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BJA Advance Access published July 26, 2004
British Journal of Anaesthesia Page 1 of 17
DOI: 10.1093/bja/aeh227
Perioperative systemic haemostatic agents
A. M. Mahdy and N. R. Webster*
Academic Unit of Anaesthesia and Intensive Care, University of Aberdeen, Aberdeen, UK
*Corresponding author: Anaesthesia and Intensive Care, Institute of Medical Sciences, Foresterhill,
Aberdeen AB25 2ZD, UK. E-mail: [email protected]
Br J Anaesth 2004
Keywords: blood, factor VIIa; blood, haemostasis; blood, loss; polypeptides, aprotinin
Skilful surgery combined with blood saving methods and
careful management of blood coagulation will all help reduce
unnecessary blood loss and transfusion requirements. Excessive surgical bleeding causes hypovolaemia, haemodynamic
instability, anaemia and reduced oxygen delivery to tissues
with a subsequent increase in postoperative morbidity and
mortality.46 Adverse effects of allogeneic blood transfusion
include transmission of infectious diseases, immunosuppression, transfusion-related acute lung injury, transfusion reactions and graft-vs-host reactions. The cost implication for
blood transfusion is also significant and includes the direct
blood transfusion costs as well as indirect costs originating
from additional treatments and prolonged hospitalization. In
a study conducted in the USA, avoiding allogeneic transfusions reduced total treatment costs in abdominal surgery by
approximately $5000 per patient.65
The role of anaesthetists in managing surgical blood loss
has grown greatly in the last decade. Intraoperative blood loss
varies according to the anaesthetic agent used7 and with
the type of anaesthesia.71 75 Simple elevation of the surgical
site may reduce blood loss, but may risk embolism in regions
with non-collapsing veins.135 Maintaining normothermia
reduces blood loss, because of the deleterious effects of
hypothermia on platelet function.76 Blood coagulation can
also be compromised by fluid replacement and profound
haemodilution. Moderate crystalloid substitution accelerates
rather than inhibits blood coagulation; however, with
advanced crystalloid haemodilution blood coagulation may
become compromised.127 The use of colloids may also compromise coagulation, hydroxyethyl starch more than gelatin
and serum albumin.31 A combination of generous amounts of
#
crystalloids with some colloids may be optimal to maintain
blood coagulation and avoid blood loss as resulting from
coagulopathy.146 Controlled hypotension has been used to
decrease surgical blood loss. The limited efficacy of this
technique may be related to the fact that relatively low
blood pressures are commonly tolerated in routine anaesthesia; thus, a further decrease in mean arterial pressure to
approximately 50 mm Hg may only offer limited benefit.146
Some surgical procedures may be associated with
excessive blood loss and/or deranged haemostasis in patients
without pre-existing haemostatic abnormalities (cardiopulmonary bypass, orthotopic liver transplantation, prostatic
surgery and some orthopaedic procedures). Moreover, we
are increasingly confronted with subgroups of patients
who refuse blood transfusion or who are likely to lose
more blood in the perioperative period (e.g. patients on antiplatelet agents or anticoagulants, patients with hepatic cirrhosis, and those with chronic renal failure). Several
pharmacological haemostatic agents are currently being
used by anaesthetists as blood-saving agents in such
circumstances.
After a brief discussion of the physiology of haemostasis,
we will review the evidence for the role of such agents
in reducing perioperative blood loss and transfusion
requirements.
Physiology of haemostasis in surgery and
trauma
Haemostasis depends on a successful balance between the
coagulation, complement and fibrinolytic pathways, with
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Skilful surgery combined with blood-saving methods and careful management of blood coagulation
will all help reduce unnecessary blood loss and transfusion requirements. Excessive surgical bleeding causes hypovolaemia, haemodynamic instability, anaemia and reduced oxygen delivery to
tissues, with a subsequent increase in postoperative morbidity and mortality. The role of anaesthetists in managing surgical blood loss has increased greatly in the last decade. Position of the
patient during surgery and the provision of a hypotensive anaesthetic regimen were once considered the most important contributions of the anaesthetist to decreasing blood loss. Now,
several pharmacological haemostatic agents are being used by anaesthetists as blood-saving agents.
After a brief discussion of the physiology of haemostasis, this article will review the evidence for the
role of such agents in reducing perioperative blood loss and transfusion requirements.
Mahdy and Webster
Coagulation cascade
Coagulation involves the laying down of a strong fibrin mesh
through the primary platelet plug and is brought about by the
action of a sequence of pro-enzymes and cofactors that work
in concert to generate the final enzyme, thrombin. Thrombin
then directly cleaves fibrinogen to produce fibrin (Fig. 1). The
enzymes involved in blood coagulation belong to a family of
proteases known as serine proteases, a class of enzymes with a
common mechanism of enzymatic action that requires the
catalytic triad of serine, aspartic acid and histidine within the
active site.
Injury to the arterial or venous wall exposes perivascular,
tissue factor-expressing cells to blood. Tissue factor (TF) is a
cellular receptor for activated factor VII (factor VIIa) and
factor VII. It is expressed constitutively in most non-vascular
cells and can be induced in monocytes, endothelial cells,
smooth muscle cells, circulating monocytes, tissue macrophages and fibroblasts. Factor VIIa, found in small amounts in
normal plasma, binds to exposed TF. Once bound to TF,
factor VIIa can catalyse the activation of factor VII, which
also binds to exposed TF. The factor VIIa–TF complex then
activates factors IX and X in the presence of Ca2+, leading to
the generation of factors IXa and Xa respectively. Activation
of factor X through the above mechanism is referred to as the
extrinsic pathway.
The intrinsic pathway is initiated by activation of factor XII
by kallikrein on foreign surfaces or damaged endothelium,
and is facilitated by kininogen. The active form of factor XII,
factor XIIa, catalyses the conversion of factor XI to its active
form, factor XIa. In the presence of Ca2+, factor XIa activates
factor IX to its active form, factor IXa. Factor IXa binds to the
cofactor factor VIIIa bound on membrane surfaces in the
presence of calcium ions to generate a complex with
enzymatic activity known as ‘tenase’, a nickname for the
enzymatic activity that acts on factor X.
Activation of factor X to factor Xa by the extrinsic or
intrinsic pathways is the start of the common pathway of
coagulation. The latter pathway is thought to be of little significance in vivo since patients with factor XII, prekallikrein
or kininogen deficiency have no bleeding disorders. These
proteins are not required for haemostasis. However, they may
play a role in fibrinolysis and in fibrin formation during
inflammation and wound healing. When factor Xa is generated, it complexes with factor Va, phospholipid and calcium
to form the prothrombinase complex, which converts prothrombin to its active form, thrombin. The generated thrombin: (i) cleaves fibrinogen, releasing fibrin; (ii) activates
factor XIII, responsible for cross-linking the fibrin polymer,
rendering it resistant to fibrinolysis; (iii) activates factors V
Fig 1 The coagulation cascade. *A small quantity of activated factor VII is physiologically present in the plasma and is responsible for the initial binding
with tissue factor (TF). Ca2+, calcium ion; PF3, platelet factor-3; HMWK, high molecular weight kininogen.
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complex interactions between plasma proteins, platelets,
blood flow and viscosity, and the endothelium. Formation
of the primary haemostatic plug at the site of a damaged
vessel is the first event in the control of bleeding. Von
Willebrand factor binds to the exposed subendothelium,
exposing multiple intrinsic binding sites for a specific platelet
membrane structure termed GPIb. This is followed by platelet
activation, adhesion and generation of a platelet plug.
Platelets adhering at the site of injury are exposed to several
activating stimuli, which enhance the initial adhesion
and allow other platelets to accrete on those already
attached. Activation of platelets by thrombin, ADP and
von Willebrand factor–GPIb progresses through several
metabolic pathways to induce spreading of the platelets
over the damaged surface.
