ARE ANTI-FIBRINOLYTIC DRUGS THE MAGIC

BULLETS FOR PERIOPERATIVE HEMOSTASIS?

Daniela Pilipescu'

Several pharmaceutical agents influencing haemostasis, coagulation andl

or fibrinolysis have been used to lessen surgical bleeding and eliminating
or reducing blood transfusion requirements. Beyond its well-known risks,
blood transfusion is suspected to carry silent risks and has been found to be
independently associated with poor outcome in a number of studies (1).
The ideal hemostatic agent has to elot inappropriate hemorrhage and not
normal vessels, has to be easy to store and use, has to be monitored by a
validated laboratory assay, inexpensive and without side effects. Obviously,
to be adopted in clinical practice, an agent must be efficacious, but safety
remains a major concern. The medications that have been most extensively
evaluated as haemostatic agents include the antifibrinolytics (aprotinin and
Iysine analoguesl. desmopressin and recombinant factor VII (2).
We review below the agents that exert antifibrinolytic activity which
comprise aprotinin and the group of Iysine analogues.

Aprotinin
Aprotinin is a 58 amine acid polypeptide, mainly derived from bovine lung,
parotid gland or pancreas. Aprotinin is a non-specific serine protease inhibitor
that directly inhibits the activity of various serine proteases, including plas-
min, coagulation factors or inhibitors, and constituents of the kallikrein-kinin
and angiotensin system which result in a complex effect on hernostasis (3).

• Bucharcst, Romania

Timişoara 2011
 The aprotininstory l' h d by Rovston in 1987 (4). who 5howed a
After the first study PUbl,S e peat valve surgery u5ing a high dose of
ic d se in blood oss 111re ,
dramatic eerea ized t Iled trials (RCTs) in primary surgery, hlgh
aprotinin, many random~ze ,cton ,ro aspirin confirmed and established the
' k e y arid in patients a kIng ,
ns surg r, " li iti ot only the blood 1055but also the requi-
efficacy of aprotrrun for Imi Ing n , ( )
rementsfor transfusion in patients undergoing cardiac surgery, 5,
Meta-ana Iyseso f RCTswere reassuring with regard to safety rssues (6,7,8), ,
However, the preliminary findings of the Canadian tria,1 Blood Conservation
Using Antifibrinolytics in a Randomized Trial (BART) pOlnte,d ,to a strong and
consistent negative mortality trend associated with aprot~nll1 as compare,d
12 with Iysine analogues in cardiac surgery (9) and the medical ~a~ety moru-
toring board of that study considered unsafe to continue this innovative
prospective RCT,
These results followed reports of large observational studies linking apro-
tinin to an increased risk of renal failure (10,11). myocardial infarction,
stroke and death (11), Two other observational studies also reported similar
findings (12,13), As a eonsequence, on November 5, 2007, after consultation
with health regulatory authorities, Bayer announced it had suspended mar-
keting of aprotinin (14), Currently, Iysine analogues are the only available
antifibrinolyties in clinieal practice todav.
The aprotinin story illustrates the limitations of RCTsand meta-analyses
of RCTsdesigned to study efficaey with regard to safety issues (15), It also
showed that improved prevention of blood 1055/transfusion does not neces-
sarily translate into improved clinical outcornes,
However, some passionate authors consider that aprotinin withd I
t ' t I d as i , rawa
5 ory 15no C ose as It was driven by media attention, lay pressure, emo-
tron, and fear of legal actlOns and not by irrefutabl id
suppor t o f thiIS oplnlon
" ,15the new data published b eK eVIk' ences (16) ' In
showinq that aprotinin may well improve outco .v ar OU:' et al. (17)
trents, me In some h'gh-risk pa-

Lysine analogues
lysine analogues include epsilon-am' ,
acid (TXA) Th InocaprOlc acid (EACA)
, '" ' ese agents are synthetie de' , and tranexamic
Inhlbltors offibrinolysis (3),ln contrast to nvatl~e~ of the amino-acid I sine
simple meehanlsm of aetion' th ' " aprotlnln, Iysine analo y

~~~st;r:v~~:~~~~~n~tio Iysine' bi~~i~nghls~~::~;nt~~~SpiSr~Ye

competit~v~~~ ~~:Cek~
, rmatlOn of a te nZYme plasm'
aclivator (t-PA) and fibrin (2) I ,rnary cOmplex with ti Inogen,
, mpalred Plasminogen b' ,'SSUeplasminogen
______ Indlrlg to fibrin delays

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the conversion of plasminogen to plasmin and subsequent plasmin-media-
ted fibnnolYSls, which then proceeds al an inefficient and slow rate.
