Sie sind auf Seite 1von 15


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 hemostatic 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)

he hemostatic system consists of 4 integrated components: 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 cardiopulmonary 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.


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,
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 Hospital, Methodist Pathology Associates, 6565 Fannin St., Suite B-490, Houston,
TX 77030. Address e-mail to
Copyright 2011 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3182354b7e

December 2011 Volume 113 Number 6

forming an initial hemostatic plug. Active factor VII (FVIIa)

in blood binds wound tissue factor (TF) leading to activation 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 widespread 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
The average amount of thrombin produced in vivo
throughout the vascular system can be estimated by measuring levels of the thrombin activation markers prothrombin 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 estimated 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



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 FXas 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.710 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 preoperative 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 hemodilution, blood loss, and transfusion with consumption having only a minor role.16,18,21,23
Hemodilution tends to obscure the underlying changes
occurring in the hemostatic system during CPB.24,25 Because 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 hemodilution, 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 occurred.26 If hemodilution-corrected results are plotted versus 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 produces 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, hemodilution, 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


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 thrombin 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; modeling is essentially a more complete method for correcting
hemodilution and other processes that affect marker
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 generation 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 approximately 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 heparinization 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. Nonwoundrelated 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 nonwound-related thrombin that protects 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 eliminated if shed blood is not reinfused.12,3236 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 generation 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 ability of plasma to generate thrombin when stimulated,
termed the endogenous thrombin potential (ETP).37,38
Briefly, the method adds TF and phospholipids to the
patients 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 possible thrombotic risk.40 Two limitations of the ETP are



Original Thrombin Marker Data



Hemodilution Corrected vs Time



Estimated In Vivo Thrombin Generation


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 patients 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.)



Hemostasis and Cardiopulmonary Bypass

that it measures the ability of plasma to produce thrombin in vitro, which is not the same as thrombin generation in vivo, hence the term thrombin potential, and

that the test cannot be run in the presence of heparin or

direct thrombin inhibitors (DTIs).

Hemostatic system activation occurs via several mechanisms including the contact system, fibrinolysis, inflammation, and platelets. This is summarized in Figure 6 and
detailed in the sections below.

The Contact System

Figure 5. Estimated thrombin, total fibrin, and soluble fibrin generation 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)

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 prekallikrein, 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 material comprising the CPB circuit.45,46 Factor XII autocleaves 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 bradykinin from HMWK. Prekallikrein and HMWK levels decrease not only because of hemodilution, but also because

Figure 6. Summary of hemostatic activation mechanisms on cardiopulmonary bypass (CPB). BK bradykinin; FXIIa
activated factor XII; TF tissue factor;
TPA tissue plasminogen activator; Plt
platelets; Fib fibrin degradation products; Endo endothelium. Details provided in text.

December 2011 Volume 113 Number 6



of consumption and binding to the CPB circuit.47 Bradykinin levels increase 10-fold due to increased HMWK
cleavage as well as reduced lung clearance because pulmonary blood flow is minimal.46,48 This has important implications for fibrinolysis because elevated bradykinin levels
induce secretion of tissue plasminogen activator (tPA) (see
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 variability 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 activity 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. Additionally, 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 inhibitor 1 (PAI-1) prevents the formation of plasmin. Although levels on CPB are initially much less than tPA,
PAI-1 is an acute phase reactant and, by 2 hours after


surgery, its secretion is increased 15-fold.66,7274 This increase 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 postoperative 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.

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, sometimes 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 syndrome, 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 circuit,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 further thrombin formation away from the wound by destroying FVIIIa and FVa. Activated protein C also binds with
endothelial protein C receptors to downregulate cytokine
production and decrease vascular permeability.93,94 In addition 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

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.64,95101 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 membrane protein 140).16,30,32,34,69,103108 Shed blood shows
evidence of platelet activation including reduced platelet
levels, increased platelet activation markers, increased microparticles, 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,


Hemostasis and Cardiopulmonary Bypass

platelet activation still occurs during CPB even when shed

blood is not reinfused.32,34,111113
During CPB, platelets are activated, platelet thrombin
receptor responsiveness is reduced, and platelet proteaseactivated receptor 1 (PAR1) cleavage is increased. This
suggests that thrombin generated during CPB is activating
platelets through PAR1.114,115 Plasmin formed by activation 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 adenosine diphosphate levels, and use of aprotinin during CPB
reduces platelet activation, preserves PAR1 function, and
reduces platelet GPIb cleavage.67,104,115,120 122

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 consumption 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 patients response to these insults.

