The Role of Anticoagulant Therapy
During Prostate Biopsy
F. Zaman, C. Bach, P. Kumar, I. Junaid,
N. Buchholz and J. Masood
Barts and the London NHS Trust
Since the advent of PSA (prostate specific antigen) in the early 1980s there has been a
dramatic increase in the diagnosis of prostate cancer and transrectal ultrasound-guided
biopsy (TRUS) has emerged as one of the most frequently performed urological procedures.
The most common complications are haemorrhagic. Haematuria (12.5 to 80%),
haematospermia (5.1 to 89%), and rectal bleeding (1.3 to 58.6%) have been reported to occur
[1-3]. However, these bleeding symptoms generally resolve without treatment. Factors other
than biopsy can influence the bleeding complication rate like anticoagulant medication and
some medical conditions.
Older patients constitute the main target group for prostate cancer screening and
subsequently undergo prostate biopsy. At the same time cardiovascular disease most
commonly affects the elderly who require low dose acetylsalicylic acid (ASA, 75 mg, once
daily), clopidogrel or warfarin as the mainstay of primary and secondary prophylaxis for
coronary and peripheral vascular disease. The optimal management of patients who receive
low doses (up to 100 mg) of acetylsalicylic acid (ASA) / clopidogrel / warfarin and who are
scheduled to undergo prostatic biopsy is still controversial. The approaches being
implemented in every day clinical practice vary and include discontinuation of
anticoagulation therapy, replacement with low-molecular weight heparin and continuing
ASA during peri-procedural period.
Little evidence is available and standardized comprehensive guidelines have not been
developed to determine how to manage antiplatelet therapy or warfarin in surgical patients.
2. Literature review
To our knowledge there has not been a comprehensive review of this topic for evaluating
haemostatic status before interventions. Here we shall provide a summation of literature
regarding the patients coagulation status, detail patient conditions that can affect
coagulation, and review common medications used to modify the haemostatic system to
2.1 Antiplatelet medication – ASA (acetylsalicylic acid, aspirin)
The mechanism of aspirin's antiplatelet action was first described in 1971 by the British
pharmacologist John Vane. It inhibits the enzyme cyclooxygenase (COX), thereby
preventing the production of prostaglandins. Subsequently, researchers identified two COX
isoenzymes, COX-1, and COX-2. Cyclooxygenase is required for prostaglandin and
thromboxane synthesis. Prostaglandins produced by COX-2 primarily trigger pain and
inflammation, while those produced by COX-1 perform maintenance functions such as
promoting normal platelet activity.
Fig. 1. Showing action of COX-1 and COX-2 enzyme - the products of COX-1 tend to have
so-called housekeeping functions. This enzyme is constitutively present in cells. In contrast,
the COX-2 enzyme is induced in cells in response to inflammatory stimuli. The products of
both enzymes tend to cause inflammation.
In platelets, the COX-1 enzyme produces thromboxane A2, which causes platelets to aggregate.
Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine
residue in the active site of the COX enzyme. Aspirin, by inhibiting the COX-1 enzyme and
therefore the production of thromboxane A2, derives a potential antiplatelet effect which lasts
for the life of the platelet (7-10 days). Because platelets do not have a nucleus and therefore
contain no DNA, no new cyclo-oxygenase can be produced, so the effect of aspirin on platelets
persists until enough new platelets have been formed to replace affected ones. This takes
approximately seven to ten days, i.e. the lifespan of a platelet as we mentioned earlier.
Therefore, the risk of increased bleeding, caused by aspirin, persists for some days after aspirin
treatment has been stopped. COX-1 catalyzes the synthesis of thromboxane A2 (Tx-A2), which
causes platelet activation, vasoconstriction, and smooth muscle proliferation. Tx-A2 levels are
elevated in conditions associated with platelet activation, including unstable angina and
cerebral ischemia. Conversely, COX-2 controls the synthesis of prostacyclin (PGI2), a local
platelet regulator with an effect opposite to that of Tx-A2. PGI2 is produced as a compensatory
response to increases in Tx-A2 during ischemic events.
Aspirin at low doses selectively inhibits the formation of Tx-A2 without inhibiting the basal
biosynthesis of cardioprotective PGI2. This effect is irreversible because platelets are
The Role of Anticoagulant Therapy During Prostate Biopsy
enucleate and, thus, unable to resynthesize COX-1. This makes aspirin different from other
NSAIDs (such as diclofenac and ibuprofen), which are reversible.
