REVIEW ARTICLE

Activation of the Hemostatic System During

Cardiopulmonary Bypass
Roman M. Sniecinski, MD,* and Wayne L. Chandler, MD†

Cardiopulmonary bypass (CPB) is a unique clinical scenario that results in widespread

activation of the hemostatic system. However, surgery also results in normal increases in
coagulation activation, platelet activation, and fibrinolysis that are associated with normal
wound hemostasis. Conventional CPB interferes with normal hemostasis by diluting hemo-
static cells and proteins, through reinfusion of shed blood, and through activation on the
bypass circuit surface of multiple systems including platelets, the kallikrein-kinin system, and
fibrinolysis. CPB activation of the kallikrein-kinin system increases activated factor XIIa,
kallikrein, bradykinin, and tissue plasminogen activator levels, but has little effect on
thrombin generation. Increased tissue plasminogen activator and circulating fibrin result in
increased plasmin generation, which removes hemostatic fibrin. The nonendothelial surface of
the bypass circuit, along with circulating thrombin and plasmin, lead to platelet activation,
platelet receptor loss, and reduced platelet response to wounds. In this review, we highlight
the major mechanisms responsible for CPB-induced activation of the hemostatic system and
examine some of the markers described in the literature. Additionally, strategies used to
reduce this activation are discussed, including limiting cardiotomy suction, increasing circuit
biocompatibility, antithrombin supplementation, and antifibrinolytic use. Determining which
patients will most benefit from specific therapies will ultimately require investigation into
genetic phenotypes of coagulation protein expression. Until that time, however, a combination
of approaches to reduce the hemostatic activation from CPB seems warranted. (Anesth Analg
2011;113:1319 –33)

T he hemostatic system consists of 4 integrated com-

ponents: the coagulation system, endothelium and
regulatory proteins, platelets, and fibrinolysis. These
elements work together to prevent blood loss from injured
vasculature without occluding the entire vessel. In certain
situations, however, this activation inappropriately spreads
systemically, creating both coagulopathy and thrombotic
complications. Cardiac surgery with the use of cardiopul-
monary bypass (CPB) is one such scenario that results in
widespread activation of the hemostatic system. This can
result in micro thrombi during CPB, coagulation defects
after its termination, and even hypercoagulability leading
to thrombotic complications in the postoperative period. In
this review, we examine the current concepts thought to be
involved with CPB-induced activation of the hemostatic
system, as well as some of the potential interventions to
minimize clinical sequelae.
THE IMPORTANCE OF THROMBIN AND
ITS MEASUREMENT
At the site of a wound (Fig. 1), platelets bind to collagen
through von Willebrand factor, activate and aggregate
From the *Department of Anesthesiology, Division of Cardiothoracic
Anesthesia, Emory University School of Medicine, Atlanta, Georgia; and
†Department of Laboratory Medicine, University of Washington, Seattle,
Washington.
Accepted for publication August 22, 2011.
The authors declare no conflicts of interest.
Wayne L. Chandler, MD, is currently affiliated with the Department of
Pathology and Genomic Medicine, The Methodist Hospital, Houston, TX.
Reprints will not be available from the authors.
Address correspondence to Wayne L. Chandler, MD, The Methodist Hos-
pital, Methodist Pathology Associates, 6565 Fannin St., Suite B-490, Houston,
TX 77030. Address e-mail to wlchandler@tmhs.org.
Copyright © 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3182354b7e
forming an initial hemostatic plug. Active factor VII (FVIIa)
in blood binds wound tissue factor (TF) leading to activa-
tion of factor IX (FIXa) and factor X (FXa), which in turn
activate prothrombin to thrombin.1,2 Once thrombin is
formed, it becomes the key regulatory protein, activating
platelets and factors V, VIII, and XI, which accelerates
coagulation, while activation of fibrinogen and factor XIII
stabilizes the hemostatic clot. Thrombin formed at the site
of a wound we term “hemostatic” thrombin because it is
participating in normal hemostasis.
Under some conditions, thrombin and fibrin may be
generated without wounds. This can occur locally as in
deep venous thrombosis or systemically because of wide-
spread organ damage (shock, sepsis) or systemic release of
procoagulants such as TF and anionic phospholipids (brain
injury). Excessive local or systemic thrombin and fibrin
formation are not being made in response to a wound site
but represent dysregulation of the coagulation system and
may result in consumptive coagulopathy and in some cases
disseminated intravascular coagulation, bleeding, and
thrombosis. This is termed “nonhemostatic” thrombin and
fibrin.
The average amount of thrombin produced in vivo
throughout the vascular system can be estimated by mea-
suring levels of the thrombin activation markers prothrom-
bin fragment F1.2 or thrombin-antithrombin complex
(TAT).3– 6 The rate of thrombin production is not the same
as the average level of thrombin activity in blood. The
average amount of thrombin activity in vivo can be esti-
mated by measuring fibrinopeptide A (FPA) levels, a
measure of fibrinogen activation to fibrin by thrombin (Fig.
2). To interpret activation markers, it is important to
understand how changes in production of the marker affect
marker levels. If the marker has a short half-life and rapid
clearance such as FPA (t1/2 4 minutes) or TAT (t1/2 10