Lysine analogues share common characterlstics: low molecular weight,
hydrophilia, renal elimination with littlc/no biolransformation and low cost
(15). Subtle molecular variations between differcnt Iysinc analogues may
nave Important consequences for their fibrinolysis-inhibiting capacity. In-
deed, TXA is 6 to 10 tirnes more potent in vitro and has a longer elimination
half-life than EACA (approximately SO min after a single intravenous (IV)
dose)(l S).
Lysine analoques have been avallable since decades. They nave bcen used
as an adjunct therapy/prophylaxis of bleeding in various indications, such as 13
oral surgery in patients with coagulation abnormalities and menorrhagia (3).
Their use in reducmq surgical blood 1055 and transfusion in patients without
mherlted haemostatic disorder is more recent. They are currently used to
reduce blood loss and transfusion in cardiopulmonary bypass (CPB) surgery,
major orthopaedic surgery and liver transplantation. Both agents have been
used with a wide range of empirical weight-based or non-weight-based
dosage and time frames for drug delivery. The usual administration route is
IV, but oral forms are available.
In general, TXA has been investigated more thoroughly than fACA. Most
climcal investigations on these cheap generic products are small single-cen-
tre trials funded by non-industry sources, with no support from pharmace-
utical companies (15). As in some countries, fACA is no longer available we
will focus below on TXA efficacy and safety.

Clinical efficacy of antifibrinolytics

In cardiopulmonary bypass surgery
Bleeding and transfusion in cardiac surgery are associated with serioLls
adverse events, including an increased length of hospital stay, infection,
return ta the operating room, length of ventilation/respiratory failure, atrial
fibrIlation. myocardial infarction, renal failure, and short-term and lonq-
terrn mortality (16). Strategies ta reduce transfusion have been advantage-
ous and prophylactic pharmaceutical agents focused on this end-point were

IIltroduced very early in cardiac surgery.

It is widely accepted that non-operative blood 1055 after CPB mainly re-
sults from a combination of excessive fibrinoly5is ano an acquired platelet
dysfunction. Con5equently, attempts have been made to reduce blood 1055
by the prophylactic U5C of antifibrinolytic drugs (19). In addition to inhibi-
tinq fibrinolysis, Iysine analogues mav lessen plasmin-inducecl platelet acti-

vation, consequently preserving platelet function.

Timişoara 20 J 1
 The efficacy of antifibrinolytic agents in cardiac surqerv was cvaluated in
several systematic reviews (6,7,8,20,21). The Cochrane group (8) analyzed
211 controlled trials with 20,781 partic'pants that were publl.shed before
J I 2006. The vast majoritv of trials (147 of 211) enrolled paticnts under-
g~i~9 cardiac surgery. Ninety eighl studics evalua led aproti~in in 5750 pati-
ents randomised to aprotinin and 4394 to control. Randnmized trials ofTXA
or EACA were much less nurnerous: 53 (3836 patients) and 14 (801 patients),
respectively. On average, TXA significantly lessened the postopera tive blood
loss by 260 mi per case, with notable variations (-50 to -460 mi). Total peri-
operative blood loss was also significantly reduced by 440 mi on average.
Both aprotinin and TXA reduced transfusion of allogeneic blood byappro-
14
ximately 30% and helped to save approximately 1 unit of blood per operati-
on, with a non-statistically significant trend toward a similar reduction with
EACA. The use of TXA significantly minimizes the relative risk of exposure to
allogeneic blood transfusion by 31% (RR 0.69; 95% CI 1/40.60-0.79). Howe-
ver, this diminution is inconsistent across trials (22-24). This heterogeneity
may be due to different dosing schedules, to a lack of power of some stu-
dies and/or to a relatively low blood transfusion rate in the control group,
suggesting that the potential benefit of TXA is limited in some centers or
in some subpopulations (15). Finally, these data should be interpreted with
caution, because of the substantial inter-center variation in blood-saving
techniques and transfusion practice, for example due to different transfu-
sion tnggers.
