an i.v. bolus injection it is
excreted largely unchanged in the urine; the tl/2 is
1.5 h. It may also be administered orally or topically.
The principal indication for tranexamic acid is to

prevent the hyperplasminaemic bleeding state that
results from damage to certain tissues rich in
plasminogen activator, e.g. after prostatic surgery,
tonsillectomy, uterine cervical conisation, and
580

menorrhagia, whether primary or induced by an
intrauterine contraceptive device. Tranexamic acid
may also reduce bleeding after ocular trauma and
in haemophiliacs after dental extraction where it is
normally used in combination with desmopressin.
The drug benefits some patients with hereditary
angioedema presumably by preventing the plasmininduced uncontrolled activation of the complement
system which characterises that condition. Tranexamic acid may be of value in thrombocytopenia
(idiopathic or following cytotoxic chemotherapy) to
reduce the risk of haemorrhage by inhibiting
natural fibrinolytic destabilisation of small platelet
plugs; the requirement for platelet transfusion is
thereby reduced. It may also be used for overdose
with thrombolytic agents.
Adverse effects are rare but include nausea,
diarrhoea and sometimes orthostatic hypotension.
It is contraindicated in patients with haematuria as
it will prevent clot lysis in the urinary tract and
result in 'clot colic'.
Aprotinin is a naturally-occurring inhibitor of
plasmin and other proteolytic enzymes which has
been used to limit bleeding following open heart
surgery with extracorporeal circulation, and for the
treatment of life-threatening haemorrhage due to

hyperplasminaemia complicating surgery of malignant tumours or thrombolytic therapy or in Jehovah's
witnesses.19 It must be administered intravenously
or topically.

Platelets
Platelets support haemostasis in three ways: first by
sticking to exposed collagen to form a physical barrier
at the site of vessel injury; second by accelerating
the activation of coagulation proteins and finally by
release of storage granule contents promotes
vasoconstriction and wound healing.

SOME PHYSIOLOGY
Circulating 'resting' platelets do not stick to healthy
endothelium or each other but if a vessel wall is
19

A religious sect that is opposed to blood transfusion on a
scriptural basis.


PLATE LETS

breached they react at the site by four steps:
attachment, spreading, secretion and aggregation.
1. Exposure of constituents of the subendothelial
matrix most notably collagen initiates platelet
attachment which is stabilised by von
Willebrand factor.
2. Shape change of the attached platelets,

spreading along the fibrils permits multiple
tight contacts with the matrix and there is
simultaneous release of thromboxane-A2 (TXA2)
and adenosine diphosphate (ADP) which recruit
additional platelets.
3. Agonists in the microenvironment also trigger
secretion of the contents of intracellular storage
granules which activate circulating platelets and
vasoconstriction (including proteins, enzymes,
enzyme inhibitors, vasoactive and other
peptides and agents that participate in the
coagulation process) and translocation of
negatively charged phospholipids to the outer
surface of the plasma membrane providing a
binding site for coagulation proteins (an activity
known as 'platelet factor 3').
4. These platelets interact with each other and
aggregate through binding of fibrinogen or
fibrin to the surface through glycoprotein (GP)
Ilb/IIIa (integrin aIIb B3) to form an effective plug
to seal the injured vessel which is stabilised by
cross linked fibrin

28

release of active substances (see above), and low
concentrations of cyclic AMP have the opposite
effect.
2. The quantity of cyclic AMP within platelets is
under enzymatic control, for it is formed by the

action of adenylate cyclase and degraded by
phosphodiesterase.
3. Platelet adenylate cyclase formation in turn is
stimulated by prostacyclin (from the endothelium,
also called PGI2) and inhibited by thromboxaneA2 (from within platelets, also called TXA2).
Hence the action of thromboxane-A2 lowers cyclic
AMP concentration and promotes platelet
adhesion; prostacyclin raises cyclic AMP
concentration and prevents platelet adhesion.
4. Prostacyclin and thromboxane-A2 are derived
from arachidonic acid which is a constituent of
cell walls, both platelet and endothelial. Cyclooxygenase (COX, PGH synthase), an enzyme
present in cells at both sites, converts
arachidonic acid to cyclic endoperoxides which
are further metabolised by prostacyclin synthase
to prostacyclin in the endothelium and by
thromboxane synthase to thromboxane-A2 in
platelets. Thus prostacyclin is principally

The system that enables platelets to distinguish
between healthy and damaged endothelium is shown
in simplified form in Figure 28.3. It is a continuation
of, and should be studied in conjunction with, the
general diagram for eicosanoids on page 281.