Limiting Use of Cardiotomy Suction

During conventional CPB, blood in the surgical field is
typically removed using cardiotomy suction (pump suckers) 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 coagulation 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.81,82,92,123125 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 standpoint, 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 hemostatic 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 conducted a study with 40 on-CPB CABG patients, demonstrated decreased blood loss and lower blood product
consumption in patients who were not retransfused cardiotomy suctioned blood. Likewise, in the latest metaanalysis 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 exposure 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 patients 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 randomized trial with high-risk patients, including those with
preexisting lung or kidney impairment, showed a decreased 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.133136 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 intensive 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, priming 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 activation, 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,



adequate antifibrinolytic therapy, and removal of cardiotomy 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 postoperatively.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 drugs variable
anticoagulation efficacy in individual patients and in various situations.25 However, AT levels alone cannot predict
UFHs ability to achieve a desired activated clotting time
(ACT) value.148 Other factors, such as the heterogeneity of
UFHs chain lengths and its variable binding to endothelial
cells, macrophages, and plasma proteins, affect its bioavailability.149 It is this variability that makes frequent monitoring necessary while on CPB, most commonly using the
ACT. Yet, the ACT itself has significant limitations, beginning 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 concentrations,151 and thrombin is still activated despite values
480.5,152 Efforts to dose UFH more effectively have centered on measuring heparin plasma levels and maintaining
a constant concentration. Although some studies have
shown decreased hemostatic activation using this strategy,153,154 others have shown no difference than ACTbased 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


inhibitor stores from the endothelium.157,158 Heparininduced thrombocytopenia (HIT), which has been extensively 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., clotbound 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 developed 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 suppression with heparin, as well as potential thrombotic
complications.175,176 Indeed, studies have shown that postCPB 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 corrects 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


Hemostasis and Cardiopulmonary Bypass

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 competitively inhibit the fibrin binding site on plasminogen, thus
reducing the rate of fibrinolysis, although plasmin production 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 Additionally, 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 demonstrated 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 involved in coagulation including kallikrein, activated protein C, and thrombin.193 Platelet activation is also reduced
with aprotinin therapy, possibly by protecting PAR4 receptors and by blocking thrombin activation of platelet PAR1
receptors.67,115 As such, it has both pro- and anticoagulation effects as well as antiinflammatory effects. Multiple
studies have shown its efficacy at decreasing markers of
hemostatic activation and preserving platelet function postCPB.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 analogues.198 The underlying cause of the increased mortality
is unclear, but it has been suggested that aprotinins
risk-benefit profile is more suited to patients undergoing
cardiac surgical procedures at high risk for massive blood


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 susceptibility to adverse postoperative events.202 Genetic variability 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 structure, changes between the initiation of CPB and its termination.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 stratification, 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 replacement therapy.
Until genetically tailored therapy becomes available,
however, it is probably best to take a combined approach in
reducing hemostatic activation. Adequate thrombin suppression 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 reduce hemostatic activation. Finally, antifibrinolytic therapy
should be used when hyperfibrinolysis occurs, either in the
operating room or in the ICU. CPB shares many characteristics 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.

Name: Roman M. Sniecinski, MD.