The other meta-analysis published in 2007 has yielded similar findings
on the efficacy d.ata of TXA as cornpared with a placebo (25). Whereas the
two meta-anal~sls and the BART study indicate that both l sin I
are less potent In decreasing blood 1055 than aprotinin t I Y : an~ ogues
cardiac surgery patients, there is no sign th t .' a :ast In hlgh-nsk
(8,9,25). a one 15 superior to the other
Of note, no meta-analysis of RCTs h h
. . as 5 own that d .
cacrous In reducing blood transfus' h'" esplte being effi-
n nt
patient outcomes (15). Moreover ti°h SYd etic Iysltle derivatives irnprove
r

f . , e re uction In th .
on or bl eedltlg was not found significant RR e risk of re-operati-
However, there evidence that aprotinin d ( 0.65, 95%CI.1/40.39-1.08) (8).
as compared with either EACA or TXA (9) ecreases reoperatlons for bleeding
Some authors point out that t ..
has profoundly chan ed w he practice of cardiac sur
recent reporr of' g. Ith the withdrawal of apr tini gery/anesthesia
wlthdrawal of ap~~~~~~gators from Emory UniverSi~ Inln. (16). In the most
Increased length of st has transla ted to Plllmo Y It IS noted that the
ay In Intensive care lInlts (26~a~ dysfunction and an
. eoperatlons for blee-

Ar/llnliiri/; ÎII '

1"'llCslezie . T.
ŞI era pir lntensivă
ding nave been documented to be increased as well. Costs have dramatlcally
increased in both drug usage (more factor Vila) as well as through the incre-
ased usage of blood products, intensive care unit time, and so ono
TXA has also been studied in paediatric cardiac surgery with different
dosage schemes and populations (27). The drug appears more efficacious in
e
children at high risk of bleeding (with congenital cyanotic heart diseas or
undergoing repeat heart surgery) (28-31). TXA significantly reduces blood
10sSand in sorne centers it decreases blood transfusion requirements and
re_exploration rate (28,30). The efficacy is less clear in non-cyanotic patients
(29). However, a recent meta-analysis conducted in major pediatric surgery
involvin9 children undergoing cardiac or scoliosis surgery suggested that, 15
compared with aprotinin, alternative antifibrinolytics are equally effective

(32).
Variability in antifibrinolytic efficacy to reduce blood 1055in cardiac sur-
qerv rnav be related to variability in dosing schemes and blood concentrati-
ons (table 1). This important issue for efficacy and safety has been debated
in the literature (33-37). TXA is eliminated rapidly by patients undergoing
CPB surgery when given as a single bolus dose and a continuous infusion or
repeated boluses are advisable (36).
Table 1. Oase and tim ing oi Iysine analagues in cardiac surgery
Drug acoed to tne
Loading doses Maintenance doses
bypass circuit.

variable amounts
BO mg to 15 g 1-2 g/hour or
EACA 12.5-30 mg/kg/hour
or 50-150 mg/ kg
infused over varying
time periods

10 mg/kg 1 mg/kg/hour
TXA 2 mg/kg
30 mg/kg 16 mg/kg/hOllr

Schematically, there have been two complementary approaches to deter-

mine the optimum dose of TXA in cardiac surgery: empirical dose-response
studies and pharmacokinetic model ing to nlaintain plasma concentrations
presumed necessary to inhibit fibrinolysis (15). Horrow et al. (33) found that
a loading dose of 10 mg{kg followed by a continuous infusion of 1 mg/kg/
hour was sufficient to decrease bleeding after CPB, and that larger doses
lup to a fourfold .ncrease) did not provide additional haemostatic benefit.
