Efficacy of Hemostatic Agents in Improving
Surgical Hemostasis
David Green, Cynthia A. Wong, and Przemyslaw Twardowski
URTAILING operative bleeding has always
C been a surgical priority. Perioperative hemor-
rhage, and the need for blood product transfusions,
increases morbidity, mortality, and cost. The driest
fields are usually attributed to the most skillful
surgeons. However, despite excellent surgical skill
there may be increased bleeding under a variety of
circumstances. These include extensive operations
versus limited ones, deep dissections versus super-
ficial ones, and reoperations versus primary proce-
dures. Furthermore, other factors over which the
surgeon has little or no control may increase
surgical hemorrhage. Examples include patient
diseases affecting the liver or kidney; recent expo-
sure to medications such as aspirin or anticoagu-
lants; and operations requiting extracorporeal circu-
lation. To control blood loss under these conditions,
physicians have turned to a variety of topical and
systemic agents thought to have hemostatic proper-
ties. In this article, we will examine the safety and
efficacy of some of these agents. Plasma, platelets,
and specific clotting factors will be excluded be-
cause a discussion of these blood components is
beyond the scope of this article.
Table 1 lists some of the hemostatic agents that
have been used at one time or another to control
operative bleeding. Many of the topical agents
listed are believed to be useful in surgical practice,
but most have not been subjected to rigorous
clinical trials. Seaweed extracts (Alginate) are used
for the arrest of capillary hemorrhage. Styptic
pencils can diminish bleeding by cauterizing small
vessels. Bismuth subgallate, an analogue of ellagic
acid, activates factor XII and may be applied to the
tonsillar fossae along with epinephrine to stem
bleeding. 1 Collagen and microcrystalline collagen
(Avitene) enhance platelet adhesion and aggrega-
tion. They have found widespread use in cardiovas-
cular, orthopaedic, and plastic surgery. 2 Gelatin
sponges and oxidized cellulose are applied to the
bleeding surface, compress severed vessels, absorb
fluid, and provide a scaffold for fibrin formation.
Russell's viper venom (Stypven) very rapidly clots
shed blood and has been used topically to staunch
bleeding from lacerations in hemophiliacs. Throm-
bin, usually of bovine origin, is applied alone or
Transfus'on Medicine Reviews, Vol X, No 3 (July), 1996: pp 171-182
with other topical agents to promote hemostasis.
However, the most popular use of thrombin is in
combination with fibrinogen to form fibrin glue.
Between 1990 and 1995, 318 articles described the
preparation, use, and adverse effects of this hemo-
static material, and a review was published in these
pages in 1993. 3 Some of the salient points about
fibrin glue are summarized below.
FIBRIN GLUE
Fibrin glue is prepared from a mixture of cryopre-
cipitated plasma, calcium, thrombin, and may in-
clude an inhibitor of proteolysis such as aprotinin.
The cryoprecipitated plasma provides factor XIII,
fibronectin, and plasminogen in addition to fibrino-
gen. The cryoprecipitate may be obtained from
either ACD or CPDA-1 donor plasma, although the
fibrinogen concentration is higher in the latter. 4
Because there is concern about viral transmission
from a product made from pooled homologous
blood, fibrin glue may be prepared from autologous
blood collected either preoperatively or intraopera-
tively. 5 The cryoprecipitate and concentrated bo-
vine thrombin are applied separately to the surgical
target, mixed, and allowed to set. The speed of
formation of the seal is proportional to the throm-
bin concentration, and its thickness and bonding
power are dependent on the concentrations of
fibrinogen, factor XIII, and fibronectin in the
cryoprecipitate.
Major benefit from fibrin glue is reported in
those situations where the use of sutures or adhe-
sive dressings would be associated with an inferior
result. Examples include dissecting aortic aneu-
rysms, where suturing through the aorta may
induce bleeding and skin grafting, where the glue
serves as a sealant and enhances graft adherence. 6,7
Other applications include sealing the dura in
patients undergoing neurosurgery, and preventing
leakage and fistulas from the pancreatic duct after
From the Departments" of Medicine and Anesthesiology,
Northwestern University Medical School, Chicago, 1L
Address reprint requests' to David Green, MD, PhD, 345 E
Superior St-Rm 1407, Chicago, 1L 60611.
