patients with liver disease is estimated to occur in 0.35% .
correcting laboratory parameters of coagulopathy in patients
with fulminant hepatic failure, as it facilitates the performance
of invasive procedures and is associated with less frequent
anasarca compared with conventional therapy. It was reported
that rFVIIa was used in a patient undergoing for liver
transplant to stop the bleeding during the procedure .
could be successfully used to perform the procedure without
any complications. However, our preliminary experience
warrants the need for further studies with a larger number of
patients to define the optimal dosing, safety, and efficacy of
rFVIIa in patients with coagulopathy requiring liver biopsy.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.
1 Aitken MG. Recombinant factor VIIa. Emerg Med Austral 2004; 16:
2 Levi M, Peters M, Buller HR. Efficacy and safety of recombinant
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3 Lloyd JV, Joist JH. Recombinant factor VIIa: a universal hemostatic
agent? Curr Hematol Rep 2002; 1: 19–26.
4 Parameswaran R, Shapiro AD, Gill JC, Kessler CM; HTRS Registry
Investigators. Dose effect and efficacy of rFVIIa in the treatment of
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5 Almeida AM, Khair K, Hann I, Liesner R. The use of recombinant
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6 Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role
of fresh frozen plasma infusion in correction of coagulopathy of
chronic liver disease: a dual phase study. Am J Gastroenterol 2003; 98:
7 Anantharaju A, Mehta K, Mindikoglu AL, Van Thiel DH. Use of
activated recombinant human factor VII (rhFVIIa) for colonic poly-
pectomies in patients with cirrhosis and coagulopathy. Dig Dis Sci
2003; 48: 1414–24.
8 Referen Jureczko L, Kolacz M, Trzebicki J, Szyszko G, Pacholczyk
M, Lagiewska B, Chmura A, Rowinski W, Mayzner-Zawadzka E.
Perioperative use of recombinant activated factor VII in liver trans-
plantation. Ann Transplant 2003; 8: 40–2.
9 Caldwell SH, Chang C, Macik BG. Recombinant activated factor VII
(rFVIIa) as a hemostatic agent in liver disease: a break from conven-
tion in need of controlled trials. Hepatology 2004; 39: 592–8.
10 Hoffman R, Mahajana A, Agmon P, Baruch Y, Brenner B. Successful
use of recombinant activated factor VII (Novoseven) in controlling
severe intra-abdominal bleeding after liver needle biopsy. Thromb
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11 Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston
SJ, Macik BG. Recombinant activated factor VII for coagulopathy in
fulminant hepatic failure compared with conventional therapy. Liver
Transpl 2003; 9: 138–43.
Assessment of hemostasis through the retrospectroscope
R. B. WEISKOPF
Novo Nordisk, Bagsvaerd, Denmark and Department of Anesthesia, University of California, San Francisco, CA, USA
To cite this article: Weiskopf RB. Assessment of hemostasis through the retrospectroscope. J Thromb Haemost 2006; 4: 2074–8.
See also Levy JH. Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: yes. This issue, pp 1875–8; Karkouti K, Beattie WS.
Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: no. This issue, pp 1879–81.
Aprotinin is approved in the USA for use in coronary artery
graft surgery with cardio-pulmonary bypass (CPB) to decrease
bleeding and transfusion of erythrocytes ; in the UK for
patients at high risk for bleeding in association with cardiac
surgery and CPB; and in many other countries for similar
indications. It is used routinely during cardiac surgery at some
institutions, while at other institutions it is used only for
patients thought to be at high risk for bleeding. There are
reports of efficacy in orthopedic surgery as well, including a
than are those from cardiac surgery .
In this issue of the Journal, Levy  and Karkouti and
its approved use. This debate was stimulated by three recent
reports of retrospective analyses of cardiac surgery databases
that have questioned the renal safety of aprotinin [6–8]. This
article addresses those reports and the issues they raise.
reported a statistically significant increase in serum creatinine
concentration ; none has reported an increased incidence of
renal failure. The major problem with the three recent
publications is their retrospective nature. Using statistical
methodology, such as propensity analysis, these authors
attempted to reduce bias. It is possible that some bias was
Correspondence: Richard B. Weiskopf, Novo Nordisk A/S, Novo
Alle, DK-2880 Bagsvaerd, Denmark.