Dowd et al. found that a hiqher loading dose of 30 mg/kg followed by a
contmuous infusion of 16 mg/kg/hour with an additional dose of 2 mg/kg
In the bypass circuit (as used in the BART study, ref 9) was required to ma-
mtain a plasma TXA concentration greater than 800 m01ol/1 (36). However,

Timişoara 201/
 impaired renal function results in highcr plasma concentratl?ns after
and other dosing schedules that take into ~ccoun.t renal lunction have bet"
suggested (37) In paediatric cardiac surgcry, oplif1lum doses are unknown,
but Chauhan et al. have shown that rcpealed doscs arc more cfficaCio\JS
than a once-only initiallarge bolus of 50 mg!kg (30) .
There are manv other tactors that mav innuence rXA haernostatic potency
at an individual level. The blood-sparing cfficacv of TXA has been shown to
be greater in patlents homozygotous for thc 5G polymorphism of the plas.
minogen aetivator inhibitor- 1 gene (38).
There is no dose-ranging outcorne study of EACA in cardiac surgery, and
theretore the optimal dosage is uncertain. Although higher doses have been
16 used in the most recent publications in adults (9,39), considerable variations
in plasma levels are observed after the administration of a given weight
adjusted EACAdose (39,40). Importantly, as for TXA, EACA is exereted by the
kidnev, and impaired renal function results in higher plasma concentrations
after CPB (15).

In major orthopaedic surgery

The ~umber of total hip or knee replacement proeedures is increasing
worldwide and methods to reduce bleeding are needed as many patients are
receiving allogeneic and/or autologous blood transfusion (41).
A large body of evidence supports the efficacy of TXA in total knee repla-
cemen~ surgery. -:he ~se of a tourniquet is assurned to increase fibrinolysis,
potentiallv contributinq to delayed bleeding (15). A nurnber of RCTs have
consistentlv reported reduced postoperative blood loss after TXA adminis-
tration (42,44-46) and recent meta-analyses conclude that TXA . ffi .
. duci IS e icacro-
us In re ucrnq the requrrements for allogeneic blood in this ty f
dure (43,47,48). pe o proce-
TXA has also been found efficacious in total hi re I
(49). The results of the meta-analysis by Zuffe ~ I P acernenr procedures
pared with a placebo TXA is more efficaci r~y e da . suggest that, as corn-
. ' 10US In re ucing bl d
In kne~ arthroplastythan in hip arthroplasty (48). 00 transfusion
A recent svstematic review and meta-analysis of 7 .
contra,lIed trials (comprising 350 tients] publlshed randomized
d pa ients evaluaf th
re uClng blood loss and transfusion in total hi ng e efficacy of TXA in
cec Intra-operative blood 1055 by a m f p replacement showed a redu-
(CI)-164to-44 _ eano 104ml(950A • •
(95% CI -263 to' ~ - 0.0~06), postoperative blood loss ~ confldence Interval
(95% CI -440 t 81, P - 0.0002) and total blood 10 bY a mean of 172 mi
S
In the proporti~n-~~8, p.< 0.0002) (50). TXA led to ; .y a. mean of 289 mi
patlents requiring aii . slgnlf!cant reduction
ogenelc blo d
o tra nsfusion (risk

Actualităţi În A ' .
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ŞI erapie [lItellsil,ă
difference -0.20, 95% CI -0.29 to -0.", p < 0.00001) without signlficant
differences in deep-vein thrombosis, pulmonary embolism, infection rates
or other complications among the study groups. TXA is also effective in
revision of total hip replacement (50').
TXA has also been evaluated in scoliosis surgery. Two RCTsusing different
dosage schemes were included in a recent meta-analysis, which concluded
that the agent successfully reduces blood lossand the total amount of blood
transfused, but not the proportion of patients exposed to allogeneic blood
(51-53). In the study of Wong et al. (54) the total estimated and calculated
perioperative blood 105Swas significantly lower by about 25% and 30%,
respectively, in the TXA group cornpared to placebo. However, the incidence 17
of perioperative blood product transfusion did not differ between the two
groupS,although it tended to be lower in the TXAgroup (31010 vs. 40010 in the
placebo group). The total arnount of units also tended to decrease, particu-
larly during the postoperative period.