Perioperative systemic haemostatic agents
and VIII, generating factors Va and VIIIa, which are cofactors
for factors Xa and IXa; and (iv) is a potent platelet-aggregating agent.
Activation of the coagulation cascade triggers several physiological pathways that tend to counteract and limit the
spread of coagulation to the area of injury.
Antithrombin
Protein C pathway
In addition to inactivation by antithrombin, thrombin is also
inhibited by binding thrombomodulin, a thrombin receptor
found on the endothelium. Once bound to thrombomodulin,
thrombin undergoes a conformational change at its active site
that converts it from a procoagulant enzyme into a potent
activator of protein C. Activated protein C serves as an anticoagulant by proteolytically degrading and inactivating factors Va and VIIIa, thereby blocking thrombin generation.
Tissue factor pathway inhibitor
Inhibition of the factor VIIa–TF complex is affected by
tissue factor pathway inhibitor (TFPI), the majority of
which is bound to endothelium. Tissue factor pathway inhibitor first complexes and inactivates factor Xa and then the
TFPI–factor Xa complex inactivates factor VIIa within the
factor VIIa–TF complex.
Fibrinolytic system
Designed to remove intravascular fibrin, thereby restoring
blood flow, fibrinolysis is initiated by plasminogen activators
that convert plasminogen to plasmin. Plasmin degrades fibrin
into soluble fibrin degradation products. It inactivates factors
Va and VIIIa, amplifies its own generation, disrupts platelet
function and degrades matrix proteins. Human plasminogen
harbours within its structure specific lysine-binding sites that
mediate the binding of plasminogen to fibrin and play a crucial role in the regulation of fibrinolysis. Regulation and
control of the fibrinolytic system is mediated by specific
molecular interactions among its main components, and by
controlled synthesis and release of plasminogen activators
and plasminogen activator inhibitors, primarily from
endothelial cells (Fig. 2). Enzymes of the fibrinolytic system
are serine proteases, whereas the inhibitors of the
fibrinolytic system are grouped into the serpin (serine
proteinase inhibitor) superfamily.
Fig 2 The fibrinolytic system. t-PA, tissue type plasminogen activator;
u-PA, urokinase type plasminogen activator; PAI-1, plasminogen activator
inhibitor I; PAI-II, plasminogen activator inhibitor II; HMWK, high molecular weight kininogen; TAFI, thrombin activatable fibrinolysis inhibitor.
Two immunologically distinct physiological plasminogen
activators have been identified in blood: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Tissue-type plasminogen activator, which is
synthesized and secreted by endothelial cells, mediates intravascular plasminogen activation and is primarily involved in
the dissolution of fibrin in the circulation. In contrast, u-PA
binds to specific cellular receptors, resulting in enhanced
activation of cell-bound plasminogen, and is primarily
involved in tissue remodelling and repair. The fibrinolytic
system can be inhibited at two levels. Plasminogen activator
inhibitors, the most important of which is endothelial cellderived type 1 plasminogen activator inhibitor (PAI-1), block
t-PA and u-PA, whereas a2-antiplasmin inhibits plasmin.
Although a2-antiplasmin rapidly complexes and inactivates
free plasmin, fibrin-bound plasmin is relatively protected
from inactivation, so that fibrinolysis can occur despite
physiological levels of this inhibitor.
A limited number of pharmacological agents have been in
use for correction of haemostatic defects in the perioperative
period. The lack of clear insight into the pathogenesis of
perioperative bleeding as well as its multifactorial origins
has hampered the development of specific and new haemostatic agents and added more confusion and ambiguity to the
mechanisms of action and clinical applications of currently
available agents.
Vasopressin analogues
Desmopressin
Desmopressin acetate, 1-desamino-8-D-arginine vasopressin (DDAVP), is a synthetic vasopressin analogue. It
is pharmacologically altered from naturally occurring vasopressin by deamination of hemicysteine at position 1 and
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Antithrombin inhibits thrombin, factor Xa and other
activated clotting factors, but these reactions are slow in
the absence of heparin. With heparin, however, the rate of
inhibition is accelerated 1000-fold. Although heparin is not
normally found in the blood, vascular endothelium is rich in
heparan sulphate. Most of the heparan sulphate is located on
the non-luminal surface of the endothelium and is exposed
only when the vessel lining is damaged.
Mahdy and Webster
Desmopressin in cardiac surgery
Cardiac surgery is one of the classic situations in which there
is a call for blood-saving measures. Factors contributing to
the relatively large blood losses include the size of the surgical wound, the exposure of blood to artificial surfaces in the
extracorporeal circuit, enzymatic and mechanical injury to
platelets and coagulation factors, and hyperfibrinolysis during and after cardiopulmonary bypass. In the mid-1980s,
there was considerable interest in the haemostatic effect of
desmopressin in patients undergoing cardiopulmonary
bypass. However, the initial promise suggested by preliminary studies was never confirmed by larger trials. In 1995,
Cattaneo and colleagues17 published a meta-analysis of 17
randomized, double blind, placebo-controlled trials which
included 1171 patients undergoing cardiac surgery; 579 of
them were treated with desmopressin and 592 with placebo.
Desmopressin significantly reduced postoperative blood loss
by 9% but had no significant effect on transfusion requirements. In a subanalysis of trials in which the mean blood loss
in placebo-treated patients fell in the upper third of distribution of blood loss, desmopressin significantly decreased postoperative blood loss by 34%. In 1997, Laupacis and
Fergusson78 published another meta-analysis showing that
desmopressin was ineffective in reducing blood loss in cardiac surgery. The primary outcome was the proportion of
patients who received at least one perioperative allogeneic
red cell transfusion. The most recent meta-analysis of randomized controlled trials studying the role of desmopressin in
cardiac surgery was performed by Levi and colleagues86 in
1999, in which the use of desmopressin resulted in a small
decrease in perioperative blood loss but was not associated
with a beneficial effect on other clinical outcomes (mortality,
repeat thoracotomy, proportion of patients receiving transfusion). Moreover, desmopressin was associated with a 2.4-fold
increase in the risk of myocardial infarction.
Therefore, the routine use of desmopressin in uncomplicated cardiac operations in patients without pre-existing
bleeding disorders cannot be recommended. However, its
use may be beneficial in subgroups of patients with an
increased risk of bleeding. In an attempt to identify a
group of patients that might benefit from desmopressin therapy, Mongan and Hosking100 used postoperative thromboelastography to stratify patients according to haemostatic
function. They found that desmopressin reduced blood loss
and transfusion needs in patients with low maximal amplitudes (<50 mm), but no decrease in blood loss occurred in
those patients with a maximal amplitude >50 mm. Despotis
and colleagues21 used a new point-of-care test (hemoSTATUS) to identify patients at risk of excessive bleeding during
cardiac surgery. Patients with abnormal hemoSTATUS
results after discontinuation of cardiopulmonary bypass
were randomly assigned desmopressin or placebo. Patients
who received desmopressin had less blood loss, required less
transfusion of red blood cells, platelets and fresh-frozen
plasma, and had less total blood-donor exposures. It should
be noted, however, that in another study values derived from
the hemoSTATUS system did not correlate with mediastinal
chest tube drainage after cardiopulmonary bypass, which
cast some doubt on the strategy used by Despotis and
colleagues.38
Desmopressin has also been useful in treating patients with
aspirin-induced platelet dysfunction undergoing cardiopulmonary bypass surgery; randomized trials have shown
decreased blood loss and transfusion requirements.27 141
Desmopressin in non-cardiac surgery
There are few clinical trials evaluating the use of prophylactic desmopressin in reducing bleeding in non-cardiac
surgery. There have been two studies evaluating the use of
desmopressin in patients having spinal fusion surgery.