2074 Letters to the Editor
? 2006 International Society on Thrombosis and Haemostasis
reduced; it is unlikely that all important bias was eliminated
[10,11]. The retrospectroscope is a wonderful instrument with
which to gain perspective and insight ; however, no matter
how carefully used, it is incapable of providing the clarity
raison d’etre for the latter: it is the best method for minimizing/
eliminating bias. The literature contains well-documented
instances where a ?finding? from a retrospective chart review
performed by the same investigators. For example, the well-
known randomized double-blind trial of erythrocyte trans-
fusion in critical care units in Canada, showing no outcome
differences between restrictive and liberal red cell transfusion
strategies , contradicted that group’s earlier retrospective
review of 4470 patients? charts that had purported to show a
benefit of a more liberal transfusion strategy .
Two of the reports regarding aprotinin and renal dys-
function/failure were analyses of databases from a single center
[6,8]; the third was an analysis of data collected at many
institutions, in several countries. In the two single-center
Thus, the reported ?results? of those two analyses are irredeem-
ably flawed. In the multi-center report, we do not know why
clinicians decided to use an antifibrinolytic agent, and having
made that decision, why aprotinin was selected rather than
another antifibrinolytic (e.g. tranexamic acid or epsilon amino
caproic acid); however, the clinicians? rationale may have been
the same as that in the two single-center reports: that is, it was
analyzed in the multi-center retrospective report , does not
compensate for the possibility of bias in theuse of aprotinin, or
the large difference in transfusion practices among institutions
in cardiac surgery, as documented by this same group , and
others [16,17], or in intensive care units . Similarly,
substantial differences in administration of antifibrinolytics
can be seen among institutions, even as portrayed in these
recent retrospective analyses [6–8], and in an earlier abstract
from the McSpi-EPI-II group . Analyses using the retro-
spectroscope may useful to formulate hypotheses, but do not
establish a clear cause-and-effect.
There is some patho-pharmacologic basis for considering
that aprotinin could have adverse renal effects. In rabbits, rats,
and mice the positively charged, strongly basic aprotinin
accumulates in renal proximal tubular cells [20–22] by a
mechanism similar to that of aminoglycosides . When
infused in rats for several days it potentiates gentamicin
nephrotoxicity , and again in rats infusion of kallikrein
(which is inhibited by aprotinin) reduces gentamicin-induced
renal toxicity . Aprotinin can cause renal damage during
highly altered physiological states in rats and pigs, and perhaps
as well in humans when used with hypothermic circulatory
arrest during surgery of the thoracic aortic aneurysms , a
condition with intravascular exposed tissue factor, platelet
renal events in that oft-quoted series of 20 patients given
aprotinin  could have resulted from inadequate anticoag-
report . Blockade of fibrinolysis under such a circumstance
could conceivably further impair renal circulation, should
fibrin deposition occur in the renal circulation. However, it is
It is possible that the association of increased serum
creatinine concentration might have been the result of
temporarily decreased renal blood flow and glomerular filtra-
tion, a previously noted effect of aprotinin during positive
sodium balance in barbiturate-anesthetized rats , and
during hemorrhagic hypotension in halothane-anesthetized
pigs , but not during normovolemia [33,34]. Such derange-
ments are morelikely tooccurin high-riskpatients and it is not
clear how these data might relate to humans anesthetized with
the usual opioid-based anesthetic regime for procedures
involving CPB. Unfortunately, the time course of serum
creatinine in the multi-center database was not presented .