A more recent meta-analysis including 4 double-blinded RCTsindicates
that the use ofTXA infusion for patients undergoing spine surgery is effec-
ti ve in reducing total blood loss, transfusion volumes and the rate of trans-
fusion, yet doesn't raise the risk of postoperative DVT (54'). On the basis of
the available efficacy and safety data it is recommended to consider Iysine
analogs as possible agents to help reduce major hemorrhage in spine surgery
(54").
As in cardiac surgery, various antifibrinolytic dosing regimens have been
experimented (table 2). The optimum regimen is unknown. However, the
results of the meta-analysis by Zufferey et al. suggest that the efficacy of
TXA as compared with a placebo on exposure to allogeneic transfusion is
greater with a dose regimen of more than 30 mg/kg than with a lower dose
reglmen and with the use of continuous infusion or repeated bolus than one
single bolus dose (48). Recently, it was shown that topical application of TXA
directlv into the surgical wound reduced postoperative bleeding resulting
in 16-17% higher postoperative hemoglobm with no clinically important
mcrease in complications (55).

Table 2. Dose and timing of Iysme analogues in arthopedic surgery

maintenonce doses
Loading doses
1 g/hour during 3 h or
EACA 10 9 or
12.5 mg/kg/hour during 5 h or
100-150 mg/ kg
10 mg/kg/hour until the end of the procedure

10 mg/kg/hour
l)'A 100 mg/kg before tncision
1 mg/kg/hour
10 mg/kg before incision

Timişoara 2011
 In liver surgery, is ls one of the rnain causes of excessive bleedillg .
As accelerated, fi~nnolysls I~ t tion the usc of antifibrinolytic drugs has
during orthotoplc uver tr~sp ~~o~s an'd blond transfusion (15), Both Iysine
been proposed to reduce 00 beeri used in liver surqerv, As for cardiac and
l
logues and aprotmm rave ied Itable J) Th
ana, ti dose of antifibrinolyllcs varied (table 3, rombo.
orthopedic surgery le . is t f
elastographic monitormq techniques are of ten used In ~hlS ype fO surge,ry,
guiding the therapeutic , use of pharmaceu t'rea I agents In case o excesslve
bleeding,

Table 3, Oase and timing a fi YSlne ana ogues In liver surgery

18
Loading doses Maintenance doses

EACA 16 mg/kg/hour

TXA 500 mg IV before the operat ion 250 mg 6 hourlv or

2 mg/kg/hour or
10 mg/kg/hour or
40 mg/kg/hour

In a RCT,a group of 42 liver transplant recipients given EACA was cornpa-

red with a similar group given TXA and with a placebo group (56), EACA was
not found to be more efficacious than placebo, whereas TXA significantly
reduced the amount of red ceIls units and the proportion of patients trans-
fused, A blood-sparing effect of TXA was also reported by Boylan et al. who
used a higher dose (57), By contrast, Kaspar et al. did not find any reduetion
in transfusion requirements with TXA, although the incidence of fibrinolysis
decreased (58), However, in the latter study, the TXA dose was small and
blood requirements were low in the control group.
A systematic review and meta-analysis of these three trials by Molenaar et
al. (59) found that, with a total of 161 patients ineluded in these studies red
cells transfusion requir,ements were significantly lower with TXA, but fresh
frozen plasma transfusion was not.
Two other RCTs('head to-head' studies) in liver transplantat' , l d'
" Ion me U Ing
127 and 51 patients, respectlvely, failed to demonstrate a diff b
TXA d . , I erence etwe-
en , an aprotirun regarding blood use (60,61),
Iiver resectlons require blood transfusions l
haemostatic drugs is ,nfrequent How W ess cOmmonly, arid the use of
, ' ever, LI et al r d .
tectomies to receive either TXA or placebo (6) .ran omlsed 214 hepa-
ents In the placebo group required bl d t 2, Whereas 16% of the pati-
glven TXA was transfused No d'ff 00 ranSfllsi.o n, none of the patients
b' , ,1 erences were ob
mor Idlty and postoperative length fi' served In the operative
o 10spitai slav,

Artualittiţi ill A ' r . , ,

IIC,ltClll' ŞI Temple Illtf'/lSH,ă
other typcs of elective surgery
Although postoperative blood 1055 may be related to an inl'!reased urlnary
fibrinolytic activity, antifibrinolytics are rarely used in urologlc surgery as
they can promote elot formation and may lead to urlnary tract obstructions
(1 sI. Moreover, blood transfusion requirements are usually 10'11 in this type
of procedure. However, a randomised placebo-controtled study was con-
ducted in 136 patients and it has shown that TXA can reduce blood loss and
improve surgical conditions in transurethral prostatectomy (63).