Kobrinsky and colleagues72 reported a beneficial effect in
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substitution of D-arginine for L-arginine at position 8. These
changes virtually eliminate vasopressor (V1 receptor agonist)
activity, and enhance the antidiuretic (V2 receptor agonist)
action. It also prolongs the duration of action from
2–6 h to 6–24 h by increasing resistance to enzymatic
cleavage.39 Desmopressin is also more potent than arginine
vasopressin in stimulating the endothelial release of factor
VIII and von Willebrand factor into the plasma (V2 receptormediated effect), where they form a complex with platelets
and enhance their ability to aggregate.39 This effect, which
mimics replacement therapy with blood products, forms the
rationale for the use of desmopressin in the treatment of
patients with mild haemophilia A and type I von Willebrand’s
disease, who have spontaneous bleeding or are scheduled to
undergo surgery.113
For haemophilia A, von Willebrand’s disease, uraemic
thrombocytopathy, and when used perioperatively, desmopressin is given in a dose of 0.3 mg kg 1 and infused slowly
because of the risk of acute hypotension.39 Plasma concentrations of factor VIII and von Willebrand factor are approximately doubled or quadrupled, reaching a peak 30–60 min
after i.v. infusion.84 These doses can be repeated as clinically
necessary at intervals of 12 to 24 h, but tachyphylaxis may
occur after three or four doses.92 After i.v. injection, desmopressin has a distribution half-life of 7–8 min and an elimination half-life of 2.5–4.4 h.62
Desmopressin shortens the bleeding time in a variety of
congenital platelet function defects. The ability to shorten the
bleeding time in these patients is unpredictable and must be
assessed individually in each patient.118 Desmopressin can
shorten the prolonged bleeding time in patients with hepatic
cirrhosis and in chronic uraemia,91 despite the fact that von
Willebrand factor and factor VIII are within normal levels. It
is therefore used to prevent haemorrhage after biopsies or
minor surgical procedures or to control acute bleeding in such
patients.128 Patients with prolonged bleeding time secondary
to antiplatelet drugs (aspirin or ticlopidine) may also benefit
from the effect of desmopressin as it promptly normalizes
primary haemostasis and shortens the bleeding time in most
of these patients.128
Perioperative systemic haemostatic agents
Adverse effects
Adverse effects of desmopressin include mild facial flushing,
headache, palpitations and hypotension. Other adverse
effects are the result of the potent antidiuretic action of
this agent, and include water retention, hyponatraemia and
seizures. Desmopressin should also be used with caution
during pregnancy, as it may induce premature labour.113
Desmopressin promotes the release into plasma of tissuetype plasminogen activator, resulting in a short-lived generation of plasmin, which is promptly neutralized by circulating
antiplasmin; no fibrinolytic activation occurs in vivo. Accordingly, inhibiting fibrinolysis when desmopressin is administered is not usually needed.128
One of the concerns that has not been substantiated to date
is the ability of desmopressin to induce a potentially prothrombotic state through enhanced platelet aggregation
and increased factor VIII activity. A recent meta-analysis
of 12 randomized controlled trials using DDAVP in cardiac
surgery reported an incidence of myocardial infarction of
4.4% in the DDAVP-treated group vs 1.6% in the placebotreated group (odds ratio=2.07; 95% confidence interval
0.74–5.85; P=0.19).78 Pooled data from 17 randomized
controlled trials in cardiac and vascular surgery that
specifically mentioned the presence or absence of thrombotic events showed an incidence of myocardial infarction
of 3.9% in the DDAVP-treated group and 3.1% in the
placebo group with an odds ratio of 1.25 (confidence interval
0.72–2.14; P=0.43).157
hyperfibrinolysis are operations requiring cardiopulmonary
bypass, orthotopic liver transplantation, and some urological
and orthopaedic operations. However, antifibrinolytics have
also been widely and successfully used in surgical procedures
not associated with hyperfibrinolysis.
Plasmin, the final enzyme in the fibrinolytic pathway, is a
serine protease. It is not surprising, therefore, that inhibitors
of serine proteases possess antifibrinolytic properties. They
do so by forming reversible enzyme–inhibitor complexes
with plasmin and other serine proteases.90 It is important
to note that coagulation enzymes are serine proteases and
therefore serine protease inhibitors will possess anticoagulation in addition to antifibrinolytic properties.
Lysine analogues reversibly bind to the lysine-binding site
on plasminogen, thereby inhibiting the conversion of plasminogen into plasmin on the surface of fibrin (Fig. 3).90 They
also prevent plasmin degradation of platelet glycoprotein lb
receptors.157 Lysine analogues can potentially enhance haemostasis when bleeding is associated with primary fibrinolysis (hyperplasminaemia). They should not, however, be
used in disseminated intravascular coagulation (DIC) as
this may increase intravascular thrombosis, unless lowdose heparin is given concomitantly. The reason is that lysine
analogues inhibit both circulating plasmin and fibrin-bound
plasmin and therefore interfere with the dissolution of clots in
Antifibrinolytics
Antifibrinolytic agents in current use include the naturally
occurring serine protease inhibitor aprotinin, the
synthetic protease inhibitor nafamostat and the synthetic
lysine analogues aminocaproic acid and tranexamic acid.
Antifibrinolytic drugs should ideally be used only in those
situations in which hyperfibrinolysis can be detected.
Typical surgical procedures which may be associated with
Fig 3 Mechanism of action of lysine analogues. On the left, EACA or
tranexamic acid (lysine analogues) blocks the lysine-binding site on plasminogen, which is essential for binding to fibrin, and thereby prevents the
activation of plasminogen on the surface of fibrin. Binding of lysine analogues to plasminogen prevents the breakdown of fibrin, even though plasmin is generated (lower left).
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terms of blood loss and transfusion requirements, while Guay
and colleagues48 found no benefit. Three trials showed no
significant differences in blood loss or transfusion requirements when desmopressin was used in elective total hip/knee
arthroplasty.37 67 136 In aortoiliac surgery, Lethagen and colleagues85 reported a small difference in blood loss with desmopressin, although this difference was not statistically
significant. However, a subgroup analysis showed that in
patients with a basal von Willebrand factor antigen concentration <150 IU dl 1, when treated with desmopressin bled
significantly less than those given placebo. Another more
recent randomized, double-blind, placebo-controlled study
found no benefit in elective aortic surgery when desmopressin
(20 mg i.v.) was given at the time of aortic clamp placement.19
The overall evidence therefore does not support a beneficial
effect of desmopressin in haemostatically normal patients
undergoing elective non-cardiac surgical procedures.
Mahdy and Webster
Epsilon-aminocaproic acid
Epsilon-aminocaproic acid (6-aminohexanoic acid; EACA)
is a competitive inhibitor of plasminogen activation and
inhibits plasmin to a lesser extent (at higher doses). It
has been used in various doses and regimens in patients
undergoing surgery. In general, the recommended dose is
150 mg kg 1 as an i.v. bolus before surgery, followed by
an infusion of 15 mg kg 1 h 1 during the operation.113
EACA is largely eliminated unchanged by renal excretion
and about 35% undergoes hepatic metabolism to the
metabolite adipic acid, which also appears in the urine.
The renal clearance (116 ml min 1) approximates endogenous creatinine clearance, and total body clearance is 169 ml
min 1. The terminal elimination half-life for aminocaproic
acid is 1 to 2 h.113
EACA in cardiac surgery
Several trials have studied the prophylactic administration of
this drug in patients undergoing cardiopulmonary bypass. In
most of these studies, aminocaproic acid was compared with
either tranexamic acid or aprotinin. Only a few studies have
compared aminocaproic acid directly with placebo. The
observed efficacy of aminocaproic acid varied somewhat
from study to study, which may be explained by differences
in dosage and time of administration. There are four metaanalyses of EACA in cardiac surgery. Levi and colleagues86
and Fremes and colleagues40 included EACA and tranexamic
acid under the same treatment group (lysine analogues), and
concluded that prophylactic administration of lysine analogues led to a significant reduction in postoperative bleeding
(30–40%), without increasing the incidence of thromboembolic complications. Munoz and colleagues103 compared the
results of five studies in which EACA was used during cardiac
surgery with 52 studies in which aprotinin was used. The
authors concluded that the two antifibrinolytic agents appear
to have similar efficacies, and that the considerably less
expensive EACA may be preferred to aprotinin for reducing
haemorrhage with cardiac surgery. However, we should
interpret the results of the latter study cautiously because
the five EACA studies were in patients undergoing primary
surgery, whereas more than 50% of the aprotinin trials were in
patients undergoing complex or repeat surgery. In one metaanalysis, aminocaproic acid was not found to have a statistically significant effect on the proportion of patients requiring transfusion.78 However, there were only three EACA
trials among the 60 trials included in the analysis. The
poor evaluation of EACA in cardiac surgery and the lack
of an adequate number of large randomized controlled trials
make it difficult to support the use of EACA in this particular
surgical setting.