Copyright 9 1996 by W.B. Saunders Company
0887- 7963/96/1003-000253.00/0
171
172
Table 1. Hemostatic Agents Other than Replacement Blood
Components (Plasma, Platelets, Specific Clotting Factors)
Topical Agents
Alginate (seaweed)
Alum (styptic pencil)
Bismuth subgallate
Collagen
Fibrin glue
Gelatin Sponges
Oxidized cellulose
Russell's Viper Venom
Thrombin
Systemic Agents
Aprotinin
Desmopressin (DDAVP)
Estrogens
~-aminocaproic acid
Tranexamic acid
Vitamins C & K
resection or injuries of this organ. 8,9 In patients with
hemophilia and other coagulopathies, fibrin glue
has been used to control bleeding after dental
extractions and circumcision. 1~ A major indica-
tion is the control of oozing from surfaces after the
removal of adhesions, as occurs in patients having
cardiac reoperations. The glue may be sprayed on
the raw surfaces of the heart or pericardium to stop
bleeding from multiple pinpoint sources. 3
Adverse reactions have been few, but potentially
significant. Transmission of viral contaminants
from homologous donor plasma is possible, but
infrequent and obviated by using autologous cryo-
precipitate. Anaphylactic reactions seem to be rare;
they may be caused by constituents in the donor
plasma or the bovine thrombin. Two instances of
severe hypotension were reported after instillation
of fibrin glue into deep hepatic wounds; entry of the
bovine thrombin into the systemic circulation with
an anaphylactic reaction was suspected. 12 There
have been several reports of patients with pro-
longed thrombin times and decreased levels of
factor V after exposure to the bovine thrombin in
fibrin glue. 13 Antibodies against bovine thrombin
and factor V, some of which cross-react with the
patient's factor V and cause bleeding, have been
reported. 14,~s This adverse reaction is more likely
after cardiac than neurosurgical procedures, prob-
ably because entrance of the bovine thrombin into
the systemic circulation is greater with the former.
DESMOPRESSIN
Desmopressin (1-desamino-8-D-arginine vaso-
pressin, or DDAVP) is a synthetic analog of the
GREEN, WONG, AND TWARDOWSKI
neurohypophyseal nonapeptide, arginine vasopres-
sin. It was developed in the 1970s for the treatment
of diabetes insipidus. Deamination of hemicysteine
at position 1 and substitution of the D-isomer of
arginine for L-arginine at position 8 produced an
analog with minimal pressor effects and markedly
prolonged biologic effect. DDAVP has been shown
to reduce prolonged bleeding times in a variety of
congenital and acquired disorders of hemostasis.
Vasopressin was known to increase factor VIII
(VIII:C) levels, but could not be used clinically for
this purpose because of its vasoactive properties. In
1977, Mannucci et a116described the use of DDAVP
in patients with mild to moderate hemophilia A and
von Willebrand's disease (vWD). DDAVP in-
creased circulating VIII:C and decreased blood loss
after major and minor surgery. Since then, many
studies have evaluated the efficacy of DDAVP in
decreasing bleeding times and surgical blood loss
in patients with preexisting hemostatic disorders
(hemophilia A, vWD, and primary platelet disor-
ders) and in patients without a known bleeding
diathesis.
Plasma levels of VIII:C, von Willebrand factor
(vWF) (especially the larger multimers), and tissue-
plasminogen activator (t-PA) increase twofold to
twentyfold immediately after the administration of
DDAVR 17 Factor release is probably mediated by
extrarenal V2 receptors, possibly via a second
messenger. 18 The clotting factors most likely are
released from endogenous storage pools because
the response to DDAVP administration is almost
immediate. 19 This explains its salutary effect in
patients with mild to moderate hemophilia A and
von Willebrand's disease, but its lack of effect in
those with the severe forms of these diseases. It
also explains the tachyphylaxis that can develop
after repeated doses because stored factors presum-
ably become depleted. Platelet membrane expres-
sion of GPIb 2~ and GPIIb/IIIa21 is also enhanced,
which may contribute to the increased platelet
adhesiveness observed after DDAVR
Hemophilia and von Willebrand's Disease
The perioperative use of DDAVP was originally
described for patients with hemophilia A and
v W D 16 and this remains its primary perioperative
indication. In hemophiliacs, a baseline VIII:C con-
centration of at least 0.10 to 0.15 IU/mL is neces-
sary to ensure a post-DDAVP factor concentration
high enough to promote hemostasis during major
HEMOSTATIC AGENTS FOR SURGERY 173

surgery.19 No response to DDAVP is usually seen in
patients with low factor levels or in patients with
high antibody titers to VIII:C. Patients with type I
vWD respond to DDAVP with an increase in the
concentration of vWE 19 DDAVP usually does not
result in increased vWF levels in patients with
type-II disease. In fact, it is contraindicated in type
liB vWD because it may cause platelet aggregation
and thrombocytopenia, although this has recently
been disputed. 2z Type III vWD patients have a
complete absence of vWF and DDAVP is not
effective.