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 REVIEW ARTICLE

Figure 1. Normal hemostasis. 1, Initial plug formation begins with von Willebrand factor (VWF) binding to collagen in the wound and platelets
(plt) adhering to VWF. 2, Coagulation is initiated by small amounts of active factor VII (FVIIa) in blood binding to the exposed tissue factor (TF)
in the wound, leading to activation of factor IX (FIXa) and factor X (FXa), which in turn initiates the conversion of prothrombin to thrombin.
Thrombin creates a positive feedback loop by activating factors VIII (FVIIIa) and V (FVa), which increases FIXa and FXa’s conversion of
prothrombin to thrombin. This local burst of thrombin production at the wound site converts soluble fibrinogen into a fibrin mesh that stabilizes
the initial plug. 3, Clot formation away from the site of injury is prevented by antithrombin (AT), which destroys thrombin and FXa, FIXa, and
FXIa, activated protein C (APC), which destroys FVIIIa and FVa, and tissue factor pathway inhibitor (TFPI), which destroys TF-VIIa complexes.
4, Additionally, the endothelium (endo) secretes tissue plasminogen activator (tPA), which binds to fibrin and converts plasminogen to plasmin,
which in turn lyses the fibrin. Once a stable clot is formed and the wounded tissue is no longer exposed, the regulatory proteins and fibrinolytic
proteins prevent further thrombus formation.

minutes), the concentration of the marker in blood will
change in parallel with the formation rate and is essentially
a direct measure of the formation rate of the marker.7–10 If
the marker has a longer half-life and slower clearance such
as prothrombin activation peptide F1.2 (t1/2 90 minutes) or
d-dimer (t1/2 8 hours), the concentration of the marker
during CPB is cumulative, thus the change or slope of the
concentration versus time curve is proportional to the
formation rate, not the concentration itself.11,12 Most
activation markers are proteins or protein fragments that
are cleared by the liver. The clearance rate remains the
same even when marker production is increased.8 In
most patients, liver blood flow is well maintained during
CPB and marker clearance seems to be similar to preop-
erative values.13
The surgical wound produces increased hemostatic
thrombin and fibrin at the wound site, but has little
systemic effect.6,7,14,15 Immediately after going on CPB,
hemodilution by the priming fluid in the bypass circuit
reduces all factors in blood including coagulation factors,
inhibitors, and activation markers, by approximately 30%
to 40% (Fig. 3).16 –23 Changes during CPB in stable factor
levels with long half-lives, such as albumin, coagulation
proteins, and antithrombin (AT), primarily reflect hemodi-
lution, blood loss, and transfusion with consumption hav-
ing only a minor role.16,18,21,23
Hemodilution tends to obscure the underlying changes
occurring in the hemostatic system during CPB.24,25 Be-
cause all proteins in the blood are diluted equally at the
start of CPB, any factor that does not decrease must be
undergoing a rapid increase in formation to maintain its
concentration at preoperative levels. Most studies present
activation data as marker level versus sample number with
no reference to time or hemodilution effects (Fig. 4). With
this kind of data, it is difficult to gauge what the underlying
rate of activation is. One approach is correction for hemodi-
lution, that is, dividing results by the average percent
change in stable factor levels to give an indication of what
the marker level would be if hemodilution had not oc-
curred.26 If hemodilution-corrected results are plotted ver-
sus sample time, it is possible to get a sense of the
magnitude and rate of change in the system (Fig. 4). The
problem with correction for hemodilution is that it pro-
duces a set of values that are not the actual measured
values from the patient, but adjusted values based on a
simple dilution model.
Another approach to the analysis of hemostatic data is to
use a computer to account for changes in marker levels
caused by alternations of patient blood volume, hemodilu-
tion, blood loss, blood transfusion, timing of samples, and
clearance of proteins. In most studies, none of these factors
is accounted for when presenting raw measurements of
marker levels in blood, yet conclusions are drawn from
changes in the marker levels as if these effects were known.
Computer analysis or modeling allows the reader to know
the specific assumptions made in analyzing the data, what
was accounted for, and what was not. As new information
is developed, the model can be updated to improve the
analysis. When all of the factors affecting marker levels are
accounted for, it is possible to estimate the formation rate in
vivo of thrombin or other factors. It is further possible to
validate the estimate of formation rate by comparing rates
based on different markers that measure the same process
but have different clearance rates and thus marker patterns