Platelet mechanisms
The mechanism which transforms a freely circulating
resting platelet (surrounded by fibrinogen and
buffeted in the circulation) into an adherent platelet
has been a frequent target for drug development.

Platelet aggregation does not occur as long as the
resting conformation of GP IIb/IIIa is maintained
and several external and internal factors dampen
activation signals.
1. Cyclic AMP plays a key role. High
concentrations of intraplatelet cyclic AMP
inhibit platelet adhesion, aggregation and the

cyclic AMP
581


28

DRUGS AND

HAEMOSTASIS

formed in the endothelium whereas
thromboxane-A2 is formed mainly in platelets.
5. These differences in the prostaglandins
synthesised in endothelium and platelets are
important. Intact vascular endothelium does not
activate platelets because of the high
concentration of prostacyclin in the intima.
Subintimal tissues contain little prostacyclin and
platelets, under the influence of thromboxaneA2/ immediately adhere and aggregate at any
breach in the intima. Atheromatous plaques do
not generate prostacyclin—which explains
platelet adhesion and thrombosis at these sites.

6. Endothelial cells also produce nitric oxide which
raises cyclic GMP levels in platelets to inhibit
activation and have on their surface ectoADPase (CD39) that metabolises secreted ADP
before it can cause platelet activation.
Inhibitors or activators of platelet aggregation act
directly or indirectly by altering the rate of formation or degradation of platelet cyclic AMP. Local
concentrations of these substances determine whether
the platelet adhesion/aggregation process will occur.

DRUGSTHAT INHIBIT PLATELET
ACTIVITY (ANTIPLATELET DRUGS)
(See also Myocardial infarction Ch. 23)
Aspirin (acetylsalicylic acid) acetylates and thus
inactivates COX, the enzyme responsible for the
first step in the formation of prostaglandins, the
conversion of arachidonic acid to prostaglandin H2.
It follows from the diagram on page 281 (Fig. 15.1)
that aspirin can prevent formation of both
thromboxane-A2 (TXA2) and prostacyclin (PGI2).
Acylation of COX is irreversible and, as the platelet
is unable to synthesise new enzyme, COX activity is
irreversibly lost for its lifetime (8-10 d). Therapeutic
interest in the antithrombotic effect of aspirin has
centred on separating its actions on thromboxaneA2 and prostacyclin formation, and this can be
achieved by using a low dose. Thus 75-100 mg/d by
mouth is sufficient to abolish synthesis of
thromboxane-A2 without significant impairment of
prostacyclin formation, i.e. amounts substantially
below the 2.4 g/d used to control pain and inflammation. Low-dose aspirin is yet not without risk:
582

some 13% of episodes of peptic ulcer bleeds in people
over 60 years can be attributed to prophylactic
asprin (use in the community about 8%).20
Dipyridamole reversibly inhibits platelet phosphodiesterase (see Fig. 28.3) and in consequence
cyclic AMP concentration is increased and platelet
(thrombotic) reactivity reduced; evidence also
suggests that its antithrombotic effect may derive
from release of prostaglandin precursors by vascular
endothelium. Dipyridamole is extensively bound to
plasma proteins and has a tl/2 of 12 h.
Ticlopidine is a thienopyridine derivative that
inhibits ADP-dependent platelet aggregation. It is
converted to its active form by metabolism by the
liver and the tl/2 of the parent drug is 40 h.
Ticlopidine is more effective than aspirin in
reducing stroke in patients with transient ischaemic
attacks (TIA) but aspirin is safer and less expensive.
It is also effective in reducing the risk of the
combined outcome of stroke, myocardial infarction
(MI) or vascular death in patients with thromboembolic stroke, decreasing vascular death and MI
in patients with unstable angina, reducing acute
occlusion of coronary bypass grafts and improving
walking distance and decreasing vascular complications in patients with peripheral vascular disease.
It may be used to prevent stroke in patients who are
intolerant of aspirin. Neutropenia is the most serious
adverse effect (risk 2.4%) and is greatest in the first
12 weeks of therapy; leucocyte counts should be
checked every 2 weeks during this period. Diarrhoea
and other gastrointestinal symptoms may be induced

in a third of patients.
Clopidogrel is also a thienopyridine derivative
which is also more effective than aspirin for the
prevention of ischaemic stroke, MI or vascular
death in patients at high risk but it is not associated
with neutropenia. It is more expensive than aspirin
though safer than ticlodipine.
Epoprostenol (prostacyclin) may be given to prevent
platelet loss during renal dialysis, with or without
heparin; it is infused i.v. and s.c (tl/2 3 min). It is a
potent vasodilator.
20

Weil J et al 1995 Prophylactic aspirin and risk of peptic
ulcer bleeding. British Medical Journal 310: 827-830.


