Anticoagulants and the
perioperative period
Key points
Anticoagulants primarily
affect either platelet activity
or the coagulation cascade.
Each patient needs to have
their risk/benefit assessed and
an appropriate perioperative
anticoagulant regimen
instituted for them.
Warfarin remains the most
common long-term oral
anticoagulant, and its manage-
ment in the perioperative
period needs careful con-
sideration owing to its long
duration of action. Many drugs
interact with warfarin.
New anti-platelet agents are
available with various
mechanisms of action. They
often have long durations of
action and some of them
cannot be reversed by platelet
transfusion.
Axial blockade in the presence
of anticoagulation poses a risk
of spinal/epidural haematoma
and cord injury; therefore,
safe margins between
administration of these agents
and performance of the block
should be observed.
Craig Oranmore-Brown MBBCh FRCA
SpR Anaesthetics and Intensive Care
Medicine
Norfolk and
Norwich University Hospital
Norwich
NR9 3LN, UK
Richard Griffiths MD FRCA
Consultant
Department of Anaesthesia
Edith Cavell Hospital
Bretton Gate
Peterborough
PE3 9GZ, UK
E-mail: richard@wothorpe.com
(for correspondence)
156
Craig Oranmore-Brown MBBCh FRCA
Richard Griffiths MD FRCA
Increasingly, we are being requested to anaes-
thetize patients who are on some form of anti-
coagulant.1 In this article, we will review the
different classes of anticoagulants and how to
manage them in the perioperative setting. Anti-
coagulants, or drugs affecting the clotting
mechanism, may be used acutely (e.g. deep
vein thrombosis), or chronically (e.g. preven-
tion of thromboembolic complications). Gen-
erally, these agents can be classified into drugs
inhibiting the coagulation cascade and those
affecting the action of platelets.2
Drugs inhibiting the
coagulation cascade
Warfarin
Warfarin, a coumarin derivative, acts by
inhibiting vitamin K synthesis and thereby
limiting the coagulation factors that are
dependent on vitamin K for their production.
These include factors II, VII, IX, X and pro-
teins C and S. It is only available enterally
(bioavailability 100%). The loading dose
causes factor VII concentration to decrease
considerably within 24 h; however, prothrom-
bin has a longer half-life and only decreases
to 50% of normal after 3 days. Therefore,
a patient is fully anticoagulated only after
this period. A normal loading dose is 10 mg
daily for 2 days followed by 5 mg per day
titrated to effect.
Warfarin is 99% protein bound (predomi-
nantly to albumin), which means it is easily
displaced by other highly protein-bound
drugs, leading to an increased anticoagulant
effect. It is almost entirely metabolized in
the liver, which exposes it to further drug
interactions. (See Table 1 for a list of drugs
interacting with warfarin.) The anticoagulant
effects can best be measured using the pro-
thrombin time (PT), a measure of the extrinsic
coagulation pathway. This is usually docu-
mented as the International Normalized
Ratio (INR), a ratio of the patient’s PT over
the control for the normal population, with
Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 4 2006
ª The Board of Management and Trustees of the British Journal of Anaesthesia [2006].
All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
correction for the sensitivity of the thrombo-
plastin used.
Uses of warfarin
Warfarin is indicated for prevention of
intravascular thrombosis in patients with a
history of deep vein thrombosis (DVT), pul-
monary embolus, prosthetic heart valves or
patients with chronic atrial fibrillation. The
recommendations by the British Society for
Haematology suggest INR 2.0–2.5 for DVT
prophylaxis; INR 2.5–3.0 for patients with a
history of pulmonary embolus, atrial fibrilla-
tion, for cardioversion, dilated cardiomyopa-
thy, mural thrombus and rheumatic mitral
valve disease; INR 3.5 for recurrent deep
vein thrombosis and pulmonary embolism
(in patients currently receiving warfarin),
and patients with mechanical heart valves.
Perioperative management of patients
on long-term warfarin
Minor/dental surgery: Reduce INR to <2.5 on
the day of surgery by reducing the dose and
monitoring the INR. Recommence standard
treatment dose the following day.
Major surgery: Stop warfarin 3 days pre-
operatively and monitor the INR in patients at
high risk (e.g. prosthetic valves or high risk
of DVT), and then start heparin infusion
once the INR is <3.0, stopping heparin 4 h
preoperatively. Restart warfarin as soon as
the risk of surgical haemorrhage is passed,
using either low molecular weight heparins
(LMWH) or i.v. heparin until the INR is in
the therapeutic range.
Warfarin during pregnancy
Warfarin is teratogenic in the first trimester,
causing mental retardation, short stature and
multiple facial abnormalities. Its use in the
second trimester is associated with foetal
blindness, microcephaly and mental retarda-
tion. There is an increased incidence of
spontaneous abortion, foetal and maternal
haemorrhage and stillbirth in women receiving
warfarin during pregnancy. Unfortunately,
heparin has also been associated with an
doi:10.1093/bjaceaccp/mkl028
 Anticoagulants and the perioperative period