Platelet Disorders
DDAVP has also been shown to be effective in
reducing prolonged bleeding times in most forms
of congenital and acquired disorders of platelet
f u n c t i o n . 19'2325 It may shorten the bleeding time in
platelet storage pool disease, thromboxane synthe-
sis defect, and in some patients with Bernard-
Soulier syndrome. 26 Reports differ on whether
patients with Glanzmann's thrombasthenia respond
to DDAVR 24,25,27 DDAVP also reduces bleeding
times in uremia, 28 cirrhosis, 29 aspirin-induced, 29-3!
and heparin-induced 32 platelet dysfunction. It is
assumed that a decrease in bleeding time correlates
with a decrease in surgical blood loss, although,
except for aspirin-ingesting cardiac surgery pa-
tients, this assumption has not been rigorously
tested.
Cardiac Surgery
Several studies have suggested that DDAVP is
efficacious in reducing surgical blood loss, even in
patients with normal preoperative coagulation. The
majority of these studies have been performed in
cardiac surgery patients because cardiac surgery
and extracorporeal circulation (ECC) are associ-
ated with an acquired coagulopathy, in part thought
secondary to platelet dysfunction. 33 In 1986, Salz-
man et a134 reported a marked reduction in blood
loss in cardiac surgery patients who received
post-ECC DDAVP compared with placebo. The
DDAVP group also had higher plasma vWF levels
than the placebo group. Low preoperative vWF
levels correlated with increased postoperative bleed-
ing. This study was followed by many others that
both supported and refuted the results. The random-
ized, double-blind, placebo-controlled studies are
listed in Table 2. Most found no statistically
significant difference in blood loss and red cell
transfusion requirements in patients receiving
DDAVP compared with placebo. However, the

Table 2. Randomized, Controlled, Double-Blind Studies of the Use of DDAVP in Cardiac Surgery

Blood Loss Decrease in

No. of Patients Transfusions
Reference DDAVP/Placebo Type of Surgery DDAVP (mL _+ SD) P}acebo (mL -+ SD) P (Yes/No)

Salzman et a134 35/35 no p r i m a r y CABG 1,317 -+ 486 2,210 • 1,415 .001 No

Rocha et a1127 50/50 no CABG 458 • 206 536 + 304 NS No
B r o w n et aP 28 10/9 CABG 879 _+ 353 803 +- 405 NS No
Hackmann et al ~29 74/76 m o s t l y CABG 1,138 1,010 NS No
A n d e r s s o n et aP 3e 10/9 1~ CABG 852 + 233 1,020 • 422 NS
Hedderich et al TM 31/31 1~ and 2 ~ CABG 1,716 +- 688 1,826 • 849 NS No
Frankville et al la2 20/20 1~ CABG 790 + 130 687 • 50 NS No
H o r r o w et a137 38/44 1~ and 2 ~ valve and CABG 418 g 386 g NS No
Reich et al ~a3 14/13 CABG and valve 624 • 351 729 -+ 200 NS No
Salmenper~ et aP ~ 15/15 1~ CABG 1,020 1,100 NS
Ansell et a113s 41/42 1~ and 2 ~ valve 1,065 • 647 844 + 508 NS No
deProst et aP 38 47/45 1~ and 2 ~ valve and CABG* 582 • 410 465 -+ 303 NS No
Kuitunen et aP a7 15/15 1~ CABG 950 + 185 1,034 -+ 321 NS No
Marquez et a135 21/22t 1~ CABG 1,157 1,180 NS No
M o n g a n et a138 44/42 1~ and 2 ~ CABG T E G - M A > 5 0 m m 770 -+ 252 865 + 384 NS Yes
M o n g a n et aP 8 13/16 1~ and 2~ CABG T E G - M A < 5 0 m m 881 -+595 1,353+773 <.05 No
Rocha et a136 25/28r 1~ and 2 ~ CABG and valve 552 + 324 439 -+ 228 NS No
Temeck et aP 38 40/43 1~ valve and CABG 1,214 • 493 1,386 • 761 NS No

Abbreviations: CABG, coronary artery bypass grafting; TEG-MA, t h r o m b e l a s t o g r a m - m a x i m u m amplitude.