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Hemostasis and Cardiopulmonary Bypass
Figure 2. Thrombin production versus activity on cardiopulmonary
bypass (CPB). Sample times are 1 ⫽ baseline (BL), 2 ⫽ after
sternotomy, 3 ⫽ after heparinization, 4 to 6 ⫽ 5, 15, and 30
minutes on CPB, 7 ⫽ before removal of aortic cross-clamp, 8 ⫽ after
removal of cross-clamp, 9 ⫽ after protamine administration, 10 ⫽ 2
hours postoperatively. (Adapted from Eisses et al.35)
Figure 3. Effect of hemodilution on stable factor levels. Hemodilution
during cardiopulmonary bypass (CPB) has a similar effect on the
level of all stable factors in blood as shown for antiplasmin,
plasminogen, fibrinogen, antithrombin, and prothrombin. (Adapted
from Chandler.23)
for raw data. Figure 4 shows the estimated in vivo throm-
bin generation rate in one patient during CPB based on
measured levels of both F1.2 and TAT, which showed
different patterns for the measured data but produced
December 2011 • Volume 113 • Number 6
similar estimates of the in vivo thrombin formation rate.
The overall best estimate can be determined based on the
average or best fit data using both markers.7 Computer
modeling is not the same as de novo simulation; model-
ing is essentially a more complete method for correcting
hemodilution and other processes that affect marker
levels.
Conventional CPB leads to substantial increases in
thrombin activation markers, unrelated to the surgical
wound itself. Figure 5 shows the estimated rate of thrombin
generation, total fibrin generation, and soluble fibrin gen-
eration using computer analysis of data from one study of
conventional CPB.7 After thoracotomy, there was only a
small increase in the total amount of thrombin and fibrin
generated.6,7,14,15 However, within 5 minutes of starting
CPB, thrombin generation and soluble fibrin formation
both increased approximately 20-fold, but because the
patient was heparinized, thrombin activity and total fibrin
generation actually decreased.7,11,14,27 Normally, fibrin
does not circulate in blood; it is present only at the site of
the wound. Soluble fibrin is nonhemostatic fibrin formed in
circulating blood due to dysregulation of hemostasis in
some way. Under normal circumstances, only approxi-
mately 1% of the fibrin formed circulates as soluble fibrin,
and the remainder stays in the wound.7 Soon after CPB is
started, total fibrin formation is reduced because of hepa-
rinization whereas soluble fibrin formation is increased to
approximately 35% of the total. This indicates that much of
the thrombin being formed during CPB is nonhemostatic
thrombin, in turn producing soluble fibrin. Non–wound-
related thrombin generation and soluble fibrin formation
continue to be 5- to 10-fold increased throughout the
remainder of CPB. Soluble and circuit-bound fibrin provide
binding sites for non–wound-related thrombin that pro-
tects this thrombin from inhibition by AT, necessitating
high-dose heparin as an anticoagulant.
Another burst of nonhemostatic thrombin and soluble
fibrin generation occurs after reperfusion of the heart and
lungs.7,11,15,28 –31 Thrombin generation after reperfusion
may be involved in myocardial ischemia-reperfusion injury
and impaired hemodynamic recovery, but the increase in
thrombin generation after reperfusion is reduced or elimi-
nated if shed blood is not reinfused.12,32–36 After protamine
reversal, there is another peak in thrombin generation as
more thrombin and fibrin are produced at the site of the
wound.7,27 The increase in postoperative thrombin genera-
tion lasts hours to days and then begins to decrease toward
baseline levels.
An in vitro thrombin generation test, also called
calibrated automated thrombography, measures the abil-
ity of plasma to generate thrombin when stimulated,
termed the “endogenous thrombin potential” (ETP).37,38
Briefly, the method adds TF and phospholipids to the
patient’s platelet-poor plasma and monitors the cleavage
of a fluorogenic substrate, producing a curve, the area
under which represents ETP. Low ETP, such as can occur
after CPB, may indicate a hypocoagulable state and
bleeding risk,22,39 whereas high ETP may predict pos-
sible thrombotic risk.40 Two limitations of the ETP are
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 REVIEW ARTICLE

Original Thrombin Marker Data

CPB CPB

Hemodilution Corrected vs Time

CPB CPB

Estimated In Vivo Thrombin Generation

CPB

Figure 4. Computer model of in vivo thrombin production. This figure shows 2 approaches used to analyze in vivo thrombin production during
cardiopulmonary bypass (CPB). The top row of graphs shows the original measured levels of thrombin activation markers. The second row shows
hemodilution corrected marker levels versus sampling time, a better indicator of the magnitude and rate of marker changes. Using both F1.2 and
thrombin-antithrombin complex data, the bottom graph shows the estimated in vivo thrombin generation rate in the patient based on analysis of the
data using a computer model of the patient’s vascular system that accounted for hemodilution, blood loss, transfusion, and marker clearance. The
2 peaks correlate with commencement of CPB and release of the aortic cross-clamp. (This research was originally published in Blood. Chandler WL,
Velan T. Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass. Blood 2003;101:4355– 4362. © the American
Society of Hematology.)