Table 1 Drug interactions with warfarin drugs, they have almost completely replaced standard heparins
Increased anticoagulant effect Inhibition of anticoagulant effect in the management of DVT and pulmonary embolus.
Decreased vitamin K absorption Hepatic microsomal augmentation
 Laxatives  Phenobarbital Fondaparinux
 Cholestyramine  Phenytoin Fondaparinux is a new thromboprophylactic drug that has been
 Broad-spectrum antibiotics  Carbamazepine
 Rifampicin
recently licensed in the United Kingdom. It is a synthetic pen-
Enhanced synthesis of clotting factors tasaccharide and achieves an antithrombotic effect via factor
Decreased protein binding  Oral contraceptives Xa inhibition. The plasma half-life is 21 h in adults, and it is
 Sulphonamides
 NSAIDs
licensed for thromboprophylaxis in major joint-replacement
 Gliclazide, tolbutamide surgery. It is administered postoperatively but there is very
 Amiodarone limited clinical experience of the drug.
Hepatic microsomal inhibition
 Cimetidine
 Allopurinol Ximelagatran
 Tricyclic antidepressants Ximelagatran is a new, oral, directly acting thrombin inhibitor
 Metronidazole
 Sulphonamides
that has been shown to be more effective than placebo in
 Alcoholic binges prevention of thromboembolism with little increase in risk of
Alteration of hepatic receptor sites for warfarin haemorrhage. However, trials comparing it with other available
 Thyroxine
 Quinidine
anticoagulants are still under way. It is not in current clinical
practice in the United Kingdom but may be a useful adjunct
in the future.4

increased incidence of spontaneous abortion, stillbirths and Danaparoid

haemorrhage. The most common practice was to use heparin
during the first and third trimester and warfarin during the
second trimester, but recent trends have been toward using
heparin throughout. The use of LMW heparins has been
under investigation recently with encouraging results.
Unfractionated heparin
Unfractionated heparin is a mucopolysaccharide with an average
molecular weight of 15 000–18 000 Da. It acts by binding
reversibly to antithrombin III (AT III), accelerating its action
on coagulation factors XII, XI, X, IX, plasmin and thrombin.
It inhibits platelet activation by fibrin. I.V. heparin is usually
given as a bolus of 100 u kg 1 followed by approximately
1000 u h 1 titrated to achieve an activated partial thromboplastin
time of 1.5–2.5 · control. The effect of heparin can be reversed
using protamine, but stopping an infusion is usually adequate
to reduce the action of the drug as the half-life of heparin is
less than 1 h. Two important side-effects of heparin are heparin-
induced thrombocytopenia (3% of patients) and osteoporosis,
which usually occurs after long-term therapy.3
Low molecular weight heparins
LMWH have an average molecular weight of 2000–10 000 Da.
They have a greater ability to inhibit factor Xa than thrombin.
They interact less with platelets and therefore have a lower ten-
dency to cause bleeding. They have a longer half-life and there-
fore can be given as a daily maintenance dose for prophylaxis.
Monitoring of activated partial thromboplastin time (APTT) is
not required; however, in cases of suspected overdose, direct
factor Xa assays can be measured. Owing to a significantly
lower incidence of haemorrhagic complications with these
Danaparoid is a low molecular weight heparinoid, consisting of
a mixture of heparin sulphate (83%), dermatan sulphate and
chondroitin sulphate. Its anticoagulant effect is mediated by
inhibition of thrombin via a combination of antithrombin
(heparin cofactor I) and heparin cofactor II, plus an unknown
endothelial cellular mechanism. The net effect is a more selec-
tive Xa inhibitor than LMWH, with a ratio of anti-factor Xa
to antithrombin activity of 28:1 as compared with 3:1 for
LMWH. It is used as an alternative anticoagulant in patients
with heparin-induced thrombocytopenia.
Drugs inhibiting platelet activity
There are many drugs in the market acting at various sites to
affect platelet function (Fig. 1).
Aspirin
Aspirin has long been used as an anti-platelet agent because of
its effect of inhibiting prostaglandin and hence thromboxane in
platelets. There is a balance between the prostaglandins at the
endothelial/platelet interface and prostacyclin produced as an
anticoagulant by the endothelium opposed by thromboxane,
a pro-coagulant produced by the platelets. Aspirin acetylates
cyclo-oxygenase, thus preventing the production of prostaglan-
dins and thromboxanes. This effect is irreversible in the platelet
(via platelet prostaglandin synthetase I) but not in the endo-
thelium. Prothrombin concentrations are also reduced after
large doses of aspirin.
The Anti-Platelet Trialists Collaborative Group reported in
1990 that patients at high risk of vaso-occlusive disease on such
therapy showed a reduction of about 1/3 in non-fatal myocardial
infarction and similarly in non-fatal stroke and vascular death.

Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 4 2006 157
Anticoagulants and the perioperative period
Fig. 1 Drugs inhibiting platelet function.
The most widely tested anti-platelet regimen was ‘medium
dose’ aspirin (75–325 mg per day). They also reported that
aspirin reduced the risk of vascular occlusion in patients at
high risk (e.g. vascular grafts). The International Stroke Trial
studied 19 000 patients and showed that the early aspirin
therapy in patients with ischaemic strokes reduced the early
mortality by 1%.
Unfortunately, most trails show a 1–2% incidence of
major cerebral or gastrointestinal haemorrhage after aspirin
therapy.
It is not necessary to discontinue aspirin for minor limb or
dental surgery; however, higher risk surgery, for example,
prostate, gynaecology, neurosurgery, require aspirin to be dis-
continued 48 h preoperatively. Some orthopaedic surgeons
discontinue aspirin and other non-steroidal anti-inflammatory
drugs (NSAIDs) for a week preoperatively in an attempt to
reduce postoperative bleeding.
NSAIDs
Non-selective cyclo-oxygenase inhibitors produce a reversible
inhibition of the enzyme, which normalizes if the drug is
stopped for 3 days. Selective COX-2 antagonists do not cause
significant platelet dysfunction.
Dipyridamole
Dipyridamole has three possible mechanisms of action: as a
phosphodiesterase inhibitor potentiating the action of prostacy-
clin; by directly stimulating the release of prostacyclin by the
158 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 4 2006
endothelium; and by inhibiting the metabolism of adenosine.
Dipyridamole has been shown to be additive in effect to aspirin,
but there is no evidence of its benefit in isolation in either stroke
or cardiac patients. There is a 25% incidence of headache
associated with its use, which often leads to non-compliance.
Clopidogrel
Clopidogrel is a thienopyridine derivative. Its mechanism of
action is not clear, but it is thought to block the ADP-induced
platelet activation pathway. It prevents platelet activation
caused by shear stress, such as after acute vessel injury; this is
not inhibited by aspirin. Clopidogrel has been found to be more
effective than aspirin in the management of all ischaemic
events, with no incidence of neutropaenia as yet. The platelet
effects are irreversible and the drug should be discontinued for
at least 7 days before surgery. In emergencies, the use of high-dose
steroids and aprotinin will reduce bleeding times.
Platelet glycoprotein IIb/IIIa antagonists
Glycoprotein IIb/IIIa is the receptor that effectively acts as the
‘Velcro hook’ of the platelet. All processes that activate platelets
end in the common denominator of expressing this ‘hook’ on the
platelet surface, which allows the platelet to adhere to fibrin,
other platelets or the endothelium. Therefore, the inhibition of
this receptor blocks the last common pathway of platelet func-
tion. Glycoprotein IIb/IIIa antagonists, apart from showing
anti-platelet activity, have also been shown to reduce thrombin
concentrations and therefore function as anticoagulants. One
study showed that, via the inhibition of integrin, there was a
reduction in neointima formation in damaged arteries. Drugs
in this category include abciximab (a monoclonal antibody
to the receptor) and peptide inhibitors, for example, lamifiban,
eptifibatide, tirofiban. They all produce a thrombocytopenia
and lead to increased bleeding perioperatively. Bleeding time
normalizes 1 h after stopping eptifibatide (at 70% receptor
occupation), but abciximab has a significantly longer duration
of action (up to 48 h). Treatment of bleeding in patients taking
these agents requires a platelet transfusion.
Axial blockade
Clearly, there is a lot of concern regarding the insertion and
removal of axial or regional catheters in patients who are anti-
coagulated.5 The following is a suggested guide:
 An epidural may be sited 4 h after subcutaneous
unfractionated heparin.
 Heparin should not be given until 2 h after an epidural
has been sited. Some argue that it is safe to give 5000 u
heparin i.v. in theatre after siting an epidural atraumatically
(no bleeding during the procedure), as long as the patient is
closely monitored postoperatively.
 A heparin infusion should not be started until 12 h after
siting an epidural (24 h if there was a bloody tap).

 The catheter can be removed 4 h after stopping the heparin
as long as the APTT is normal and the platelets count is
>100 · 109 litre 1.
 An epidural catheter can be inserted/removed 12 h after the
last dose of LMWH. The next dose of LMWH can then be
given 2 h after removing the catheter.
 For patients on warfarin, the INR must be <1.5 before
epidurals are inserted or removed.
 In the absence of other complicating factors, aspirin does
not need to be stopped for the insertion of blocks.
 The same principles should apply for spinals or spinal
catheters.
Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 4 2006
Anticoagulants and the perioperative period
References
1. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring
during cardiac surgery. Anaesthesiology 1999; 91: 1122–51
2. Joseph JE, Macjin SJ. New antiplatelet drugs. Blood Rev 1997; 11: 178–90
3. Kaplin KL, Frascis CW. Heparin induced thrombocytopenia. Blood Rev
1999; 13: 1–7
4. Rosencher N. Ximelagatran, a new direct thrombin inhibitor. Anaesthesia
2004; 59: 803–10
5. Horlocker TT, Vedel DJ, Benzon H, Brown DL. Regional anaesthesia in
the anticoagulated patient: defining the risks. Reg Anesth Pain Med 2003;
28: 172–97
Please see multiple choice questions 16–19.
159