*Chest tube o u t p u t > 7 5 m L / m J h and bleeding t i m e m o r e than 10 minutes, w i t h i n 6 hours of postsurgery.
t A third g r o u p o f 22 patients received 2 doses of DDAVP, w i t h o u t i m p r o v e d hemostasis.
SA third g r o u p of 28 patients received 2 doses of DDAVP, w i t h o u t i m p r o v e d hemostasis.
174
majority of patients in these studies underwent
primary coronary artery bypass procedures, a group
of patients at relatively low risk for postoperative
hemorrhage.
Two studies evaluated repeat doses of DDAVP in
the postoperative period and found them to be of no
value. 35,36 Horrow et al37 compared DDAVP with
tranexamic acid and placebo, whereas Rocha et a136
compared DDAVP with aprotinin and placebo.
Both tranexamic acid and aprotinin resulted in
significantly less blood loss than DDAVP or pla-
cebo.
Mongan et a138 attempted to identify a subgroup
of patients that might benefit from DDAVP therapy.
They found DDAVP to be efficacious in the sub-
group of patients who had abnormal platelet func-
tion as diagnosed by a post-ECC thromboelasto-
gram-maximum amplitude value (TEG-MA) less
than 50 mm.
A second subgroup who might benefit from
prophylactic DDAVP treatment are those patients
receiving aspirin therapy before coronary artery
bypass surgery. Decreased blood loss 39,40 and de-
creased transfusion requirements in the DDAVP
group 39,41 have been described.
Two studies found no effect of DDAVP on blood
loss after cardiac operations for congenital heart
disease in children. 42,43
Cattaneo et a144analyzed 18 randomized, placebo-
controlled, double-blind studies of DDAVP and
found that patients with larger perioperative blood
loss benefitted most from DDAVP, in terms of a
decrease in blood loss and transfusion require-
ments. A meta-analysis of 13 randomized, placebo-
controlled studies (774 patients) found an 11%
reduction in blood loss in the DDAVP group, a
mean difference in blood loss of 85.8 mL. 45 This
difference is statistically (P < .002), but probably
not clinically significant, a conclusion supported by
the meta-analysis of transfusion requirements in 8
of the studies45: DDAVP did not decrease postopera-
tive transfusion requirements. In conclusion, pro-
phylactic DDAVP probably produces clinically
significant decreases in blood loss in patients
undergoing complicated cardiac procedures (reop-
erations, combined valve replacement-coronary ar-
tery bypass grafting (CABG), double-valve) or in
patients with documented platelet dysfunction, but
not in less complicated procedures (primary CABG
and single valves).
GREEN, WONG, AND TWARDOWSKI
Other Surgical Procedures
Kobrinsky et al46 reported a 32% reduction in
blood loss and a 26% decrease in transfusion
requirements in healthy patients undergoing Har-
rington rod procedures who received DDAVP com-
pared with placebo. However, Guay et a147 could
not replicate this result, despite recording larger
perioperative blood losses then Kobrinsky et al. 46
Flordal et al48 evaluated 50 patients undergoing
elective total hip arthroplasty under epidural anes-
thesia who received DDAVP at the start of surgery
and 6 hours later. There were no significant differ-
ences in measured intraoperative blood loss or
transfusion requirements between the DDAVP and
placebo groups. However, the total calculated blood
loss was reduced by 310 mL in the DDAVP group.