EACA in non-cardiac surgery
In patients undergoing orthotopic liver transplantation, Kang
and colleagues66 described a beneficial effect of low-dose
aminocaproic acid (1 g, single infusion). On the other
hand, in a large double-blind trial in which EACA and tranexamic acid were compared with placebo, no significant
difference in transfusion requirements was found between
the EACA and the placebo group.20 However, administration
of the study medication was discontinued at reperfusion of the
new liver, and a possible therapeutic effect could have been
missed because hyperfibrinolytic bleeding is mainly seen
after graft reperfusion. Very low dose EACA (single infusions of 300 mg) is still widely used to treat severe bleeding in
liver transplantation; however, there are no randomized trials
confirming the efficacy of EACA in this setting.
Primary hyperfibrinolysis may occur in patients undergoing prostatic surgery as a result of the release of plasminogen activators from the prostatic tissue. High levels of
plasminogen activators can also be found in urine; this contributes to dissolution of haemostatic clots and haematuria. In
a clinical trial involving patients who had undergone prostatectomy, EACA was effective in controlling postoperative
haematuria compared with placebo, and its use was not
accompanied by significant complications.95 The drug is
not known to reduce the need for transfusion or to decrease
mortality after uncomplicated prostatectomy, and therefore is
not given routinely.
Although EACA has also been used in patients undergoing
other types of surgery, there are not enough data from prospective studies to support the wider application of this agent.
In a recently published Cochrane systematic review of the use
of antifibrinolytics in elective surgery, the results suggested
that EACA might be as effective as other antifibrinolytics.
However, the reviewers could not endorse this finding as they
were able to include only four trials of EACA (208 patients)
compared with 61 trials of aprotinin (7027 patients) and 18
trials of tranexamic acid (1342 patients).57
Adverse effects
The most common acute side-effect with EACA is hypotension that is usually associated with rapid i.v. administration.
Other reported adverse effects are occasionally encountered
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small blood vessels, further aggravating the condition. This is
at variance with aprotinin, which inhibits circulating plasmin
and spares fibrin-bound plasmin. Additionally, clinical studies indicate that antifibrinolytic amino acids are haemostatically effective even when bleeding is not associated with
overt laboratory signs of hyperfibrinolysis.128 Both drugs
have been widely used to prevent or treat bleeding during
tooth extraction in haemophilia and some other coagulation
disorders. They are used in the management of recurrent
epistaxis, upper gastrointestinal bleeding and primary menorrhagia. Moreover, tranexamic acid appears to reduce the frequency of attacks of hereditary and non-hereditary
angioneurotic oedema. Epsilon-aminocaproic acid and tranexamic acid have been used in the past to reduce the incidence of rebleeding in subarachnoid haemorrhage; however,
this is not currently adopted because both drugs may induce
vasospasm and ischaemic stroke.153
Perioperative systemic haemostatic agents
Tranexamic acid
Tranexamic acid (trans-4-aminomethyl-cyclohexane carboxylic acid) is a competitive inhibitor of plasminogen activation and, at much higher concentrations, a non-competitive
inhibitor of plasmin. Its actions are similar to those of aminocaproic acid, but tranexamic acid is about 10 times more
potent in vitro, with higher and more sustained antifibrinolytic activity.154 Tranexamic acid is usually given as a bolus
dose of 10–15 mg kg 1 i.v. before surgery. In cardiac surgery,
this is followed by 1 mg kg 1 h 1 for 5–8 h. However, a wide
range of dosage regimens has been used in different surgical
procedures.39 113 Only a small fraction of administered tranexamic acid is metabolized; most is excreted unchanged by
the kidney. The dose must be substantially decreased in renal
impairment. Pharmacokinetic studies have revealed that tranexamic acid has a volume of distribution of 9–12 litres and
an elimination half-life of about 2 h.39
There are a number of clinical studies that attest to its
effectiveness in decreasing blood loss and transfusion
requirement after cardiopulmonary bypass. There is also
some evidence that it may be effective in other surgical
procedures.
Tranexamic acid in cardiac surgery
Prophylactic administration of lysine analogues has been
shown to reduce bleeding after cardiopulmonary bypass by
30–40%.40 86 In a recent meta-analysis of 12 trials in patients
undergoing cardiopulmonary bypass, tranexamic acid treatment was associated with a reduction in perioperative blood
loss and allogenic blood transfusion requirements.78 The timing of administration of tranexamic acid in relation to the
onset of cardiopulmonary bypass seems to be crucial for its
beneficial effect. Brown and colleagues10 showed that tranexamic acid was less effective when given after commencement of bypass. Casati and colleagues15 compared
tranexamic acid with high-dose aprotinin in primary elective
cardiac operations. The authors concluded that tranexamic
acid and aprotinin show similar clinical effects on bleeding
and allogeneic transfusion. Because tranexamic acid is about
100 times cheaper than aprotinin, the authors recommend that
its use would be preferable in this setting. Mongan and colleagues99 reported similar results in a similar patient population. However, there seems to be no proof of a reduction in the
operative mortality risk when tranexamic acid is used in
patients undergoing cardiac surgery, an effect that has
been reported with aprotinin.86 The use of tranexamic acid
in adult and paediatric patients undergoing repeat cardiac
surgery was associated with significant reduction in blood
loss and transfusion requirements in two studies.29 120 On the
other hand, Kovesi and Royston thought that the evidence for
the use of tranexamic acid in repeat cardiac surgery is neither
powerful nor consistent.73 Tranexamic acid might also
be effective in reducing blood loss and the need for allogenic
blood products in patients undergoing off-pump coronary
surgery14 and in those undergoing elective thoracic aortic
surgery.16 The use of tranexamic acid in cardiac surgery is
not associated with an increased risk of postoperative myocardial infarction. Wells157 pooled data from 10 randomized
trials that have commented on adverse events, including
thrombosis. The incidence of myocardial infarction in tranexamic acid-treated patients was 0.36% compared with
1.5% in the placebo group. However, the end-points used
for detection of myocardial infarction varied among the different studies and may not always have been adequate. Current evidence suggests that tranexamic acid can safely and
effectively reduce blood loss and allogenic transfusion in
patients undergoing cardiac surgery. It is as effective as aprotinin in the setting of primary cardiac surgery and is far more
cost-effective. The evidence for its use in patients on aspirin
and those undergoing repeat operations is, however, not compelling.