PLATE LETS

Glycoprotein (GP) IIb-IIIa antagonists. The platelet
glycoprotein Ilb-IIIa complex is the predominant
platelet integrin,21 a molecule restricted to megakaryocytes and platelets which mediates platelet
aggregation via the binding of adhesive proteins
such as fibrinogen and von Willebrand factor
(vWF). Where there is hereditary absence of the GP
Ilb-IIIa complex (Glanzmann's thrombasthenia)
platelets are incapable of aggregation by all physiological agonists. GP Ilb-IIIa antagonists have been
developed as antiplatelet agents and administered
intravenously, they inhibit the final common pathway
of platelet aggregation: binding of fibrinogen or

vWF to the GP IIb-IIIa complex. They are more
complete inhibitors than either aspirin or clopidogrel
which inhibit only the cyclo-oxygenase or ADP
pathway respectively. GP IIb-IIIa antagonists also
have an anticoagulant effect through inhibition of
prothrombin binding to the complex and inhibition
of procoagulant platelet-derived microparticle
formation. Platelet aggregation is inhibited in a
dose-dependent manner.
Abciximab is a human-murine chimeric monoclonal
antibody Fab fragment that binds to the GP IIb-IIIa
complex with high affinity and slow dissociation
rate. After i.v. administration it is cleared rapidly
from plasma (tl/2 20 min). Abciximab (0.25 mg/kg
bolus then 0.125 microgram/kg/min infusion for
12 h) produces immediate and profound inhibition
of platelet activity that lasts for 12-36 h after
termination of the infusion. This reduces the risk of
death, MI or need for urgent coronary artery bypass
grafting after percutaneous coronary angioplasty
and benefit is maintained up to 3 years. The dose
causes and maintains blockade of > 80% receptors,
causing > 80% reduction in aggregation. Patients
also receive aspirin and heparin and if a coronary
stent has been inserted, either clopidogrel or
ticlodipine. Abciximab is also effective in refractory
unstable angina prior to percutaneous coronary
intervention. It has a potential role in combination
with low dose thrombolysis in acute myocardial
infarction and as a single agent in stroke.

28

Eptifibatide is a cyclic heptapeptide based upon
the Lys-Gly-Asp sequence. Tirofiban and lamifiban
are nonpeptide mimetics. All three are competitive
inhibitors of the GPIIb-IIIa complex with lower
affinities and higher dissociation rates than abciximab
and short plasma tl/2 (2-2.5 h). Platelet aggregation
returns to normal 30 min to 4 h after discontinuation.
Eptifibatide and tirofiban are effective in acute
coronary syndromes. Lamifiban is undergoing clinical
development.
Adverse effects. Haemorrhage occurs but is less of
a problem with low doses of heparin; it remains a
particular risk in patients treated after failed
fibrinolytic therapy for acute myocardial infarction.
Platelet transfusion after cessation of abciximab is
necessary for refractory or life threatening bleeding.
After transfusion, the antibody redistributes to the
transfused platelets, reduces the mean level of
receptor blockade and improves platelet function.
Thrombocytopenia may occur from 1 hour to days
after commencing treatment in up to 1% of patients.
This necessitates platelet counts at 2-4 hours and
then daily; if severe, therapy must be stopped and,
if necessary, platelets transfused. EDTA-induced
pseudothrombocytopenia has been reported and a
low platelet count should prompt examination of a
blood film for agglutination before therapy is stopped.

Other drugs
Dazoxiben, an inhibitor of thromboxane-A2 but
not of prostacyclin synthesis, is being evaluated in
cardiovascular disease.
Dextrans, particularly of MW 70 000 (dextran 70),
alter platelet function and prolong the bleeding
time. Dextrans differ from the other antiplatelet
drugs which tend to be used for arterial thrombosis;
dextran 70 reduces the incidence of postoperative
venous thromboembolism if it is given during or
just after surgery. The dose should not exceed 10%
of the estimated blood volume. They are rarely used.
USES OF ANTIPLATELET DRUGS

21
Integrins are cell surface adhesion receptors consisting of
non-covalently associated alpha- and beta- subunits, now
redesignated integrin aIIb B3.