Similarly, in patients undergoing total hip arthro-
plasty under general anesthesia, Karnezis et a149
found no effect of DDAVP given at skin closure.
Wingate et al 5~reported decreased blood loss and
transfusion requirements in hemostatically normal
spinal cord patients undergoing flap reconstruction
for pelvic pressure sores. This salutary effect was
not found in burn patients undergoing debridement
and grafting, 51 nor in patients undergoing aorto-
iliac graft surgery. 52
An in vitro study suggested that DDAVP may
improve coagulation after reperfusion in liver trans-
plantation. 53
Thus, the overall evidence does not support the
routine use of DDAVP in hemostatically normal
individuals, although patients undergoing large
blood loss procedures are more likely to benefit
from its use.
Pharmacology
DDAVP is available as a concentrated nasal
spray and an intravenous preparation (4 ~tg/mL).
An intravenous (or subcutaneous) dose of 0.3
~tg/kg, or an intranasal dose of 300 lag yields
maximal VIII:C and vWF releaseY ,55 DDAVP is
metabolized by the kidney and liver. 56 Intravenous
elimination follows first order kinetics with t]/2 =
2.5 - 4.4 hours. The biological effect may last 6 or
more hours. Repeated doses in 12-24 hours are
usually equally effective as the initial dose in
elevating clotting factor levels; however, there may
be a decreased response after several doses because
of depletion of clotting factor stores. Twenty-four
to forty-eight hours may be required to reaccumu-
late stores. 56
HEMOSTATIC AGENTS FOR SURGERY
Side Effects
The side effects of DDAVP are minimal. Facial
flushing and hypotension occur with rapid infusion,
secondary to a direct dilating effect of unknown
mechanism, and an indirect prostacyclin effect.5v
Tissue plasminogen activator levels increase after
DDAVP administration; however, alpha 2-plasmin
inhibitor levels also increase and there is no
increase in fibrin- or fibrinogen-split products) 8
Although there are anecdotal reports of coronary
and cerebral thrombosis associated with DDAVP
administration, 59,6~a review of the controlled clini-
cal trials did not show an increase in thrombotic
events. 61 Serum sodium concentrations and urine
output decrease because of the antidiuretic property
of the drug. Water intoxication, especially with
inappropriate intravenous water administration, 17
and allergy to the preservative chlorobutanol,62
have been reported.
ESTROGENS
Estrogens have a variety of effects on hemosta-
sis. They increase the levels of several clotting
factors including factor XII, 63 factor VII, 64 and
vWF. 65 They also decrease physiological clotting
inhibitors such as antithrombin III and protein S, 66
while increasing plasminogen and decreasing plas-
minogen activator inhibitor- 1.17,67Clinically, estro-
gens have been used either alone or with progester-
one to stem bleeding in patients with renal failure, 68
vascular malformations of the gastrointestinal
tract, 69,7~and vWD71;in the latter, they decreased
surgical bleeding. However, to our knowledge
there have not been randomized, placebo-con-
trolled trials to determine whether preoperative
estrogens decrease blood loss.
APROTININ
Aprotinin is a broad-spectrum serine proteinase
inhibitor used primarily in cardiovascular surgery
to improve perioperative hemostasis. Aprotinin
was originally tested in Europe in the 1960s for the
treatment of acute pancreatitis, but its efficacy in
that setting remains unproven. 72 However, experi-
mental and clinical data accumulated in the last
decade have established aprotinin as a useful agent
for improving surgical hemostasis.
Aprotinin is a polypeptide composed of 58
amino acid residues with a molecular weight of 6.5
kDa. Enzymes inhibited by aprotinin include vari-
ous serine proteinases: trypsin, chymotrypsin,
thrombin, glandular and plasma kallikrein, acti-
175
vated protein C, and plasmin. Aprotinin blocks
serine proteinases by binding to their active, serine
containing sites. The specific activity of various
aprotinin preparations is expressed in terms of
kallikrein inhibitor units (KIU)--amount of aproti-
nin that decreases the in vitro activity of two
biological KIU by 50%. Aprotinin is metabolized
in the proximal renal tubules and is not excreted in
urine. It has a biphasic pattern of elimination with a
rapid phase half-life of about 40 minutes and a
slower phase half-life of 7 hours. 73 Initially isolated
from bovine tissues, aprotinin is now also available
in the recombinant form. TM
The modern era of aprotinin use began in 1987
with a report by Royston et a175 that high doses of
aprotinin decreased blood loss and reduced the
need for blood transfusions associated with cardiac
surgery. This observation was confirmed by subse-
quent clinical trials and in 1993 led to United States
Food and Drug Administration approval of bovine
aprotinin for use in cardiovascular surgery.