2.1.1 Mechanism of action of aspirin (C9H8O4)
Aspirin is rapidly absorbed in the stomach and upper small intestine, primarily by
passive diffusion of nondissociated acetylsalicylic acid across gastrointestinal membranes.
It takes 30-40 minutes to reach plasma peak level for an uncoated aspirin whereas three to
four hours for enteric coated formulations. Aspirin first comes into contact with platelets
in the portal circulation, and as a consequence, platelets are exposed to substantially
higher drug level than are present in the systemic circulation. Aspirin has a half life of 15-
20 minutes in the plasma. Despite rapid clearance of aspirin from the circulation, its
antiplatelet effect lasts for the life of platelet owing to the permanent inactivation of a key
platelet enzyme, an effect that can only be reversed through the generation of new
platelets. Thus there is a complete dissociation between pharmacokinetics and
pharmacodynamics of aspirin, allowing the use of a once-a-day regimen for antiplatelet
therapy despite the very short half-life of the drug.
By diffusing through the cell membranes, aspirin enters the COX channel, a narrow
hydrophobic channel connecting the cell membrane to the catalytic pocket of the enzyme.
Aspirin first binds to an arginine-120 residue, a common docking site for all non-steroidal
anti-inflammatory drugs. It then acetylates a serine residue (serine 529 in human COX-1 and
serine 516 in human COX-2) located in the narrowest section of the channel, thereby
preventing arachidonic acid from gaining access to the COX catalytic site of the enzyme .
This is an esterification reaction, so the linkage that is formed is covalent. It means that the
inhibition is irreversible.
Higher levels of aspirin are needed to inhibit COX-2 than to inhibit COX-1  These
differences may account, at least in part, for the need to use considerably higher dose of
aspirin to achieve analgesic and anti-inflammatory effects, whereas antiplatelet effects can
be obtained with daily doses as low as 30 mg .
Protein-Serine-CH2-OH + Aspirin → Protein-Serine-CH2-O-CO-CH3
Antiplatelet agents are principally aspirin and clopidogrel, used alone or in combination –
have been shown to reduce the formation of fibrin clots by irreversibly inhibiting platelet.
Patients who have cardiovascular events like myocardial infarction (MI), ischaemic heart
disease, stroke, and unstable angina, non-ST-elevation (NSTE)-acute coronary symdromes
(ACS) and ST-elevation MI (STEMI), take aspirin for secondary prevention – that is, to
prevent a recurrence. Aspirin also often prescribed for primary prevention, that is, to
prevent cardiovascular events in patients with risk factors and is recommended as life-long
therapy. Clopidogrel is recommended for periods ranging from 1 to 12 months or as life-
long substitute for aspirin in patients in whom aspirin is contraindicated. We shall discuss
clopidogrel later in the article. As a result, antiplatelet agents have become essential
components of the treatment of these conditions.
The exact time to stop or discontinue antiplatetet therapy prior to surgery or invasive
procedure is still controversial. Discontinuation of antiplatelet agents results in recovery of
platelet function which contributes to the occurrence of ischaemic events. Unfortunately,
neither good evidence from clinical trials nor authoritative guidelines are available to guide
physicians faced with this dilemma.
A meta-analysis determined that patients taking aspirin had twice the risk of moderate to
severe post-operative complications, although this increase translated only to an increased
absolute risk of 2% (1). Most of the centres in the UK recommend discontinuation of aspirin
for 7 days prior to the scheduled prostate biopsy. Zhu et al  from Denmark also
recommended stopping aspirin 1 week prior to all invasive urological procedures. However,
there are some published data suggest that aspirin in standard doses do not increase the risk
of significant bleeding after prostate biopsy (Table 1 and 2).
Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843
Fig. 2. Aspirin inhibition of COX-1 decreases TXA2 production.
In all of the above studies, regarding haemorrhagic complication rates, there were no
statistically significant differences between the two groups. Haematuria, rectal bleeding and
haemospermia rates between the groups were also comparable. No severe bleeding
complications occurred. Some studies showed that an increasing number of cores might
increase haemorrhagic events, but it does not affect the duration of bleeding [2,3].
Interestingly, one study showed  that aspirin users were significantly older than non-
users and haematuria became less likely with increasing age.