Tranexamic acid in non-cardiac surgery
There have been several double-blind trials in patients undergoing total knee arthroplasty in which prophylactic administration of tranexamic acid significantly reduced total blood
loss by up to 50% and decreased transfusion requirements
without increasing the risk of thromboembolic manifestations.58 64 152 Benoni and colleagues5 found no benefit
from administering tranexamic acid after the release of the
tourniquet and stated that for optimum efficacy tranexamic
acid should be administered prophylactically at an earlier
stage. Tanaka and colleagues149 found that two injections
of tranexamic acid, one given before surgery and one on
deflation of the tourniquet, was the optimal technique. In
patients undergoing total hip replacement, Ekback and colleagues32 and Benoni and colleagues4 independently
reported a reduction in intraoperative blood loss when tranexamic acid was given prophylactically. However, when
tranexamic acid was given at the end of the operation, it
did not reduce postoperative blood loss in hip arthroplasty.5
In spite of its effectiveness, tranexamic acid cannot be recommended for every patient undergoing joint replacement; it
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with longer-term administration, and include rash, nausea
and vomiting, weakness, retrograde ejaculation, myopathy
and even rhabdomyolysis.39 Between 1972 and 1995, 31
cases of EACA-induced myonecrosis and myoglobinuria
were reported. All patients received high doses of oral
EACA for more than 28 days. There are no reports of myonecrosis associated with the i.v. use of EACA in the perioperative setting.138 EACA has been implicated in isolated
cases of diffuse thrombosis and fatal pulmonary embolism
after prostatectomy. However, these reports were never
substantiated and the evidence from controlled studies
indicates that the use of EACA is not associated with an
increased incidence of thrombotic events.157 EACA is
contraindicated in patients with bleeding from the upper
urinary tract because of the risk of clot retention in the ureter
and bladder. It is also teratogenic and is therefore contraindicated in pregnancy.128
Mahdy and Webster
Adverse effects
Gastrointestinal side-effects, such as nausea, diarrhoea and
abdominal cramping, have been reported primarily with oral
forms of tranexamic acid but were not reported with i.v.
administration. Rapid i.v. administration of tranexamic
acid may, however, cause hypotension and should therefore
be administered slowly as an infusion. As with aminocaproic
acid, the major concern with tranexamic acid is the potential
for increasing the perioperative risk of thromboembolic complications (arterial thrombosis, myocardial infarction and
pulmonary embolism). However, apart from anecdotes and
case reports, there is no clear-cut evidence that tranexamic
acid is associated with an increased risk of thromboembolic
complications. With respect to renal toxicity from the use of
tranexamic acid, there is little to suggest concern. However,
in one study a group of patients were given tranexamic acid
intraoperatively and for 12 h after surgery, while another
group received tranexamic acid only intraoperatively. The
continued postoperative use of tranexamic acid added no
advantages in terms of blood saving and was associated
with a tendency to renal dysfunction.13
Nafamostat
In 1981, Fujii and Hitomi44 first reported the use of nafamostat mesilate as a synthetic protease inhibitor. It inhibits
thrombin, factors Xa and XIIa, kallikrein, plasmin and complement factors (C1r, C1s). As such, it works as an antifibrinolytic, anticoagulant and anti-inflammatory agent.
Moreover, it has also been shown to preserve platelet function
during cardiopulmonary bypass. Clinically, it has been used
in the treatment of disseminated intravascular coagulation
and acute pancreatitis. It has also been investigated as an
anticoagulant in extracorporeal circuits and as a haemostatic
agent in cardiac surgery. Several studies conducted in Japan
reported a significant reduction in postoperative blood loss
when nafamostat was used in cardiac surgery.104 132 148
Moreover, in a controlled study of 22 patients undergoing
hepatic resection for hepatocellular carcinoma, there was a
significant reduction in fibrinolytic activity together with a
reduced blood transfusion rate in patients who were treated
with nafamostat.143
Aprotinin
Aprotinin is a naturally occurring 58-residue polypeptide
derived from bovine lung with a molecular weight of
6512 Da. It is a powerful inhibitor of plasmin, trypsin, chymotrypsin, kallikrein, thrombin and activated protein C,
through the formation of reversible enzyme–inhibitor complexes.90 157 The enzymatic activity of aprotinin is generally
expressed in kallikrein inactivator units (KIU), with 1 KIU
defined as the amount of aprotinin that decreases the activity
of two biological kallikrein units by 50%.39 The mechanisms
by which aprotinin exert its haemostatic effects are not fully
understood. Studies of perioperative haemostasis have shown
that plasma markers of fibrinolytic activity, such as D-dimers,
are suppressed during the use of aprotinin.109 119 This led to
the conclusion that aprotinin reduces perioperative bleeding
by acting as a powerful antifibrinolytic. It inhibits circulating
plasmin without interfering with fibrin-bound plasmin, and
therefore it does not prevent the dissolution of clots in small
blood vessels, an effect that is not observed with antifibrinolytic lysine analogues.128 At higher doses, aprotinin also
inhibits kallikrein and thus the intrinsic pathway of coagulation with a subsequent reduction in contact-factor-dependent
fibrinolysis and bradykinin production. Plasma concentrations of 125 KIU ml 1 are usually needed to inhibit plasmin,
whereas concentrations of 300–500 KIU ml 1 are needed to
inhibit kallikrein.61
There is controversy in the literature regarding the effects
of aprotinin on platelets. Initial studies in patients undergoing
cardiac surgery suggested that aprotinin protects platelets
against the initial effect of cardiopulmonary bypass.79 151
This has been challenged recently by other studies suggesting
that aprotinin does not influence platelet function.109 156 The
currently held view is that the haemostatic effect of aprotinin
is exerted mainly through inhibition of plasmin. Although
aprotinin does not directly affect platelet adhesion or
aggregation, it may indirectly protect platelets through the
inhibition of various platelet agonists produced during cardiopulmonary bypass, including plasmin.142
In addition to its haemostatic properties, aprotinin has multiple actions that may suppress the inflammatory response,
particularly at higher dosages. By inhibiting kallikrein, aprotinin blocks the conversion of kininogen to the inflammatory
mediator bradykinin.155 It also inhibits the activation of C1 of
the complement system,155 attenuates the release of TNF-a,59
interleukin (IL)-6 and IL-8,50 inhibits endogenous cytokineinduced nitric oxide synthase induction,60 decreases bypassinduced leucocyte activation155 and inhibits monocyte and
granulocyte adhesion molecule up-regulation.45
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should be considered for patients in whom large blood losses
are predicted or for those who refuse blood transfusion.
Tranexamic acid has also been used in the setting of orthotopic liver transplantation. In a small randomized, placebocontrolled study, it was shown that prophylactic infusion of
low-dose tranexamic acid (2 mg kg 1 h 1) reduced fibrinolysis but not transfusion requirements during orthotopic liver
transplantation.68 On the other hand, Boylan and colleagues9
and Dalmau and colleagues20 independently examined the
effect of high-dose tranexamic acid (10–40 mg kg 1 h 1) in
primary orthotopic liver transplantation; both groups
reported a significant reduction in intraoperative blood loss
and transfusion requirements. The use of tranexamic acid in
prostatic surgery is not very well studied, although it has been
reported that prolonged oral administration of tranexamic
acid (1 g three times daily orally for 3 weeks) may reduce
the incidence of secondary bleeding and the number
of readmissions for haemorrhagic complications after
prostatic surgery.30
Perioperative systemic haemostatic agents
Aprotinin has been used in different dose administration
regimens, the most common being a loading dose of 2 million
KIU followed by continuous infusion of 500 000 KIU h 1.125
In cardiac surgery, an additional 2 million KIU is added to the
bypass pump prime.39 After i.v. injection, rapid redistribution
of aprotinin occurs into the extracellular space, leading to a
rapid initial decrease in plasma concentration. It is metabolized in the proximal renal tubules and eliminated in a
biphasic pattern: a rapid-phase half-life of approximately
40 min and a slower phase half-life of 7 h.113
Aprotinin in cardiac surgery
Aprotinin in non-cardiac surgery
In major thoracic surgery, blood loss can be a serious problem. This is particularly noticed in surgery for inflammatory
pulmonary disease, decortication procedures and re-thoracotomies for recurrent tumours. Kyriss and colleagues77 and
Bedirhan and colleagues3 independently reported a significant reduction in perioperative transfusion requirements and
postoperative bleeding when aprotinin was used during major
thoracic surgery. This was not accompanied by increased
thromboembolic complications. Available data suggest
that aprotinin may be also beneficial in reducing blood
loss in lung transplant recipients.70 High-dose aprotinin
has been used almost routinely in Europe to reduce blood
loss in orthotopic liver transplantation, the first experience
dating back to 1989.108 Recently, two placebo-controlled
trials have shown beyond doubt that aprotinin reduces
blood transfusion requirements during orthotopic liver transplantation by 30–40% compared with placebo.36 114 Moreover, there is emerging evidence that aprotinin might have a
stabilizing effect on haemodynamics after reperfusion of the
new liver.98 This is probably attributable to its antikallikrein
activity, blocking activation of the contact system and
the subsequent release of vasodilating substances, such as
bradykinin.