There are many factors responsible for nonsurgi-
cal bleeding during cardiac surgery. Passage of
blood through the cardiopulmonary bypass circuit
is associated with massive activation of the contact
system (factor XII, XI, prekallikrein, high molecu-
lar weight kininogen), intrinsic coagulation, and
the complement systems. 76 To prevent dissemi-
nated coagulation, large doses of heparin are given
throughout the bypass period. The half-life of
platelets is decreased, the bleeding time is pro-
longed, and abnormal platelet aggregation studies
indicate platelet dysfunction.77 These adverse ef-
fects on platelets are mediated by various factors
including mechanical trauma, hypothermia, in-
crease in circulating fibrinogen degradation prod-
ucts (FDPIS), and plasmin-induced changes in
GPIb surface receptors. The fibrinolytic system is
activated as manifested by increased levels of
tissue plasminogen activator, d-dimers, and
FDPIS. 78 The total-body inflammatory response
creates derangement of hemostasis and multiple
other organ systems.
The exact mechanisms by which aprotinin re-
duces blood loss are not fully understood and are
undoubtedly very complex. Because most of the
enzymes of the hemostatic system are serine protein-
ases, aprotinin can affect multiple steps of coagula-
tion and fibrinolysis. Aprotinin directly inhibits
plasmin, which diminishes fibrinolysis. At higher
concentrations it inhibits kallikrein, which is ca-
pable of converting plasminogen to plasmin. Sev-
176 GREEN, WONG, AND TWARDOWSKI

eral randomized trials confirm decreased markers
of fibrinolysis (d-dimers, FDP's) in aprotinin-
treated patients compared to patients who received
placebo. 79,s~ The activity of protein C (a potent
anticoagulant) is also decreased by aprotinin.
Whether aprotinin is capable of protecting platelets
from activation during cardiopulmonary bypass is
not clear. Some studies have documented preserva-
tion of platelet receptors GPIb and GPIIb/IIIa, 81
whereas other studies have been unable to confirm
the protective effect of aprotinin on platelet func-
tion. 82
The efficacy of aprotinin in improving hemosta-
sis during cardiovascular surgery has been corrobo-
rated by multiple clinical trials conducted over the
last several years (Table 3). The shown benefit
consists of reduction of blood loss by about 50%
and similar decreases in blood transfusion require-
ments. The most extensive data exist for patients
undergoing coronary artery bypass grafting, but
very similar results have been obtained in the
setting of heart valve replacement, valve replace-
ment for active endocarditis, cardiac transplanta-
tion, and congenital heart disease. Comparable
effects of aprotinin are seen in situations where the
risk of perioperative bleeding is high. These in-
clude repeat operations and operations on patients
pretreated with thrombolytics83 or taking aspi-
rin.84,85
The most widely used regimen for administering
aprotinin is based on the original report from
London's Hammersmith Hospital and consists of a
2 million KIU intravenous bolus after the induction
of anesthesia, an additional 2 million KIU in the
prime solution of the ECC, and a continuous
infusion of 500,000 KIU/h until the end of surgery.
Lower doses are being investigated and seem to be
effective.V4,86, 87
The incidence of adverse reactions to aprotinin is
low. Anaphylaxis occurs in less then 0.5% of
patients but the risk is increased after repetitive use.