There is no guideline on the management of aspirin before taking prostate biopsy. A National
Survey performed by Masood et al  showed, that only 44% of urology departments have
protocols in place relating to aspirin use before prostate biopsy. Of those who replied 65% do
The Role of Anticoagulant Therapy During Prostate Biopsy
not routinely stop aspirin before biopsy. 35% stop aspirin and of these, 52% 1 week before,
41% 2 weeks and 6% >2 weeks before the biopsy. A third of the urologists felt that aspirin
increases bleeding complications and 59% stated that the cerebrovascular risks of stopping
aspirin outweigh the benefit of stopping aspirin for bleeding.
et al 2010 
et al 2008 
et al 2007 
Maan Z 2003 
Jan 2005 to Aug
Feb 2007 to
aspirin group /
Number of Biopsy
530/434 1520/1512 200/196 200/177
152/282/NA 387/1125/NA67/66/67 36/141/
12 cores NA 10 cores 6 cores
18G NA 18 G 18G
30 day from
the date of
from the date
14 day post-
7 day post-biopsy
ASA – acetylsalicylic acid, NA – Not Available
Kariotis I et al
Halliwell OT et
Giannarini G et al
Maan Z 2003
ASA NASAASANASA ASAHep NASAASA NASA
60.65 72% 61% 78.5% 69.7%81.5% 56% 59%
2.4 ± 2.6 4.05 2.85 6 4 2 NA NA
25.9% 21% 13% 31.3% 29.9%NA 0% 22%
3.3 ± 1.3 1.9 ± 0.7 2.41 2.03 3 2 1 NA NA
17% 21% 21.4% 18.5%9.3% 11% 28%
6.8 4.0 NA NA NA NA NA
A meta-analysis incorporating almost 50,000 patients (14,981 of these on aspirin) found that
although aspirin increased the rate of bleeding complications by 1.5 times, it did not lead to
greater severity of bleeding complications except for intracranial surgery and possibly
2.1.2 Risk of antiplatelet withdrawal and bridging therapy
There is no doubt that cessation of antiplatelet therapy in patients with a recent coronary
stent carries a significant risk . In addition, one French study suggests that recent
withdrawal of this therapy may be harmful in patients with coronary artery disease. Half of
the withdrawers underwent substitution therapy in the form of non-selective NSAIDS or
low molecular weight heparin, which did not protect the patients .
2.1.3 Evidences from other specialties
Multiple studies from other specialties have shown the safety of aspirin during a wide array
of interventions. Peritoneal dialysis catheter insertion and removal , 9-14 gauge core
needle breast biopsy  and dental extraction  all have been shown to be safe with
aspirin. Aspirin does not increase the risk for haematoma with spinal or epidural
anaesthesia , or bleeding with spinal surgery .
There are certain clinical instances in which continued aspirin coverage is critical: Aspirin
should never be stopped in patients with coronary stents because they face a 45%
complication rate and a 20% mortality rate with the highest risk for those with a stent placed
in the previous 35 days .
2.1.4 Restarting aspirin
A UK National survey  reported that the urologists who routinely stop aspirin, the
medium (range) time for restarting aspirin after biopsy was 2 (0-10) days.
2.2 Antiplatelet medication – Clopidogrel bisulphate (Plavix, Bristol-Myers Squibb)
Clopidogrel is a thienopyridine that inhibits platelet aggregation by selectively blocking the
binding of adenosine diphosphate (ADP) to its platelet receptor, and subsequently ADP-
mediated activation of the GP IIb/IIIa complex. ADP stimulates expression of the GP IIb/
IIIa receptor and may mediate release of other aggregation agonists and enhance platelet
binding of von Willebrand factor. Hence, the end result of ADP inhibition is impairment of
platelet aggregation and fibrinogen-mediated platelet crosslinking. Because it irreversibly
modifies the platelet ADP receptor, platelets exposed to clopidogrel are affected for the
remainder of their life span (7-10 days). After stopping clopidogrel, platelet aggregation and
the bleeding times gradually return to baseline value, usually within 5 days.
Clopidogrel has a mixed safety record depending on which intervention is studied. It does
not increase the risk of haematoma with spinal anaesthesia . The maintenance of
clopidogrel during surgery or invasive procedures has not been extensively studied.
Patients taking clopidogrel after coronary artery intervention have a high risk of late stent
thrombosis if they interrupt their medications (usually clopidogrel & aspirin). Of patients
who stopped medications prematurely, 29% suffered stent thrombosis and 45% of those
patients died . There have been several non-urological studies assessing the risk of
bleeding in patients on clopidogrel undergoing cardiothoracic surgery , plastic
surgery , ophthalmology  and vascular surgery . However, conclusions
regarding the risk of bleeding are contradictory. To date, there have been very few reports
The Role of Anticoagulant Therapy During Prostate Biopsy
in the urological literature regarding the risks associated with clopidogrel continuation
and urological surgery.