In major orthopaedic surgery, several controlled trials have
shown that aprotinin significantly reduces the transfusion
requirement compared with placebo. This is of particular
benefit in spine surgery, revision or bilateral hip surgery,
total knee arthroplasty, pelvic surgery and surgery for
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It was the anti-inflammatory properties of aprotinin that first
prompted its use in cardiac surgery but, coincidentally, the
initial studies showed a significant reduction in blood loss
and transfusion requirements.123 Subsequently, multiple
well-designed double-blind trials have demonstrated the
effectiveness of aprotinin in patients undergoing procedures
requiring cardiopulmonary bypass.6 49 81 Aprotinin has been
of particular benefit in operations characterized by
large blood losses, such as those in patients taking aspirin,126
in patients with endocarditis,150 and in patients undergoing
re-operation144 or heart transplantation.115 Moreover, aprotinin significantly reduces blood loss in patients undergoing
off-pump coronary artery bypass surgery.33 There are four
recent meta-analyses, each of which confirms the efficacy of
aprotinin in reducing blood loss and the need for blood transfusion without increasing the risk of myocardial infarction.40 78 86 103 The use of aprotinin was also associated
with a two-fold reduction in mortality, an effect that was
not shared by other antifibrinolytics.86 In a multicentre, double-blind placebo-controlled trial, Levy and colleagues87
studied the effect of three different regimens of aprotinin
in patients undergoing coronary artery bypass graft surgery.
Patients were randomly assigned to either high-dose aprotinin (2·106 KIU loading dose, 2·106 KIU added to the circuit
prime, and a continuous infusion of 5·105 KIU h 1 during
surgery); low-dose aprotinin (1·106 KIU loading dose,
1·106 KIU added to the circuit prime, and a continuous
infusion of 2.5·105 KIU h 1 during surgery); and a pumpprime only regimen (2·106 KIU aprotinin added to circuit
prime). The percentage of patients requiring donor blood
transfusions in the high- and low-dose aprotinin groups
was reduced, whereas pump-prime-only aprotinin had no
effect. The efficacy of different low-dose aprotinin regimens
has also been reported by other research groups,53 69 but there
has been a lack of consistency in the literature regarding the
efficacy of prime-only aprotinin regimens.87 131
In contrast to low-dose aprotinin, high-dose aprotinin has
an anticoagulant activity and decreases thrombin generation,
which does not seem to interfere with its haemostatic activity.24 Interestingly, a recent meta-analysis reported a lower
incidence of stroke in patients receiving high dose aprotinin,105 and Lemmer and colleagues suggested that pumpprime-only regimens are possibly associated with more
frequent myocardial infarctions.80 In clinical studies,
high-dose aprotinin reduces post-bypass myocardial ischaemia and myocyte damage,159 and hospital length of stay in
high-risk patients.47 In addition to its haemostatic effect,
aprotinin decreases experimental bypass-induced and
cytokine-induced bronchial inflammation,11 and attenuated
lung reperfusion injury following bypass in one small clinical
study.117 It seems, however, that aprotinin in doses currently
used to reduce blood loss has no significant influence on the
systemic inflammatory response during moderate hypothermic cardiopulmonary bypass.134
Although not overwhelming, evidence favours the use of
aprotinin over other antifibrinolytics as a haemostatic agent in
cardiac surgery. It is the most extensively studied antifibrinolytic in this setting. It has consistently been reported to
reduce blood loss and transfusion requirements. It is the
only antifibrinolytic that has been associated with reduced
mortality, a reduced incidence of strokes and shorter hospital
stay. Moreover, there are suggestions that its use might be
associated with reduced myocardial reperfusion injury and
post-bypass inflammatory response. It should, however, be
noted that aprotinin is the least cost-effective antifibrinolytic.
Some argue that the routine use of aprotinin in all patients
should be discouraged because many cardiac surgical procedures are not associated with the need for blood transfusion.
This would also avoid the unnecessary risk of sensitization as
well as other adverse effects.
Mahdy and Webster
Adverse effects
Administration of aprotinin introduces a foreign polypeptide
into the systemic circulation; it is therefore not surprising that
hypersensitivity reactions may occur. These reactions range
from mild skin flushing to severe anaphylaxis and circulatory
shock. Most of the published case reports of severe anaphylactic reactions with aprotinin occurred in patients with a
history of being exposed to the drug.22 23 133 Dietrich and
colleagues26 evaluated 121 patients undergoing repeat cardiac surgery who were re-exposed to aprotinin. Preoperative
anti-aprotinin IgG and IgE antibodies were detected in 18 and
nine patients respectively. Three patients out of the 121
(2.5%) experienced an anaphylactic reaction after aprotinin
exposure, followed by full recovery; these patients had reexposure intervals of less than 6 months and the highest
preoperative IgG concentrations of all patients. The authors
concluded that quantitative detection of anti-aprotinin IgE
and IgG lacks specificity for predictive purposes; however,
quantitation of anti-aprotinin IgG may identify patients at risk
of developing an anaphylactic reaction to aprotinin reexposure. It has been estimated that on first-time exposure
the risk of anaphylaxis is less than 0.5%.15 This increases to
4–5% in those re-exposed within 200 days and drops to 1–2%
in those re-exposed after more than 200 days.25 Pretreatment
with corticosteroids and antihistamines seems to have limited
effect in preventing such reactions.157
Isolated case reports of graft occlusion and pulmonary
artery catheter thrombosis after the use of aprotinin in cardiac
surgery have fuelled an ongoing debate concerning its
safety.8 124 In the international study of perioperative transfusion,78 the incidence of perioperative myocardial infarction
was 8% in patients receiving aprotinin vs 5.6% in the placebo
group. Although this difference was not statistically significant, the number of patients was not enough to exclude a small
but clinically important increase in myocardial infarction in
patients treated with aprotinin. However, it is to be noted that
in controlled studies in which coronary angiography was used
to assess graft patency, aprotinin did not lead to an increased
rate of early occlusion of saphenous vein or internal mammary artery grafts.51 81 Moreover, Alderman and colleagues1
demonstrated no difference between 436 patients who used
high-dose aprotinin and 434 treated with a placebo in the
incidence of perioperative acute myocardial infarction and
mortality.
There has been some concern regarding the possibility of
an increased risk of postoperative deep-vein thrombosis in
patients treated with aprotinin. Samama and colleagues129
recently conducted a multicentre, double-blinded study to
compare the risk/benefit ratio of large- and small-dose aprotinin with placebo after major orthopaedic surgery. In their
study, bilateral ascending venography was systematically
performed on the third postoperative day. There was no
increase in deep vein thrombosis or pulmonary embolism
in the aprotinin groups. In another study, by Murkin,106 compression ultrasonography with colour Doppler imaging was
used to evaluate the presence of deep-vein thrombosis in
patients undergoing unilateral hip replacement. There was
no significant increase in the rate of deep-vein thrombosis in
patients treated with low- or high-dose aprotinin compared
with placebo. The possibility that low-dose aprotinin might
lead to more thrombotic events compared with high-dose
aprotinin is still controversial.