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Hemostasis and Cardiopulmonary Bypass
that it measures the ability of plasma to produce throm-
bin in vitro, which is not the same as thrombin genera-
tion in vivo, hence the term thrombin “potential,” and
Figure 5. Estimated thrombin, total fibrin, and soluble fibrin genera-
tion rates during conventional cardiopulmonary bypass (CPB). Error
bars indicate the standard error. White squares indicate a significant
difference (P ⬍ 0.05) from baseline. Values based on computer
modeling. (Adapted from Chandler and Velan7 and Eisses et al.12)
Figure 6. Summary of hemostatic activa-
tion mechanisms on cardiopulmonary by-
pass (CPB). BK ⫽ bradykinin; FXIIa ⫽
activated factor XII; TF ⫽ tissue factor;
TPA ⫽ tissue plasminogen activator; Plt ⫽
platelets; Fib ⫽ fibrin degradation prod-
ucts; Endo ⫽ endothelium. Details pro-
vided in text.
December 2011 • Volume 113 • Number 6
that the test cannot be run in the presence of heparin or
direct thrombin inhibitors (DTIs).
MECHANISMS OF ACTIVATION
Hemostatic system activation occurs via several mecha-
nisms including the contact system, fibrinolysis, inflamma-
tion, and platelets. This is summarized in Figure 6 and
detailed in the sections below.
The Contact System
Kinins are a diverse set of proteins involved in vascular
tone, patency, and tissue repair.41 The best studied member
of this family is bradykinin, which may have a role in
attenuating cardiac ischemia and hypertension.42 Kinins
are synthesized as kininogens, of either high molecular
weight (HMWK) or low molecular weight, and are inactive
until cleaved by proteins known as kallikreins. In plasma,
kallikrein circulates in an inactive form known as prekalli-
krein, or Fletcher factor, until activated by factor XIIa, also
known as Hageman factor. The “contact system” refers to
factor XII, factor XI, HMWK, and prekallikrein, which are
associated proteins that travel together in the plasma. There
is normally a low level of kallikrein activity on endothelial
cell surfaces producing kinins, including bradykinin, that
are rapidly degraded by kininases, which are enzymes
found in plasma and in high concentrations in kidney and
lung tissue.43,44
Once CPB is initiated, there is a dramatic increase in
contact system activity as blood touches the artificial ma-
terial comprising the CPB circuit.45,46 Factor XII auto-
cleaves itself upon contact with a variety of anionic surfaces
including glass, polyethylene, and silicone rubber, and
produces FXIIa, which converts prekallikrein to active
kallikrein. Plasma kallikrein creates a positive feedback
loop by cleaving more FXII, as well as producing brady-
kinin from HMWK. Prekallikrein and HMWK levels de-
crease not only because of hemodilution, but also because
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 REVIEW ARTICLE
of consumption and binding to the CPB circuit.47 Brady-
kinin levels increase 10-fold due to increased HMWK
cleavage as well as reduced lung clearance because pulmo-
nary blood flow is minimal.46,48 This has important impli-
cations for fibrinolysis because elevated bradykinin levels
induce secretion of tissue plasminogen activator (tPA) (see
below).49,50
The role of FXIIa in activation of the hemostatic system
remains unclear.51 Besides producing kallikrein, FXIIa has
been shown to convert FXI to FXIa in vitro, thus initiating the
intrinsic pathway of coagulation. However, FXII-deficient
patients do not have hemostatic defects, indicating that FXIIa
does not normally have a role in hemostasis.52 Indeed, FXII
deficiency does not stop the increase in thrombin generation
during CPB.53,54 However, FXIIa has been shown to activate
plasminogen to plasmin in vitro, suggesting its possible role
in inducing fibrinolysis during CPB.55,56 Additionally, FXIIa
and other fragments of FXII activate the classic complement
cascade, accounting for some of the “crosstalk” between
coagulation and inflammation.
The Fibrinolytic System
Endothelial cell release of tPA is a major activator of
plasminogen, turning it into fibrin-degrading plasmin. On
average, CPB stimulates a 5-fold increase in tPA secretion
and active tPA levels,15,57,58 although there is some vari-
ability and approximately one-third of patients may show
no change.59 Although active thrombin has been shown to
release tPA in vitro,60 human in vivo studies are lacking
and it is more likely that bradykinin is the main stimulus.
Indeed, tPA release has been shown to be reduced by
blocking bradykinin receptors or reducing its production
by inhibiting kallikrein.61,62
Increased tPA alone does not increase fibrinolytic activ-
ity if no fibrin is present. d-dimer levels, an indicator of
fibrin degradation, do not change under normal conditions,
even when tPA levels are transiently increased 10-fold.63 In
the setting of CPB, however, soluble and circuit-bound
fibrin provide a huge surface for plasminogen activation to
occur.56,64,65 There is a 10- to 100-fold increase in plasmin
generation shortly after the commencement of CPB, and
plasmin generation, along with fibrin degradation, remain
increased 10- to 20-fold throughout the duration of CPB.66
Normally only 1% of fibrin is degraded by the fibrinolytic
system, with the remainder being removed by cells during
wound healing. During CPB, however, fibrin formation
and degradation rates are nearly equal, indicating that
much of the fibrin degradation is not at the sites of vascular
injury. This hyperfibrinolytic state consumes fibrinogen,
leaving less available for coagulation postoperatively. Ad-
ditionally, large amounts of plasmin can damage platelets