All patients should receive a test dose before
administration of the full loading dose. 88 One of the
potential side effects associated with the use of an
agent that inhibits fibrinolysis is the possibility of
inducing a prothrombotic state. Cosgrove et a187
reported an increased incidence of perioperative
myocardial infarction (MI) and graft thrombosis in
aprotinin-treated patients. A subsequent clinical
trial addressing this issue did not confirm this
observation, s9 Bidstrup et al90 evaluated the pa-
tency of grafts using magnetic resonance imaging
and found no difference between placebo and
aprotinin groups. However, the incidence of periop-
erative MI was very low. A likely explanation for
the increased incidence of thrombosis in the earlier
studies was inadequate anticoagulation. Celite acti-
vated clotting times are prolonged in the presence
of aprotinin, and do not accurately reflect in vivo
heparin concentrations. Therefore, less heparin is
given and thrombosis may occur. When this phe-
nomenon was recognized, new reagents such as
kaolin were substituted for celite, 91 and thrombotic
events became relatively infrequent. Isolated early
reports of strokes and renal insufficiency associated
with aprotinin have not been confirmed in clinical
trials.
Potential indications for the use of aprotinin are
not limited to cardiac surgery. For example, it has
been effective in decreasing blood loss in ortho-
topic liver transplantation 92 and complex orthopae-
dic surgeries. 93

Table 3. Clinical Trials of the Use of Aprotinin in Open-Heart Surgery

No. of Blood Loss
Reference Type of Study Type of Surgery Patients Treatment Reduction PValue
Royston et aJ75 Prospective randomized CABG, valve 22 High-dose aprotinin 81% <.001
Blauhat et a179 Prospective randomized CABG 26 High-dose aprotinin 50% <.0082
Havel et al so Prospective randomized CABG 22 High-dose aprotinin 38% <.03
Dietriech et aP39 Prospective randomized CABG, valve 1,784 High-dose aprotinin 35% <.05
Biagini et a1140 Prospective randomized Redo CABG, valve 58 High-dose aprotinin 22% <.01
Cosgrove et a187 Double-blind placebo-controlled CABG 169 High-dose aprotinin, 36% <.001
low-dose aprotinin 23%
Bidstrup et al so Randomized placebo-controlled CABG 96 High-dose aprotinin 40% <.01
Murkin et al s5 Double-blind placebo-controlled CABG, valve patients 54 High-dose aprotinin 50% <.0001
on aspirin
Dementieva et a1141 Randomized placebo-controlled CABG 100 High-dose aprotinin 33% <.005
Green et al TM Randomized placebo-controlled CABG and redo 84 Recombinant aprotinin, 34% <.02
high and low dose
HEMOSTATIC A G E N T S FOR SURGERY
In summary, aprotinin is an effective agent for
reducing blood loss and transfusion requirements
in the setting of cardiac surgery and other major
operative procedures. It is particularly useful in
patients at high risk for perioperative bleeding and
it has an acceptable safety profile. The exact
mechanism of aprotinin action and other potential
clinical applications are currently under investiga-
tion.
ANTIFIBRINOLYTIC AGENTS
Epsilon-aminocaproic acid and tranexamic acid
are synthetic lysine analog plasmin-plasminogen
inhibitors. Epsilon aminocaproic acid (EACA) is
older, cheaper, and ten times less potent than
tranexamic acid (TA). Both drugs inhibit fibrinoly-
sis by binding to plasminogen lysine binding sites,
thus preventing plasminogen from binding to fi-
brinogen. 17
Cardiac Surgery
Both EACA and TA have been used to treat and
prevent excessive bleeding in cardiac surgery pa-
tients. Fibrinolysis has been implicated as a cause
of post-ECC bleeding; t-PA, fibrinogen and fibrin-
split products increase during ECC. 78 Antifibrinol-
ytics not only inhibit the activation of plasminogen,
they also block plasmin receptors on platelets, iv
Plasmin may act as a weak platelet agonist or
antagonist. 94 Therefore, antifibrinolytics may act to
preserve or enhance platelet function and inhibit
plasminogen and plasmin.
Epsilon-aminocaproic acid has been used in
cardiac surgery since the late 1950s. However, the
early studies were not controlled and primarily
involved surgery for congenital heart disease. 95
Recent randomized, double-blind, placebo-con-
trolled studies are listed in Table 4 and support the
conclusion that prophylactic EACA decreases blood
loss after cardiac surgery. The efficacy of antifibri-
nolytics may differ, depending on whether they are
administered before or after ECC. 96 This has not
been studied prospectively, nor has the optimal
dose of EACA been evaluated.