Aprotinin has a high affinity for renal tissue, and is potentially nephrotoxic in high concentrations. Feindt and colleagues35 suggested that aprotinin causes a reversible overload
of the tubular reabsorptive mechanisms, resulting in transient
renal dysfunction. Aprotinin may also exert direct toxic
effects on the proximal tubular cells or alter intrarenal
blood flow through inhibition of renin and kallikrein activity.157 Several randomized studies in patients undergoing
cardiac surgery81 137 or orthotopic liver transplantation surgery97 have shown no adverse effects of aprotinin on postoperative renal function. However, other studies reported a
trend towards a mild to moderate increase in postoperative
serum creatinine; this was not associated with clinically
important adverse outcome (e.g. need for dialysis or irreversible renal failure).82 147
Aprotinin, being extracted from bovine lungs, has been
recently withdrawn in Italy because of concerns that it
might transmit the agent responsible for bovine spongiform
encephalopathy and new-variant Creutzfeldt–Jakob disease.
The manufacturers of aprotinin state that the bovine lungs
used to extract aprotinin were collected in geographical areas
in which no cases of transmissible spongiform encephalopathy had been recorded, and there is no evidence that any
patients with the disorder have received aprotinin.90
Conjugated oestrogens
Conjugated oestrogens, like desmopressin, shorten prolonged bleeding times and reduce or stop bleeding in patients
with uraemia. The effect of conjugated oestrogens on the
bleeding time is more prolonged (10–15 days) than that of
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infectious or neoplastic bone diseases.12 83 107 129 In one of
these studies, the authors suggested that a much higher dose of
aprotinin (4·106 KIU initial dose followed by 1·106 KIU
h 1) might be required to obtain a significant blood-sparing
effect in this group of patients.129 None of these trials has
reported an increased incidence of postoperative deep venous
thrombosis or pulmonary embolism associated with aprotinin. Recently, Palmer and colleagues110 studied the efficacy
of prophylactic high-dose aprotinin in reducing intraoperative blood loss in neurosurgery in 100 patients enrolled in a
randomized, double-blind, placebo-controlled trial. There
was a significant reduction in intraoperative blood loss in
the aprotinin group and aprotinin treatment was not associated with an increased risk of thrombotic events, even
though patients did not receive prophylactic anticoagulation
therapy in the postoperative period.
Perioperative systemic haemostatic agents
Recombinant activated factor VII
Recombinant factor VIIa (rFVIIa) was originally developed
for the treatment of bleeding complications in haemophilia
patients with inhibitors against factors VIII or IX.54 In this
group of patients, surgery has always been a challenge as it
may result in life-threatening bleeding that is difficult to
manage by usual measures. Studies have shown that surgery
in patients with high-titre inhibitors against factor VIII or IX
can be performed safely using rFVIIa.52 139 Therapeutic
effects of rFVIIa begin at doses up to 10 times higher
than physiological concentrations of endogenous factor
VII. It is therefore used as a pharmacological intervention
rather than a mere replacement of a deficient coagulation
factor. Recombinant factor VIIa acts by enhancing the natural coagulation pathway through the formation of tissue
factor–factor VIIa complex at the site of endothelial damage.
This strictly localized effect is what makes rFVIIa different
from other haemostatic agents and almost eliminates all
undesirable side-effects. Moreover, studies have shown
that rFVIIa, when given in supraphysiological dosage, can
bind to the phospholipid membranes of activated platelets
where it activates factor X independent of the tissue factor
pathway, leading to a massive rise in thrombin generation at
the platelet surface.101 High-dose rFVIIa can therefore compensate for a lack of factor VIII or factor IX through what has
been described as a bypass effect,28 which explains its efficacy in treating patients with haemophilia with inhibitors.
This may also explain the effectiveness of rFVIIa in treatment of bleeding episodes in patients with platelet function
disorders.112
Because of its a short half-life (2.7 h), rFVIIa has to be
given as 2-hourly boluses or as a continuous infusion. Which
of these regimens is better is still a matter of debate. Some
studies have shown that continuous infusions result in a satisfactory haemostatic response.130 However, others have
reported that continuous infusions can be ineffective.145
Despite these conflicting results, rFVIIa can be administered
by continuous infusion as long as levels of factor VII:C of
30–40 IU ml 1 are achieved in the immediate postoperative period and levels are maintained above 10 IU ml 1
thereafter.34
Recombinant factor VIIa is a pan-haemostatic agent and as
such can be used in treating bleeding episodes in other disorders of haemostasis, such as factor VII deficiency, quantitative and qualitative platelet disorders, acquired von
Willebrand disease, uraemia and liver disease.18 43 63 74 112 121
The use of rFVIIa in patients without pre-existing haemostatic defect is currently under intense investigation. Preliminary results suggest that it can be used safely and
effectively to control life-threatening bleeding in surgery
and trauma, when all other measures have failed. It can
also be used to reduce blood loss and transfusion requirements in elective surgical procedures associated with excessive bleeding. It should be noted, however, that rFVIIa has not
been approved for use in any of these applications. The
mechanism of action of rFVIIa suggests enhancement of
haemostasis limited to the site of injury without systemic
activation of the coagulation cascade. Therefore, the use of
the drug in trauma patients suffering uncontrolled haemorrhage appears to be rational. Martinowitz and colleagues93
reported the use of rFVIIa in seven massively bleeding, multitransfused, and coagulopathic trauma patients after failure of
conventional measures to achieve haemostasis. Administration of rFVIIa in a dose range of 120–212 mg kg 1 resulted in
cessation of the diffuse bleeding, with significant reduction
in blood transfusion requirements, and shortening of
prothrombin time and activated partial thromboplastin
time. The results of this report suggest that rFVIIa may
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desmopressin (6–8 h). However, they must be administered
for a few days before a clinically significant effect can be
noticed.89
Conjugated oestrogens (e.g. Premarin, Wyeth-Ayerst
Laboratories, Philadelphia, PA, USA), given i.v. at a cumulative dose of 3 mg kg 1 (0.6 mg kg 1 daily for 4–5 consecutive days), have been reported to considerably shorten
the bleeding time, by 50%, for at least two weeks in uraemic
patients.89 A daily oral dose of 50 mg shortened the bleeding
time after an average of 7 days of treatment.140
The mechanism of the effect of conjugated oestrogens
on the bleeding time in patients with uraemia is unknown.
However, there is evidence that they increase levels of von
Willebrand factor and factors VII and XII. They may also
increase levels of physiological inhibitors of coagulation,
such as antithrombin.113
In patients with chronic renal insufficiency, recombinant
erythropoietin causes a dose-dependent increase in haematocrit, which is paralleled by a pronounced shortening of the
bleeding time and improvement of platelet adhesion.96 The
routine use of erythropoietin in chronic renal insufficiency
has therefore limited the scope for the use of haemostatic
drugs such as desmopressin and conjugated oestrogens.
Very few trials have been conducted to determine the efficacy of oestrogens in reducing blood loss during surgery. In
one randomized, placebo-controlled trial in patients undergoing orthotopic liver transplantation, conjugated oestrogens
significantly reduced transfusion and coagulation factor
requirements.41 In another study, the use of conjugated oestrogens was associated with a 37% reduction in postoperative
bleeding after paediatric scoliosis surgery.94
Conjugated oestrogens are well tolerated and side-effects
are negligible or absent. Since no more than five to seven daily
doses are recommended, adverse effects due to oestrogenic
hormonal activity are usually avoided. However, in a case
report by Litwack and Horrow,88 the authors thought that the
use of conjugated oestrogens might have contributed to the
development of fatal occlusion of all saphenous vein grafts
after coronary artery bypass grafting. In general, the role of
conjugated oestrogens in perioperative haemostasis is limited
and at best not well investigated.