through cleavage of their glycoprotein (GP)Ib receptor,67,68
and partially activate them (see below), making them less
responsive to further activation with agonists such as
adenosine diphosphate and arachidonic acid.69 –71
It is important to recognize that a hypofibrinolytic state
can also occur postoperatively. Plasminogen activator in-
hibitor 1 (PAI-1) prevents the formation of plasmin. Al-
though levels on CPB are initially much less than tPA,
PAI-1 is an acute phase reactant and, by 2 hours after
1324 www.anesthesia-analgesia.org
surgery, its secretion is increased 15-fold.66,72–74 This in-
crease may continue into the first postoperative day, which
is associated with an increased risk of coronary graft
occlusion.75 Similar to tPA levels, there is some variability
with approximately one-third of patients showing no post-
operative PAI-1 increase.59 This individual variability is
one of the reasons it is difficult to predict which patients are
at risk for bleeding versus thrombosis.
Inflammation
The coagulation and immune responses are linked; a break
in the vasculature not only must be fixed, but also any
foreign invaders neutralized. Inflammation has multiple
mediators that can create profound amplification, some-
times resulting in an out-of-proportion response to the
stimulating event and causing pathologic conditions in the
host. A sepsis-like clinical picture that often results from
CPB, termed the systemic inflammatory response syn-
drome, can be linked to “crosstalk” with the coagulation
system and has been extensively reviewed elsewhere.76 – 80
A few key points will be emphasized here.
Leukocytes, including neutrophils and monocytes, bind
to and are activated by the surface of the bypass cir-
cuit,64,81– 88 which leads to an increase in TF expression,
procoagulant activation, and thrombin generation on these
cells.83– 85,89 Shed blood contains increased numbers of
activated leukocytes and levels of TF bound to cells and
microparticles, as well as soluble TF.81,82,90 –92 CPB also
alters the protein C system. Protein C is activated by the
binding of thrombin to thrombomodulin expressed on
endothelial cells. This normally functions to suppress fur-
ther thrombin formation away from the wound by destroy-
ing FVIIIa and FVa. Activated protein C also binds with
endothelial protein C receptors to downregulate cytokine
production and decrease vascular permeability.93,94 In ad-
dition to hemodilution, CPB further decreases protein C
levels by downregulating thrombomodulin and endothelial
protein C receptor expression of the endothelium. Overall,
systemic inflammatory response syndrome caused by CPB
increases TF expression while simultaneously depressing
protein C activation, thereby favoring the production of
thrombin.
Platelets
Fibrinogen bound to the CPB circuit provides a large
binding site for platelets through their GPIIb/IIIa receptors.
Once platelets bound to either the vascular system or to the
circuit are activated, they spread pseudopods, express
receptors, release granules and microparticles, and support
thrombin formation.64,95–101 Additionally, there is some
evidence that leukocytes may stimulate TF release directly
from platelets.102 CPB increases platelet activation markers
including ␤-thromboglobulin, platelet factor 4, soluble and
platelet P-selectin, and platelet GMP140 (granule mem-
brane protein 140).16,30,32,34,69,103–108 Shed blood shows
evidence of platelet activation including reduced platelet
levels, increased platelet activation markers, increased mi-
croparticles, and decreased platelet responsiveness.32,108 –110
When shed blood is reinfused, part, but not all, of the
increase in systemic platelet activation markers can be
accounted for by markers in the shed blood. However,
ANESTHESIA & ANALGESIA
Hemostasis and Cardiopulmonary Bypass
platelet activation still occurs during CPB even when shed
blood is not reinfused.32,34,111–113
During CPB, platelets are activated, platelet thrombin
receptor responsiveness is reduced, and platelet protease-
activated receptor 1 (PAR1) cleavage is increased. This
suggests that thrombin generated during CPB is activating
platelets through PAR1.114,115 Plasmin formed by activa-
tion of the fibrinolytic system can damage and directly
activate platelets through PAR4, causing them to aggregate
and release ␣ and dense granule contents.116 –119 Use of
tranexamic acid (TXA) during CPB preserves platelet aden-
osine diphosphate levels, and use of aprotinin during CPB
reduces platelet activation, preserves PAR1 function, and
reduces platelet GPIb cleavage.67,104,115,120 –122
REDUCING ACTIVATION
Ideally, hemostatic activation should be minimized during
CPB and then quickly maximized after its termination.
Placing the system in a sort of “hibernation” until needed
would not only maintain required fluidity and reduce
thrombotic risk, but also prevent the unproductive con-
sumption of coagulation factors, fibrinogen, and platelets.
Efforts to achieve this goal have focused both on modifying
the conduct of CPB and its circuit, as well as pharmacologic
methods to reduce the patient’s response to these insults.
Limiting Use of Cardiotomy Suction
During conventional CPB, blood in the surgical field is
typically removed using cardiotomy suction (“pump suck-
ers”) and returned to the venous reservoir where it can be
oxygenated and reinfused into the patient via arterial
inflow. Advantages include returning red cells and coagu-
lation factors back to the patient. However, shed blood that
has been exposed to wounded tissue surfaces has already
started to activate hemostatic proteins, albeit appropriately.