A UK survey  on the peri-operative management of Urological patients with clopidogrel
showed that majority of the urologists stop clopidogrel prior to TUR surgery (96.6%), major
urological surgery (91.7%), TRUS Biopsy (90.6%), ESWL (81.8%), and Cystoscopy & Biopsy
(70.1%). Almost half of the respondents (total 570 respondents) would stop aspirin
irrespective of its indication and 40.7% never consulted a cardiologist/haematologist before
stopping clopidogrel. Over half (55%) reported bleeding complications in patients who
continued clopidogrel during interventions and 7.4% responders reported an adverse
thrombotic event after discontinuing the drug.
Fig. 3. Pathway of blockage of ADP receptors by clopidogrel. Source: Harvey, R; Champe, P
“Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.
2.2.1 Bridging therapy
If patients take aspirin in addition to clopidogrel because of a coronary artery stent, the
aspirin should be continued to mitigate the risk of late stent thrombosis  and clopidogrel
should be restarted following TRUS biopsy as soon as possible using a loading dose.
Bridging anticoagulation for patients who must interrupt clopidogrel is controvertial.
Anticoagulation with warfarin or heparin has not proven useful  and is questionable
. In general, antiplatelet therapy should not be interrupted until patients are beyond the
safety window. If an intervention cannot be delayed, the risks of drug interruption should
be weighed carefully against the risk of bleeding. As a practical matter, the surgeon,
cardiologist, haematologist and anaesthesiologist should consult on each case regarding the
risk of peri-operative bleeding if antiplatelet therapy is continued and the risk of ischaemic
events if therapy is discontinued. If the course is not acceptable, postponement of the
surgery should be considered if possible.
2.2.2 Re-starting clopidogrel
The decision of each patient should be individualised based on the clinical situation. An
attempt should be made to restart the clopidogrel as soon as possible after the procedure,
when the risk of bleeding is minimal, to minimise the risk of thrombo-embolic phenomena.
It should be restarted using a loading dose.
2.3 Warfarin (4-hydroxycoumarins)
Warfarin inhibits the formation of vitamin K-dependent coagulation proteins, i.e., factor II,
VII, IX, X and protein C and S. These are proteins of the extrinsic pathway and thus would
be monitored by INR. These diminished factors lead to decreased fibrin clot formation and,
to a lesser extent, primary haemostasis by platelets (because thrombin is an important
activator of platelets).
2.3.1 Mechanism of action of warfarin
Warfarin is a vitamin K antagonist. It produces its anticoagulant effect by interfering with
the vitamin K cycle. Specifically, it interacts with the KO reductase enzyme so that vitamin
KO cannot be recycled back to vitamin K. This leads to a depletion of vitamin KH2, thereby
limiting the γ- carboxylation of the coagulation factors mentioned above. Factors like
prothrombin are not carboxylated, and cannot effectively bind to phospholipid membranes.
Its activation by Factor Xa is not affected. Thus blood coagulation is limited. Therapeutic
doses of warfarin decrease the effects of Vitamin K-dependant clotting factors by
approximately 30 to 40%.
Fig. 4. The carboxylation process is associated with the vitamin K cycle. In this cycle, vitamin
K is reduced by enzyme Vitamin K reductase to its hydroquinone form, vitamin KH2, which
then catalyses the carboxylation process and is converted to its epoxide (vitamin KO). This is
then converted back to vitamin K by the enzyme Vitamin KO reductase.
The Role of Anticoagulant Therapy During Prostate Biopsy
2.3.2 Bleeding risks during invasive procedures
Bleeding is the obvious risk when continuing warfarin during surgical interventions. One
study found a seven fold increase in moderate to severe post-operative complications in
patients taking the medication .
The relation between warfarin use and the frequency of bleeding complications after TRUS
biopsy was reported in a prospective study of 1000 patients. Forty nine patients
continuously used warfarin before and after the biopsy. The prevalence and severity of
bleeding complications were assessed by a questionnaire 10 days after the biopsy. There
were no significant difference in the severity of bleeding between patients taking warfarin
and controls . However, limitations of this study include non-randomized design,
patients had either 4 or 6 core biopsies and complications were entered retrospectively 10
days after biopsy.
Some studies showed that maintaining a therapeutic level of warfarin anticoagulation is safe
for many interventions. Ihezu et al  showed less bleeding in patient taking warfarin with
an average INR of 2.2, than in control subject. Similar evidences are found in some non-
urological invasive interventions – trans-femoral coronary angiography using 5 or 6 French
sheaths [INR 2.0-3.0] , cataract surgery , dental surgery [INR upto 4.2] , and
dermatologic surgery [INR upto 4.5] .