Thus, we are not able to determine the duration of increased
serum creatinine concentration, and whether this represents a
clinically insignificant transient increase, owing perhaps to a
transient decrease in renal perfusion and glomerular filtration
rate, or a more clinically important long-term effect, signifying
permanent renal dysfunction. One alternative hypothesis could
be that the retrospectively noted association of aprotinin with
?renal events? (defined in that report as an increase in serum
creatinine concentration of > 0.7 mg dL)1, or absolute creat-
inine concentration of > 2.0 mg kg)1, or the need for dialysis,
or renal failure proven by autopsy) was caused by increased
hemorrhage and perhaps hypotension, resulting in decreased
renal perfusion. This suggestion is consistent with that analysis
failing to findaneffect of aprotinin onblood loss, which differs
from many other publications, suggesting the possibility that
the group given aprotinin was at high risk for bleeding, but
of the efficacy of aprotinin. Perhaps this thought is supported,
as well, by the absence of an increase in cardiovascular events
associated with aprotinin administration in patients undergo-
ing repeat coronary artery graft surgery that was associated
with primary coronary artery graft surgery . This difference
is more universal and less selective than during the latter. The
treating physicians may have been sufficiently astute to select
those patients who were at the greatest risk for hemorrhage to
receiveaprotinin.Furthersupport of this hypothesisappearsin
the data analysis of that report: that transfusion of erythro-
cytes, or of fresh-frozen plasma, or the use of inotropic agents
had an incidence of adverse ?renal events? with statistical
and from another report from this group, of an association of
renal dysfunction after cardiac surgery with episodes of peri-
operative hypotension .
There are other important, useful pieces of information that
interferes with the test of anticoagulation commonly used
Letters to the Editor 2075
? 2006 International Society on Thrombosis and Haemostasis
during CPB, activated clotting time (ACT), when celite is used
as the activator [36,37]. If celite were used as the ACT activator
in assessing anticoagulation in some patients, those patients
might have been insufficiently anticoagulated during CPB,
perhaps leading to some of the adverse events, included renal,
that were reported. In addition, thedose of aprotininmay have
varied substantially among the many institutions, but this was
not specified, further complicating interpretation of the data.
Further uncertainty regarding aprotinin and adverse renal
effects after cardiac surgery is found in a publications that
noted a statistical increase in urinary alpha-1 microglobulin
[38,39], but not serum creatinine  or B-N-acetyl D-glucosa-
appear toshow adose relationship, but were not publishedin a
manner that would allow for a full analysis of this issue .
There are several reports of prospective, randomized, blinded
trials of aprotinin in cardiac surgery, but only one found a
statistically significant increased incidence of increased serum
creatinine in those patients given aprotinin, which appeared to
be of limited duration . However, other studies were of
limited power to detect such changes, and some excluded
patients with increased serum creatinine [40,41], while others
did not provide adequate information regarding study exclu-
sion criteria [42,43]. Unfortunately, the trial with the largest
number of patients per group did not report data regarding
renal function . Furthermore, a change in serum creatinine
from a normal value is a relatively insensitive measure because
of its hyperbolic relationship to creatinine clearance. The one
study reporting values for creatinine clearance did not note a
significant difference between patients given aprotinin and
those given placebo . When examining the data for
approval of aprotinin in coronary artery surgery, the US Food
and Drug Administration (FDA) evaluated data from several
prospective, randomized, double-blind trials, with more than
2000 patients given aprotinin, and more than 1000 patents
given placebo . No statistically significant increase in adverse
> 99.99% to detect a level of increased incidence of renal
failure as recently reported from the McSPI-EPI-II database
. However, the data regarding renal dysfunction, as analyzed
by the FDA, were not presented in a manner that would allow
full evaluation by others . Additionally, an extensive analysis
of prospective, randomized, blinded trials failed to find an
adverse renal effect of aprotinin .
Decisions regarding therapy should be based on an evalu-
ation of risk:benefit. In the present case, the benefit of using
aprotinin to decrease blood loss and requirement for erythro-
cyte transfusion during coronary artery graft surgery has been
accepted , although that benefit is relatively modest
(approximately 1 U of erythrocytes for primary surgery;
approximately 1–2 U of erythrocytes for complex or revision
surgery).Thus,assessmentof therisk:benefit of usingaprotinin
should include the reduction of risk associated with the
decreased erythrocyte transfusion. The risks of transfusion
generally are related to the number of components transfused.