Pericardial blood in particular shows increased levels of
F1.2, TAT, fibrin degradation products, and elevated levels
of TF.81,82,92,123–125 From a purely research perspective,
reinfusing the already activated blood complicates data
analysis by increasing the measured level of activation
markers in the patient, although it may not represent
“new” formation of the markers.26,32 From a clinical stand-
point, shed blood contains fibrin and fibrin degradation
products that can stimulate increased activity of tPA and
contribute to platelet dysfunction.33,117 Thus, use of the
cardiotomy suction may contribute to both “true” and
“false” increases in nonhemostatic thrombin formation.
Small observational studies showed a reduction in he-
mostatic activation if shed blood was not reinfused, or if the
cells were washed (i.e., “cell saver” was used in lieu of
cardiotomy suction). Four recent studies ranging from 29 to
75 on-CPB coronary artery bypass graft (CABG) patients
have shown lower markers of inflammation and platelet
activation in patients in whom cardiotomy suction blood
was not retransfused.112,126 –128 de Haan et al.,33 who con-
ducted a study with 40 on-CPB CABG patients, demon-
strated decreased blood loss and lower blood product
consumption in patients who were not retransfused car-
diotomy suctioned blood. Likewise, in the latest meta-
analysis of cell-saver use during cardiac surgery from 1982
to 2008, the authors concluded that cell-saver use, versus
December 2011 • Volume 113 • Number 6
retransfusion of cardiotomy suction blood, reduces expo-
sure to allogeneic blood products when used throughout
the entire surgical procedure.129 The results of all of these
studies must be interpreted with the caveat that study
populations were almost exclusively first-time CABG pa-
tients with CPB runs in the 2-hour range and blood volumes
of approximately 1000 mL being processed through the cell
saver. More-complex operations result in higher hemostatic
activation,113 and longer CPB exposure resulting in higher
cell-saver use would likely result in more coagulation
factors and platelets being washed out.
Increasing Circuit Biocompatibility
As mentioned above, the large foreign surface of the CPB
circuit provides ample space for the deposition of fibrin
and other proteins that activate platelets and leukocytes.
Efforts to increase the biocompatibility of these circuits
have focused on either incorporating heparin into the
tubing or modifying the surface polymers to decrease
protein adsorption.130 Heparin-bonded circuits have been
around the longest and are the best studied. One random-
ized trial with high-risk patients, including those with
preexisting lung or kidney impairment, showed a de-
creased incidence of postoperative renal dysfunction and
fewer days of mechanical ventilation.131 In a meta-analysis
of heparin-bonded circuits versus conventional tubing, the
authors showed a modest decrease in bleeding and red cell
transfusion with heparin circuits.132 Other than heparin,
circuits have been coated with polymethoxyethylacrylate,
phosphorylcholine, and siloxane in an attempt to make the
tubing less favorable for cell binding.133–136 None of the
coatings, however, has demonstrated in vivo reductions in
hemostatic activation.137 A more recent systematic review
of biocompatible CPB circuits concluded that although they
may offer some benefit in reducing red cell transfusions, a
decreased incidence of atrial fibrillation, and shorter inten-
sive care unit (ICU) stays, high-quality studies are limited
and the surfaces alone do little to contain hemostatic
activation without implementing additional measures.138
Decreasing CPB Circuit Size
So-called “miniaturized” CPB has been developed with the
idea of reducing blood contact with foreign material and air
by using low prime-volume tubing and eliminating the
venous reservoir and cardiotomy suction. In general, prim-
ing volume for miniaturized CPB systems is on the order of
500 mL versus the 1500 to 2000 mL in conventional circuits,
and virtually all systems use some type of heparin-bonded
tubing. Lower levels of thrombin activation have been
reported with the use of miniaturized CPB.139,140 Two
recent meta-analyses of randomized trials confirmed a
reduced need for blood-product transfusions using the
smaller circuits.141,142 However, this would be expected
given the significant reduction in hemodilution using lower
prime volumes. Additionally, because reinfusion of shed
blood alone has been shown to increase hemostatic activa-
tion, it is not clear whether miniaturized CPB systems offer
any benefit regarding hemostatic activation other than
simply eliminating the cardiotomy suctions. It is likely that
any combined approach using heparin-bonded circuits,
www.anesthesia-analgesia.org 1325
 REVIEW ARTICLE
adequate antifibrinolytic therapy, and removal of car-
diotomy suction will reduce hemostatic activation.35
Off-Pump Coronary Artery Bypass
Of course, the ultimate reduction in CPB circuit size is to
eliminate CPB entirely. Although not practical for many
cardiac operations, off-pump coronary artery bypass
(OPCAB) currently comprises about 20% of coronary bypass
graft procedures, and has been shown to be a viable
technique with regard to graft patency.143 Although the
patient still undergoes thoracotomy, heparinization, and
grafting, there is no blood contact with foreign material and
blood in the surgical field is generally cleared using a
cell-saver device because there is no cardiotomy suction.
The time course for hemostatic activation is somewhat
different for OPCAB. In general, there is no early peak of
thrombin generation, presumably because of the lack of