TXA significantly reduced bleeding during elective cesarean section in a
prospective, double-blind, placebo-controlled study, as well as the percen-
tage of patients with blood 1055> 1000 mi, and the need for additionai ute- 19
rotonic agents (63'). Furthermore, the incidence of thromboembolic events
did not increase. An tntemationailv, multi-center study on the effect of TXA
in postpartum hemorrhage in on the way (64").
Choi et al. randomized 73 patients undergoing orthognathic surgery to
receive either a single IV dose (20 mg/kg) of TXA or placebo immediately
before surgery (64). Blood 1055 was significantly reduced in the TXA group.
The rate of patients requiring transfusion was lessened in the TXA group
(12.5010)as compared with the placebo group (24.10f01,but the difference is
not statistically significant.

In trauma patient
Extensive tissue trauma may lead to excessive fibrinolysis, contributing
to the coagulopathy of severely injured patients (65). Given the efficacy of
prophylactic Iysine analogues on blood loss in various elective surgeries, it
may be hypothesized that these agents are useful in the trauma setting. The
guidelines issued by a group of European experts recommends monitoring
of fibrinolysis in aII patients and administration of antifibrinolytic agents in
patients with established hyperfibrinolysis (66). Recently, the results of the
CRASH (Clinical Randomization of an Antifibrinolytic in Significant Hae-
morrhage) II trial were published (67). This randomized control led trial was
undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients
with, ar at risk of, Slgnificant bleeding were randomly assigned within 8 h
of mjury to either TXA (Ioading dose 1 9 over 10 min then infusion of 1 9
over 8 h) or matching placebo. The primary outcome was death in hospital
within 4 weeks of injury, and was described with the foliowinq categories:
bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary
embalism). multi-organ farlure, head injury, and other. AII-cause mortali-
ty was slgnificantly reduced with TXA (14.50f0 TXA group vs 16.00f0 placebo
graup; relative risk 0.91, 950f0 CI 0.85-0.97; p=0.0035). 1he risk of death due

Tilnj~oara 20 II
 to bleeding was significantly reduced (4.9% vs. 5.7%; relative risk 0.85,
CI 0.76-0.96; p=O.0077). The author concluded that TXA safely reduced
risk of death in bleeding trauma patients an.d should be consld~red for
in bleeding trauma patients. TXA should be ~Iven as early as posslble,
by thrombelastometric monitoring if possible and stopped once bl
has been adequately controlled (68).
The most recent Cochrane review of the use of TXA in traumatic i
Includ ing 4 clinical trials states that the agent safely reduces mortality
bleeding trauma patients without increasing the risk of adverse events
that further trials are needed to determine the effects of TXA in
with isolated traumatic brain injury (68'). However, on the basis of
20 results, TXA may be appropriate for early use in wider range of patients.

Safety of antifibrinolytics
By definition, any therapy that promotes hernostasis is likely to induce
thrombosis. Unfortunately, a favorable balance between the desired effect
(hemostasis) and the unwanted (thrornbosis] may be difficult to achieve.
Since Iysine analogues inhibit fibrinolysis without suppressing thrombin ge-
neration, concerns have been raised regarding their prothrombotic potentia
and an increased risk of vascular events.
The safety of aprotinin was questioned by an observational and non-ran-
domised study in 4374 patients who underwent elective coronary-artery
bypass surgery (11). A propensity score method was used to balance the
covariates. Compared with untreated controls, aprotinin (but neither EACA
nor TXA) doubled the occurrence of severe renal failure, increased the inci-
dence of myocardial infarction or heart failure by 55% and was associated
with a nearly two-fold increase in stroke or other cerebrovascula ts
S··I I f . r even .