Using the data of Feibig and Busch , it is possible to
calculate the overall risk of viral transmission incurred by
blood component transfusion as approximately less than
1:100 000. The risk of bacterial contamination of a blood
component inducing symptomatic disease is approximately
1:100 000 for platelets, and approximately 1:1 000 000 U for
erythrocytes [45,46]. However, this risk assessment cannot
account for the risk posed by viruses that have not been
identified. The risk of transfusion-related acute lung injury
(TRALI) is difficult to quantify because of varying clinical
definitions and likely under- and over-reporting, but is thought
blood or blood components . The risk of acute hemolytic
reaction from erythrocyte transfusion is approximately
1:1 000 000 [48–50], but the full immunomodulatory effects
of transfusion are not clear. For example, donor white blood
cells have been found in recipients more than 1 year following
transfusion , and this result is not affected by transfusion of
leuko-reduced, in stead of non-leuko-reduced, blood compo-
An underlying premise of the use of antifibrinolytics to
decrease blood loss in cardiac surgery is that CPB is accom-
panied by ?hyper-fibrinolysis?. However, it is not clear in this
circumstance that fibrinolysis is routinely activated beyond its
normal activity. Reduced concentrations of platelets and
coagulation factors result in a porous fibrin network that is
less resistant to plasmin and thus is more easily lyzed than is a
normal clot [53–57]. Clinically, it is exceedingly difficult to
that is greater than normal) from normal fibrinolysis in the
presence of hemodilution consequent to blood loss and
appropriate consumption, without replacement of coagulation
factors or platelets. Furthermore, an analysis of the data 
included in the reports of orthopedic surgery  shows
reasonably similar decreases, by aprotinin in cardiac and
orthopedic surgery, of blood loss and transfusion . This
suggests that hemodilution may be a more important influence
than CPB in the generation of a poorly formed clot that is
hemostasis resulting from CPB in cardiac surgery would not
apply to orthopedic surgery conducted without CPB.
artery surgery by reduction of blood loss and erythrocyte
transfusion. Evaluation of safety of drugs and biologics can be
more difficult than that of efficacy, because of the usually low
incidence of serious adverse events, necessitating large studies
for their clarification. Thus, it is not uncommon to uncover
adverse effects, after regulatory approval, when many more
patients have been exposed to the pharmaceutical than is
possible in some phase II or III clinical trials. In as much as
some of the issues regarding safety arise after approval, and
after many physicians have used the pharmaceutical and
developed opinions, bias is difficult to eliminate. Regulatory
authorities not infrequently attach to approval the requirement
for additional studies (phase IV) to clarify an unresolved issue.
The recent retrospective reports questioning the safety of
aprotinin, when used in conjunction with CPB, cannot elimin-
2076 Letters to the Editor
? 2006 International Society on Thrombosis and Haemostasis
represent a ?phase IV clinical trial? as has been suggested .
There are several publications of prospective, randomized,
double-blinded trials regarding aprotinin and renal effects that
been published after, rather than before, the recent retrospec-
tive analyses of databases, we might have concluded that the
issue is resolved: that is, an hypothesis was generated, but was
not supported by prospective, randomized, blinded clinical
could resolve this issue: such a study with an alpha of 0.05 and
a power of 80% would require 365 patients per group to detect
the renal effect noted in the multi-center post hoc analysis.
Although some have thought that such a study is not possible,
many institutions do not useaprotinin routinely during cardiac
surgery; more than 30% of patients in the McSPI Epi-II
database received no antifibrinolytic for cardiac surgery (more
than received aprotinin) . However, such a study may not be
necessary. Several prospective, randomized, blinded trials were
conducted in support of the registration of aprotinin for use in
cardiac surgery. Undoubtedly more data were collected than
have been published. Publication of complete data from these
randomized studies, regarding the renal effects of aprotinin,
should have a power of more than 99.9% to detect the 5%
increase in renal ?events? recently reported in the retrospective
analysis of multi-center database , and a power of approxi-
mately 85% to detect an increase of half that reported (2.5%).
Assessment of a change in renal function of patients with pre-
operative dysfunction would be of special interest, as it would
likely provide a more sensitive test of a potential adverse renal
effect of aprotinin.
It is possible that the data from completed prospective,
for patients with pre-operative renal dysfunction, potentially
necessitating an additional prospective trial. The retrospectro-
scope is a valued instrument, but cannot eliminate bias, and
thus should not replace a study with a design that best reduces
or eliminates important bias, when that better alternative
(prospective, randomized, double-blinded) has been, or can be,
Disclosure of Conflict of Interests
The author is an employee of Novo Nordisk A/S, the
manufacturer of recombinant activated coagulation factor
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