contact activation, and activation of the fibrinolytic system
is less.106 However, there is equal activation of the TF
pathway, and thrombin generation and fibrinolytic activity
are actually equal to CPB patients within 24 hours postop-
eratively.144 In general, studies have shown less platelet
activation and dysfunction with OPCAB, leading to the
potential concern of a greater prothrombotic state in the
early postoperative period.145,146 Increased prothrombotic
states may last as long as 1 month after surgery for both
OPCAB and standard CABG on CPB, and there does not
seem to be a greater risk of graft thrombosis at experienced
OPCAB centers.147
Heparin Versus DTIs
Unfractionated heparin (UFH) has been, and continues to
be, the mainstay anticoagulant used for CPB, primarily
because of its rapid effect and availability of a neutralizing
agent (protamine). It is not a direct inhibitor of thrombin,
but instead enhances the effects of AT. It is this dependency
on AT that partially accounts for the drug’s variable
anticoagulation efficacy in individual patients and in vari-
ous situations.25 However, AT levels alone cannot predict
UFH’s ability to achieve a desired activated clotting time
(ACT) value.148 Other factors, such as the heterogeneity of
UFH’s chain lengths and its variable binding to endothelial
cells, macrophages, and plasma proteins, affect its bioavail-
ability.149 It is this variability that makes frequent monitor-
ing necessary while on CPB, most commonly using the
ACT. Yet, the ACT itself has significant limitations, begin-
ning with a lack of consensus as to what ACT value reflects
adequate anticoagulation for CPB.150 ACT values do not
correlate well with actual heparin plasma concentra-
tions,151 and thrombin is still activated despite values
⬎480.5,152 Efforts to dose UFH more effectively have cen-
tered on measuring heparin plasma levels and maintaining
a constant concentration. Although some studies have
shown decreased hemostatic activation using this strat-
egy,153,154 others have shown no difference than ACT-
based dosing.155
Aside from dosing problems, there are other issues that
prevent UFH from being an ideal anticoagulant. Heparin
itself is known to cause platelet activation and stimulate
fibrinolysis.156 Heparin-induced release of TF pathway
inhibitor occurs as well, potentially exhausting TF pathway
1326 www.anesthesia-analgesia.org
inhibitor stores from the endothelium.157,158 Heparin-
induced thrombocytopenia (HIT), which has been exten-
sively reviewed elsewhere,159 –162 is a result of antibodies
formed to the complex of heparin and platelet factor 4.
Approximately 25% to 50% of patients will develop the
antibodies 5 to 10 days after surgery, which can lead to
thrombotic complications if heparin therapy is continued in
the postoperative period.163
The above limitations of heparin have helped drive the
development of DTIs. A major advantage of DTIs is that AT
is not required and their smaller molecular size enables
greater inhibition of thrombin bound to fibrin (i.e., clot-
bound versus free thrombin).164 More effective thrombin
inhibition with less platelet activation would obviously be
desirable for decreasing hemostatic activation. Bivalirudin,
a DTI with a half-life of 25 minutes, has been shown to
adequately suppress hemostatic activation on CPB when
cardiotomy suction is not used.165 Interestingly, when
cardiotomy suction was used, markers of activation such as
d-dimer, TAT, and FPA levels were significantly increased.
This is likely attributable to the fact that stagnant blood
causes a tremendous amount of thrombin generation,
which may locally overwhelm the reversible inhibition of
the DTI. Multicenter trials using bivalirudin for CABG
patients both on and off CPB have demonstrated the same
safety and procedural efficacy as heparin anticoagulation,
although in the United States it is currently only approved
for patients with HIT undergoing percutaneous coronary
interventions.166,167 Argatroban is another DTI that has
been used in the setting of HIT, although the development
of intraoperative thrombi has been reported when used for
CPB anticoagulation.168 –170 Use of DTIs in the setting of
CPB is also currently limited by lack of a neutralizing agent.
Oral DTIs, such as dabigatran etexilate, have been devel-
oped as potential replacements for coumadin therapy, and
may pose a bleeding risk when patients present to surgery.
It is recommended that dabigatran therapy be discontinued
2 to 4 days before cardiac surgery, and longer in patients
with impaired renal function.171
AT Supplementation
AT levels show a 30% to 50% decrease from baseline after
initiation of CPB, a consequence of both acute hemodilution
and typical heparin administration, then recover, although
not fully, several hours postoperatively.23,172,173 However,
after prolonged CPB use, especially that associated with
deep hypothermic circulatory arrest, AT levels can decrease
even further and can take days to return to baseline
levels.174 This can contribute to inadequate thrombin sup-
pression with heparin, as well as potential thrombotic
complications.175,176 Indeed, studies have shown that post-
CPB patients with AT levels ⬍60% of normal have a greater
risk of adverse neurologic and cardiac events in the ICU.177,178
Most studies of low-dose AT supplementation during CPB
have failed to show a decrease in thrombin generation,
plasmin generation, or platelet activation.175,179 –182 Although
clinical trials have shown that AT supplementation cor-
rects heparin resistance in patients with low AT activity
and reduces the need for fresh frozen plasma, outcomes