Imi ar resu ts were ound In an observational survey conduct d b th _
f t . 67000'· e y e ma
nu ac urer In , p~tlents u~d.ergorng cardiac surgery (69). The BART
prospect.ve RCTco~parrng aprotlnln and Iysine analogues in 2 . .
cardiac surgery patlents confirmed a higher 30 d . 331 hlgh rrsk
. . group ()6.0% In
tinin . comparison with 3.9% in -th ayTX mortalrty in the apra- .
the EACA (9). e A group and 4.0% In
As for aprotinin, the possibility of a caus l' .
operative thrombo-embolism and EACA da I~e Ilnk. between fatal intra-
However, this concern has not been sub ta 1~lnlstratlon has been raised
tic .
ma le revlews or meta-analyses (70) N .
s antlated by. th e results of svste-
infa t k . o Increase in ti
re Ion, stro e, deep vein thromb . le rate of mvocardia'
othe,r meta-analysls (8,22), Yet, pati~~~so: pulmonary e~bolism appears in
selected, Ihus, the findings ofsuch t . I ho take. part 111 RCTs are highly
rra S regarding t d
o a .verse drug reactions

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mav not be transferred to other patients (15). Intriguing, former meta-ana-
Iysesdid not yield any safety issue regarding aprotinin!
However, in contrast to aprotinin, the use of EACAor TXA was not associ-
ated with increased odds of renal failure, myocardial infarction and stroke
as compared with no ~reatmcnt in the observational study by Mangano et
al. (11). An [ncreased nsk of thrombosis of the liver grafl vasculature has not
oeen documented, either (59).
Ihe rnost frequently reported adverse effects of TXA are minor gastroin-
testinal symptoms such as nausea and vomiting, especially when administe-
red at high dose or injected rapidly (15).
More worrisome side effects of TXA in some special patient groups have
recently been highlighted in cardiac surgery. In 2008, Martin et al. from the 21
German Heart Center investigated postoperative complications and mortali-
ty after switching from aprotinin to TXA in a consecutive cohort of unselec-
ted cardiac surgery patients (71). They reported on more than 1,100 patients,
noting that TXA was associated with increased seizures in the subgroup of
primary valve surgery (7.90J0 vS.l.20J0in the aprotinin group). The conclusion
of the authors is that TXA should not be used in open-heart procedures until
the mechanism of this side effects is clear.
Other reports of seizures arising frorn TXA have been forthcoming in the
literature as well, so it is not just isolated (72). TXA is well known in neu-
rosurgery to be associated with seizures and is avoided during craniotomy
(73). TXA exerts an epileptogenic action if applied topically to the cortex
or mtrathecallv (74). It may be due to microcirculatory disturbances, to a
blockage of the gamma-aminobutyric acid..driven inhibition of the central
nervous svstern, or to another yet unknown mechanism. Seizures, in cardiac
surgery with TXA 50 far has not translated ta documented worse permanent
neurologic deficits (16).

In conclusion, prophylactic use of Iysine analogues decreases peri opera-

tive blood 1055 in cardiac surgery, major orthopaedic procedures and liver
transplantation. However, the reduction in allogeneic blood consumption is
variable and they do not represent the magic bullets for perioperative he-
mostasis.The decslon to use these haemostatic agents prophylactically sho-
uld take into consideration local transfusion requirements for the type of
procedure and population. Curently, TXA is the most appropriate antifibri-
nolytic agent for use in perioperative bleeding. However, it is not clear from
the literature which patients benefit most from this treatment, what is the
most effective dose with the least side effects and how to perioperatively
select patients who should receive tranexamic acid. Due to their short half-

Timisoara 20 J J
 life, Iysine analogues usually require a mainlenance infusion or
administration for an optimum Ilaemostatic effect, cspccially in cardiac
knee replacement surgery. The dosage of Iysinc analoguC's should be
in patients with impaired renal function. Tranexamic acid mav increase th
risk of seizures, particularly in open-heart procedures. t
Antifibrinolytic agents should be used in trauma patients with establisheq
hyperfibri nolysis.
Large clinical evaluations are needed to determine the best combination
of d.ose,efficacyand safety of Iysine analogues in a broad range of clinical
setttnqs, popuiatlOn5 and co-morbid conditions.

22

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