Antiplatelet therapy protects 'at risk' patients
against stroke, myocardial infarction or death. A
meta-analysis of 145 clinical trials of prolonged
583


28

DRUGS AND

HAEMOSTASIS

antiplatelet therapy versus control and 29 trials
between antiplatelet regimens found that the chance
of nonfatal myocardial infarction and nonfatal
stroke were reduced by one-third, and that there
was a one-sixth reduction in the risk of death from
any vascular cause.22 Expressed in another way, in
the first month after an acute myocardial infarction
(a vulnerable period) aspirin prevents death, stroke
or a further heart attack in about 4 patients for
every 100 treated. Aspirin is by far the most
commonly used antiplatelet agent. The optimum
dose is not certain but one not exceeding aspirin 325
mg is acceptable, and 75-100 mg/d may be as
effective and preferred where there is gastric
intolerance. Aspirin alone (mainly) or aspirin plus
dipyridamole greatly reduced the risk of occlusion
where vascular grafts or arterial patency was
studied systematically.23
Many patients who take aspirin for vascular
disease may also require an NSAID for, e.g. joint
disease, and it may be argued that the NSAID renders
aspirin unnecessary as both act by inhibition of
prostaglandin G/H synthase. As inhibition by
aspirin is irreversible and that by NSAIDs may not
be, continued use of aspirin in such circumstances
seems prudent, especially if NSAID use is
intermittent.

Haemostatics
Etamsylate (Dicynene) is given systemically to
reduce capillary bleeding, e.g. in menorrhagia.
Adrenaline (epinephrine) may be useful for
epistaxis, stopping haemorrhage by local vasoconstriction when applied by packing the nostril
with ribbon gauze soaked in adrenaline solution.
Fibrin glue consists of fibrinogen and thrombin
contained in two syringes, the tips of which form a
common port. The two components are thus
delivered in equal volumes to a bleeding point where
fibrinogen is converted to fibrin at a rate determined
by the concentration of thrombin. Fibrin glue can be
used to secure surgical haemostasis, e.g. on a large
raw surface, and to prevent external oozing of blood
in patients with haemophilia (see also below).
22

Antiplatelet Trialists' Collaboration 1994 British Medical
Journal 308: 81.
23
Antiplatelet Trialists' Collaboration 1994 British Medical
Journal 308:159.
584

• Myocardial infarction.Aspirin should be given
indefinitely to patients who have survived myocardial
infarction.There is as yet no case for using aspirin to
prevent myocardial infarction in those without
important risk factors for the disease.
• Transient ischaemic attacks (TIAs) or minor ischaemic

stroke.There is grave risk of progression to
completed stroke and patients should receive aspirin
indefinitely. Before starting treatment it is important
to exclude intracerebral haemorrhage (by computed
tomography) and other conditions that mimic TIAs,
e.g. cardiac arrhythmia, migraine, focal epilepsy and
hypoglycaemia.
• Unstable angina.The chance of myocardial infarction is
high and aspirin should be used with other drugs, i.e. a (3adrenoceptor antagonists nitrate, a calcium channel
blocker and possibly heparin i.v. as is judged appropriate.
• Arterial grafts, peripheral vascular disease.Aspirin
(possibly combined with dipyridamole for grafts)
should be given to prevent occlusion.These drugs may
also be used to protect against thrombotic occlusion
following percutaneous transluminal coronary
angioplasty.
• Inhibitors of ADP-dependent platelet aggregation, e.g.
ticlopidine.clopidorgrel.and glycoprotein llb-llla
antagomists, e.g. abciximab, can be expected to form
part of regimens for cardiovascular disease, as
evidence accumulates.

Sderosing agents. Chemicals may be used to
cause inflammation and thrombosis in veins so as
to induce permanent obliteration, e.g. ethanolamine
oleate injection, sodium tetradecyl sulphate (given
i.v. for varicose veins) and oily phenol injection
(given submucously for haemorrhoids). Local
reactions, tissue necrosis and embolus can occur.

Haemophilia
Management of the haemophilia A and haemophilia
B (genetic deficiencies of factor VIII or IX) is a
matter for those with special expertise but the
following points are of general interest.
• Haemorrhage can sometimes be stopped by
pressure; edges of superficial wounds should be
strapped, not stitched.
• Minor bleeding can be stopped with plasma
factor levels of 25-30% but severe bleeding
requires a level of at least 50% and surgical