Table 4. EACA Studies in Cardiac Surgery
Before ECC
Reference No. of Patients Type of Surgery
Vander Salm et a1103 60 CABG
DelRossi et al T M 350 CABG and valve
Daily et a1142 40 1~ CABG
177
Horrow et a197studied 38 primary and secondary
coronary artery bypass and valve replacement
procedures in a randomized, double-blind, placebo-
controlled study of TA. TA, administered before
and during ECC, significantly reduced 12-hour
blood loss compared with placebo (496 _+ 228 v
750 _+ 314 mL), and decreased transfusion require-
ments. A follow-up study comparing TA with
DDAVP and placebo found TA alone reduced blood
loss, and DDAVP did not potentiate the effect.37 A
dose-response study of TA found that 10 mg/kg
bolus before ECC, followed by 1 mg/kg/h infusion,
was optimal. 98 Other nonrandomized99,1~176and non-
blinded studies 99-~~ support the conclusion that
pre-ECC TA decreases blood loss. One study of
post-ECC TA found no positive effect.I~
A meta-analysis of four double-blinded, placebo-
controlled studies of EACA 103,l~ and TA37,97 sup-
ports the conclusion that EACA and TA decrease
blood loss and the volume of transfused blood
products, but not the percent of patients requiring
transfusion. 45 No prospective study has compared
the two drugs. A retrospective study comparing
EACA with TA found a smaller percent of patients
receiving TA received blood products.I~ However,
equipotent doses of EACA and TA were not used.
Two nonblinded studies compared TA, aprotinin,
and a control group, x~176 The TA groups did not
differ significantly from aprotinin groups, but the
number of patients in each study may not have been
large enough to detect a difference.
Oral Surgery
There is a high degree of fibrinolytic activity in
saliva. 1~ Oral TA has been used in conjunction
with DDAVP to decrease bleeding after oral sur-
gery in patients with hemophilia ~6 and vWDJ ~
Topical TA has also been used in hemophiliac
patients to reduce bleeding. 1~ Patients with factor
XI deficiency,l~~ and acquired VIII:C inhibitors 1]]
have also benefited from perioperative TA. In two
randomized, blinded, placebo-controlled studies,
tranexamic acid mouth wash, prepared by mixing
equal volumes of TA and saline, was efficacious in
Blood Loss Decrease in
Transfusions
Yes/No EACA mL (-~SD) Placebo mL (-+SD) Yes/No
No 273 +_ 106 332 -+ 10 0.02
Yes 617 • 44 883 -+ 29 <.05 Yes
Yes 623 +- 380 845 _+ 339 .012 Yes
178
reducing bleeding episodes in patients receiving
oral anticoagulants who underwent oral sur-
gery.ll2,113
Other Surgical Procedures
Patients undergoing prostate surgery may suffer
primary fibrinolysis secondary to the release of
t-PA from prostatic tissue. Systemic EACA de-
creases this type of bleeding. However, intravesical
EACA had no significant clinical effect on bleeding
when administered routinely after transurethral
resection procedures,l~4,Jl5 and clots formed in the
bladder may obstruct the urethra. Kang et al H6
described the use of EACA during the reperfusion
phase of liver transplant surgery in patients for
whom the thrombelastogram-maximum amplitude
tracing improved with the in vitro addition of
EACA. A small, retrospective study found no
benefit to prophylactic EACA in liver transplanta-
tion. 117Prophylactic TA significantly reduced wound
drainage and length of hospital stay in a random-
ized, double-blind study of breast surgery for
cancer. 118
The use of EACA to decrease aneurysm rebleed-
ing after subarachnoid hemorrhage is controversi-
al. 119EACA lowers the incidence of rebleeding, but
complications, including decreased cerebral blood
flow and increased neurologic deficits, j2~ may
offset its usefulness. Doses higher than those
recommended by the manufacturer may actually
increase bleeding by inhibiting platelet function.12~
Pharmacology
Epsilon-aminocaproic acid and TA are available
in oral and intravenous formulations. Both drugs
undergo minimal metabolism and are excreted
largely unchanged in the urine.
Side Effects
Nausea, diarrhea, and hypotension (with rapid
injection) have been noted. Myalgias are a known
side effect and myonecrosis is a rare complication
reported with EACA.122 Antifibrinolytics are contra-
indicated in disseminated intravascular coagulation
and in macroscopic and microscopic bleeding of
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