A survey among urologists and radiologists found that 84% of urologists stopped it 4 days
before TRUS biopsy and 95% of radiologists stopped it 5 days before TRUS biopsy. An
international normalized ratio below 1.5 is accepted for most elective procedures .
2.3.3 Bridging therapy and risk of warfarin withdrawal
The decision whether to stop anticoagulants depends on the indications for anticoagulation
and the risk of thrombosis in a particular patient. The decision should be discussed with the
patient and the primary physician managing the anticoagulant. Several regimens have been
developed to increase the safety of warfarin interruption. The simplest involves stopping
the medication 3-5 days before the intervention and restarting it immediately afterwards
. An anticoagulation effect generally occurs within 24 hours after the drug
administration, though peak anticoagulant effect may be delayed 72 to 96 hours. The action
of a single dose of warfarin lasts 2 to 5 days, & the effects of warfarin may become more
pronounced as effects of daily doses overlap.
An alternative regimen is to reduce the warfarin dose to achieve an INR of 1.5-2.0 for
surgery or interventions . Bridging anticoagulation with unfractionated heparin or low-
molecular weight heparin (LMWH) should be considered for patients at the highest risk of
thromboembolism, such as those with prosthetic metallic heart valves. This involves
stopping warfarin 3-5 days before the surgery and administering unfractionated heparin or
LMWH until 6-24 hours before the procedure .
Heparin, containing the unique five-residue sequence, forms a high-affinity complex with
antithrombin. The formation of antithrombin - heparin complex greatly increases the rate of
inhibition of two principle procoagulant proteases, factor Xa and thrombin. The normally
slow rate of inhibition of both these enzymes (~ 103 - 104 M-1s-1) by antithrombin alone (see
graph below) is increased about a 1,000-fold by heparin. Accelerated inactivation of both the
active forms of proteases prevents the subsequent conversion of fibrinogen to fibrin that is
crucial for clot formation.
On the other hand, compared with the unfractionated heparin, low-molecular weight
heparin has a greater ratio of anti-factor Xa / anti-factor IIa activity, greater bioavailabity,
and longer duration of action. It is also suitable as outpatient treatment and requires less
monitoring . It does not cross placenta, therefore it can be used during pregnancy.
Graph: Effect of action of heparin
Patients with an acute venous thromboembolism in the previous 3 months or an arterial
embolism in the previous month should receive unfractionated heparin or LMWH. The risk
for recurrent venous thromboembolism is high  if anticoagulation is stopped in the first
month after an acute event (40%), and decreases if the anticoagulants are not stopped until
the second or third month (10%). The bridging anticoagulant is usually restarted as soon
after the procedure as is considered safe to do so and continued until a therapeutic INR has
been established with warfarin.
3. Other inherent bleeding risks
Identification of patients at high risk for bleeding is the first step in managing those on
antiplatelet agents or warfarin who require invasive procedures. Demographic factors that
increase the likelihood of bleeding are advanced age, previous history of bleeding events,
haemorrhagic peptic ulcer or haemorrhagic stroke . Medical conditions that increase the
risks of bleeding include obesity, diabetes, hypertension, renal impairment, heart failure,
other major organ dysfunction and haemostatic disorders [31, 41]. Patients with these
conditions present a particularly difficult dilemma for clinicians. Data on patients with these
conditions are not found in the medical literature. A unified validated method of sorting
patients in terms of their bleeding risk and weighing it against their risk of ischaemic events
is sorely needed but is yet unavailable.
The Role of Anticoagulant Therapy During Prostate Biopsy
There is insufficient clinical evidence to establish comprehensive guidelines regarding
continuation of aspirin during TRUS biopsy. However, data are emerging and from some
level 2 evidence it appears that patients on ASA should have this maintained during TRUS
biopsy. In clearly identified cases, where bleeding might threaten the patient’s life e.g. after
acute cardiac events, the discontinuation protocol must be established in conjunction with
cardiologist and the ASA therapy resumed as soon as possible. Bridging with LMWH is not
recommended in the aspirin or clopidogrel group. Consideration should be given to
postponing TRUS biopsy in high risk individuals. Patients with combination of aspirin and
clopidogrel should at least continue aspirin during the procedure. Evidence on
discontinuation of warfarin is sparse but emerging. However, bridging therapy with
heparin in this situation could be an effective replacement of warfarin. There is an urgent
need for research in order to change the practice of stopping anticoagulants and to establish
a comprehensive set of recommendation before the TRUS biopsy.
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