Mahdy and Webster
Adverse effects
A major concern when using activated coagulation factors
such as rFVIIa is the possible induction of DIC or thromboembolism. However, in the many studies performed so far,
rFVIIa was not associated with systemic activation of the
coagulation cascade. An analysis of nearly 2000 patients
treated with rFVIIa showed neither venous nor arterial thromboembolic events.122 Between July 1996 and August 2000
more than 140 000 single doses of rFVIIa were administered:
seven myocardial infarctions have been reported, all in
patients with predisposing risk factors; four cases of cerebral
ischaemia; four cases of pulmonary embolism; and three
cases of venous thromboembolism in other parts of the
body.116
The use of rFVIIa in sepsis is potentially hazardous; this is
because tissue factor is inducible in monocytes by toxins
risking intravascular clot formation. However, the application of active site inhibited FVIIa in a sepsis model in
baboons blocked tissue factor and reduced intravascular
fibrin deposition and secondary organ failure.158
Conclusions
Control of intraoperative blood loss requires contribution
from both the surgeon and anaesthetist. Meticulous surgical
haemostasis, proper positioning, control of blood pressure,
judicious fluid replacement, maintenance of normothermia
and correction of clotting factor deficiencies are the basic
components of surgical field haemostasis. Such measures
will suffice in most patients. Systemic pharmacological
haemostatic agents may be of additional benefit in surgical
settings associated with excessive surgical bleeding and/
or hyperfibrinolysis, in patients with borderline or mild
haemostatic defects, or in those who refuse blood transfusion
(Table 1). Anticipating the need for the use of these agents is
important, as they have always been more effective when
used prophylactically.
Desmopressin is useful in patients with mild haemophilia
or type I von Willebrand’s disease who are undergoing surgery. It has also been used successfully to treat or prevent
bleeding in patients with congenital or acquired defects of
platelet function, chronic liver disease and uraemia. There
have been no well-conducted clinical trials demonstrating the
efficacy of prophylactic desmopressin in surgical patients
with no previous haemostatic defects.
Antifibrinolytics are perhaps the most extensively studied
haemostatic agents in the perioperative period. Most of the
studies have focused on their use in patients undergoing cardiopulmonary bypass. Aprotinin is the antifibrinolytic agent
that has the best evidence supporting its use. Its efficacy and
safety have been evaluated more extensively. It consistently
reduces blood loss and transfusion requirements, and it is the
only antifibrinolytic agent that has been associated with
reduced mortality, a decreased incidence of stroke, and shortened hospital stay. There are suggestions that its use might be
associated with reduced myocardial reperfusion injury and
post-bypass inflammatory response. The lysine analogues
aminocaproic acid and tranexamic acid are probably as effective as aprotinin in reducing blood loss during cardiac surgery.
However, they are poorly evaluated and data supporting their
use are rather scarce. This is unfortunate because they have a
good safety profile and are significantly cheaper than aprotinin. In non-cardiac surgery, there is some evidence to support the use of antifibrinolytic drugs in patients undergoing
orthotopic liver transplantation, and in major orthopaedic,
vascular and thoracic surgery.
Recombinant FVIIa is a novel and potent haemostatic
agent that has been used for the prevention or treatment
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prove to be of value as an adjunctive haemostatic agent in
trauma patients. In other case reports of patients without preexistent coagulation disorders, who bled profusely during
various surgical procedures, the use of rFVIIa was reported
to stop bleeding very efficiently.56 102
Recombinant factor VIIa has also been investigated in the
elective settings of cardiac, prostatic and liver transplant
surgery. Al-Douri and colleagues2 evaluated the role of
rFVIIa in five patients (one child aged 2.5 yr and four adults)
undergoing surgical procedures including arterial switch,
closure of atrial septal defect, and mitral valve replacement
with tricuspid valve repair. Haemostasis was achieved with a
single dose (30 mg kg 1) of rFVIIa. The authors concluded
that rFVIIa represents an effective and well-tolerated treatment for serious bleeding episodes both during cardiac surgery and postoperatively.
A recently reported pilot study in six patients undergoing
orthotopic liver transplantation showed a significant reduction of blood loss and red cell transfusions in patients
treated with a single dose of rFVIIa.55 A limitation of
this study was the use a historical control group for comparison. Moreover, a recently performed placebo-controlled
randomized, controlled trial using single-dose rFVIIa (20,
40 or 80 mg kg 1) in liver transplantation did not confirm
the previous findings.111 In both trials, rFVIIa was not
associated with an increased risk of thromboembolic complications, in particular hepatic artery thrombosis. Friederich and colleagues42 reported the use of rFVIIa in patients
undergoing transabdominal prostatectomy. Before surgery,
a single dose of rFVIIa (20 or 40 mg 1 kg) was given and
compared with placebo. A significant reduction of blood
loss, of 45%, was seen in patients treated with rFVIIa, with
no adverse effects noted. This study is of major importance
as it is the first randomized controlled trial to indicate
that surgical blood loss can be reduced in individuals
with normal haemostatic function by the use of a single
dose of rFVIIa.
It is clear that rFVIIa is a novel haemostatic agent that has
the potential to reduce perioperative blood loss in patients
with or without preoperative haemostatic abnormality.
Results of currently ongoing large trials are awaited before
wider application of rFVIIa is considered.
Perioperative systemic haemostatic agents
Table 1 The advantages and disadvantages of the various haemostatic agents
Advantages
Disadvantages
Desmopressin
Useful in patients with mild haemophilia or type I
von Willebrand’s disease undergoing surgery.
Can be used to treat or prevent bleeding in
patients with congenital or acquired defects of
platelet function, chronic liver disease and uraemia.
Useful in treating patients with aspirin-induced
platelet dysfunction undergoing cardiopulmonary bypass.
Available evidence does not support its use in haemostatically
normal patients undergoing elective cardiac or non-cardiac
surgical procedures.
Reports of increased risk of postoperative myocardial
infarction in patients undergoing coronary
artery bypass grafting.
Epsilon-aminocaproic
acid
Has been poorly evaluated in cardiac and non-cardiac surgery and adequate large randomized controlled trials are lacking.
This makes it difficult to draw conclusions for or against its use in surgical patients.
Tranexamic acid
Effective in reducing the need for blood transfusion in
patients undergoing primary cardiac surgery, off-pump
coronary surgery and thoracic aortic procedures.
Effective in reducing blood loss in joint replacement
operations and orthotopic liver transplantation.
Inexpensive with adequate safety profile.
In cardiac surgery, it has not been effective in reducing
blood loss in patients on aspirin and those undergoing
repeat operations.
Anecdotes suggesting an increased incidence of
thromboembolic manifestations associated with its use.
Concerns regarding renal toxicity if its use is continued
postoperatively.
Nafamostat
Effective in reducing blood loss when used in orthotopic
liver transplantation,
and cardiopulmonary bypass procedures.
No experience with its use in the UK, Europe or the USA.
Aprotinin
Has been consistently reported to reduce transfusion
requirements in cardiac surgery. It is of particular
benefit in patients taking aspirin, in patients with
endocarditis, and in patients undergoing repeat
operations, off-pump surgery or heart transplantation.
Hypersensitivity reactions, particularly on re-exposure.
Case reports of graft occlusion after cardiopulmonary bypass;
other reports suggest an increased incidence of
thromboembolic manifestations.
Trend towards a mild to moderate increase in postoperative
serum creatinine.
The only antifibrinolytic that has been associated with
reduced mortality, reduced incidence of strokes and
shorter hospital stay.
Has been effective in reducing blood loss in major thoracic
surgery, in major orthopaedic surgery, and orthotopic
liver transplantation.
Factor VIIa
Has not been approved for use as a haemostatic agent in
patients without pre-existing bleeding disorders
undergoing elective surgery.
More clinical trials are awaited before definitive conclusions
can be made about the safety and the exact role of this
new drug in surgical patients.
Case reports of myocardial infarction, cerebral ischaemia,
pulmonary embolism and deep-vein thrombosis.
Preliminary results suggest that it can be used safely and
effectively to control life-threatening bleeding in surgery
and trauma, when all other measures have failed.
It can also be used to reduce blood loss in elective surgical
procedures associated with excessive bleeding.
of bleeding in patients with haemophilia and inhibitors.
Preliminary data and one controlled trial indicate that it
may also be effective in surgical patients without pre-existing
coagulation abnormalities. More clinical trials are awaited
before definitive conclusions can be made about the safety
and the exact role of this new drug in surgical patients.
5
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