have been similar to patients simply receiving additional
heparin.183–185
ANESTHESIA & ANALGESIA
Hemostasis and Cardiopulmonary Bypass
Antifibrinolytics
As previously noted, tPA and plasmin production are
increased during CPB. The lysine analogs, ␧-aminocaproic
acid (EACA) and TXA, are frequently used to mitigate this
potentially hyperfibrinolytic state. Both agents competi-
tively inhibit the fibrin binding site on plasminogen, thus
reducing the rate of fibrinolysis, although plasmin produc-
tion is unaffected.12,186 TXA is more potent than EACA, has
a longer elimination half-life, and is the better studied agent
in cardiac surgery.187 Its prophylactic use has been the
subject of 2 large meta-analyses, with one demonstrating a
reduced need for blood transfusions,188 and the other
showing no benefit compared with placebo.189 Addition-
ally, TXA may increase the risk of seizures during open
heart procedures.190 By decreasing fibrinolysis without
reducing thrombin generation, there is the potential for
thrombotic complications. Although studies have not dem-
onstrated increased risk of myocardial infarction, stroke,
deep vein thrombosis, or pulmonary embolism from TXA
or EACA use in cardiac surgery, there are case reports of
retinal artery and glomerular capillary thrombosis, and the
agents should probably be used with caution in patients
with other risk factors for hypercoagulability.191
Aprotinin is a nonspecific serine protease inhibitor that
also inhibits plasmin. Aprotinin therapy has been shown to
increase the rate of plasmin inhibition 10-fold during CPB,
which in turn reduced the rate of fibrin degradation a
similar amount.192 Unlike the lysine analogs, however,
aprotinin inhibits a broad spectrum of other proteins in-
volved in coagulation including kallikrein, activated pro-
tein C, and thrombin.193 Platelet activation is also reduced
with aprotinin therapy, possibly by protecting PAR4 recep-
tors and by blocking thrombin activation of platelet PAR1
receptors.67,115 As such, it has both pro- and anticoagula-
tion effects as well as antiinflammatory effects. Multiple
studies have shown its efficacy at decreasing markers of
hemostatic activation and preserving platelet function post-
CPB.29,30,62,67,194 –196 Additionally, multiple clinical trials
have demonstrated its efficacy at reducing transfusion of
blood products during cardiac surgery.186,197 However,
marketing of the drugs was suspended in November 2007
after preliminary results of the BART trial, which showed
an increasing mortality trend relative to the lysine ana-
logues.198 The underlying cause of the increased mortality
is unclear, but it has been suggested that aprotinin’s
risk-benefit profile is more suited to patients undergoing
cardiac surgical procedures at high risk for massive blood
loss.199
GENOMICS AND FUTURE DIRECTIONS
CPB-induced hemostatic activation leads to both pro- and
anticoagulant activity. Despite an improved understanding
of these mechanisms, it is difficult to predict whether any
single patient is at greater risk for bleeding or thrombosis.
There is a strong heritability of coagulation protein levels
such as PAI-1, FVII, fibrinogen, and tPA.200 Although some
experts have argued for routine testing of certain inherited
thrombophilias such as factor V Leiden,201 the answer is
not quite so simple. The dilemma has its roots in our DNA,
December 2011 • Volume 113 • Number 6
because gene polymorphisms can significantly affect sus-
ceptibility to adverse postoperative events.202 Genetic vari-
ability is certainly present in the modulation of thrombin
production, and genetic factors have been identified that
contribute to bleeding after cardiac surgery.203 However,
expression of certain proteins, particularly those associated
with adrenergic sensitivity and cardiac myofilament struc-
ture, changes between the initiation of CPB and its termi-
nation.204 Therefore, it is not sufficient to know that a gene
polymorphism is present, but the knowledge of how it is
expressed under CPB conditions is also needed. Future
directions will need to concentrate not only on risk strati-
fication, but also on trying to discern how individual
patients will react to CPB and who will benefit most from
certain therapies such as antifibrinolytics or factor replace-
ment therapy.
Until genetically tailored therapy becomes available,
however, it is probably best to take a combined approach in
reducing hemostatic activation. Adequate thrombin sup-
pression while on CPB should be the goal, either by
ensuring adequate heparin and AT levels or by using DTIs
in cases of HIT. During procedures in which blood loss is
not expected to be massive, specialized circuits to minimize
hemodilution and avoiding reinfusion of cardiotomy blood
are probably appropriate adjuvants, and may further re-
duce hemostatic activation. Finally, antifibrinolytic therapy
should be used when hyperfibrinolysis occurs, either in the
operating room or in the ICU. CPB shares many character-
istics with disseminated intravascular coagulation, and
suppressing hemostatic activation while it is occurring is
probably the best way to avoid a massive consumptive
coagulopathy or devastating thrombotic complications.
DISCLOSURES
Name: Roman M. Sniecinski, MD.
Contribution: This author helped write the manuscript.
Attestation: Roman M. Sniecinski approved the final
manuscript.
Name: Wayne L. Chandler, MD.
Contribution: This author helped write the manuscript.
Attestation: Wayne L. Chandler approved the final manuscript.
This manuscript was handled by: Jerrold H. Levy, MD,
FAHA.
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