Contribution: This author helped write the manuscript.
Attestation: Roman M. Sniecinski approved the final
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,
1. Nomura S, Ozaki Y, Ikeda Y. Function and role of microparticles in various clinical settings. Thromb Res 2008;123:8 23
2. Roberts HR, Hoffman M, Monroe DM. A cell-based model of
thrombin generation. Semin Thromb Hemost 2006;32:32 8
3. Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B.
Thrombin production, inactivation and expression during
open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1
2. Thromb Haemost 1993;70:253 8
4. Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheifh S,
Hunt B, Smith KJ. Mechanisms of thrombin generation during
surgery and cardiopulmonary bypass. Blood 1993;82:3350 7
5. Slaughter TF, LeBleu TH, Douglas JM, Leslie JB, Parker JK,
Greenberg CS. Characterization of prothrombin activation
during cardiac surgery by hemostatic molecular markers.
Anesthesiology 1994;80:520 6
6. Philippou H, Adami A, Boisclair MD, Lane DA. An ELISA for
factor X activation peptide: application to the investigation of
thrombogenesis in cardiopulmonary bypass. Br J Haematol



7. Chandler WL, Velan T. Estimating the rate of thrombin and

fibrin generation in vivo during cardiopulmonary bypass.
Blood 2003;101:4355 62
8. Bauer KA, Goodman TL, Kass BL, Rosenberg RD. Elevated
factor Xa activity in the blood of asymptomatic patients with
congenital antithrombin deficiency. J Clin Invest 1985;76:
826 36
9. Shifman M, Pizzo S. The in vivo metabolism of antithrombin
III and antithrombin III complexes. J Biol Chem 1982;257:
3243 8
10. Leonard B, Bies R, Carlson T, Reeve EB. Further studies of
the turnover of dog antithrombin III: study of 131I-labelled
antithrombin protease complexes. Thromb Res 1983;30:
11. Knudsen L, Hasenkam JM, Kure HH, Hughes P, Bellaiche L,
Ahlburg P, Djurhuus C. Monitoring thrombin generation
with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery. Thromb Res 1996;84:4554
12. Eisses MJ, Velan T, Aldea GS, Chandler WL. Strategies to
reduce hemostatic activation during cardiopulmonary bypass. Thromb Res 2006;117:689 703
13. Hampton WW, Townsend MC, Schirmer WJ, Haybron DM,
Fry DE. Effective hepatic blood flow during cardiopulmonary
bypass. Arch Surg 1989;124:458 9
14. Hunt BJ, Parratt RN, Segal HC, Sheikh S, Kallis P, Yacoub M.
Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 1998;65:712 8
15. Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during
cardiac surgery: release of tissue plasminogen activator in
arterial and coronary sinus blood. Eur J Cardiothorac Surg
1994;8:324 30
16. Harker LA, Malpass TW, Branson HE, Hessel EA II, Slichter
SJ. Mechanism of abnormal bleeding in patients undergoing
cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha-granule release. Blood
1980;56:824 34
17. Pickering NJ, Brody JI, Fink GB, Finnegan JO, Ablaza S. The
behavior of antithrombin III, alpha 2 macroglobulin, and
alpha 1 antitrypsin during cardiopulmonary bypass. Am J
Clin Pathol 1983;80:459 64
18. Gelb AB, Roth RI, Levin J, London MJ, Noall RA, Hauck WW,
Cloutier M, Verrier E, Mangano DT. Changes in blood
coagulation during and following cardiopulmonary bypass:
lack of correlation with clinical bleeding. Am J Clin Pathol
19. Mammen EF, Koets MH, Washington BC, Wolk LW, Brown
JM, Burdick M, Selik NR, Wilson RF. Hemostasis changes
during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985;11:28192
20. Welters I, Menges T, Ballesteros M, Knothe C, Ruwoldt R,
Gorlach G, Hempelmann G. Thrombin generation and activation of the thrombomodulin protein C system in open heart
surgery depend on the underlying cardiac disease. Thromb
Res 1998;92:19
21. Chandler WL, Patel MA, Gravelle L, Soltow LO, Lewis K,
Bishop PD, Spiess BD. Factor XIIIA and clot strength after
cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001;12:
101 8
22. Davidson SJ, Burman JF, Philips SM, Onis SJ, Kelleher AA, De
Souza AC, Pepper JR. Correlation between thrombin potential
and bleeding after cardiac surgery in adults. Blood Coagul
Fibrinolysis 2003;14:1759
23. Chandler WL. Effects of hemodilution, blood loss, and consumption on hemostatic factor levels during cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2005;19:459 67
24. Moor E, Hamsten A, Blomback M, Herzfeld I, Wiman B,
Ryden L. Haemostatic factors and inhibitors and coronary
artery bypass grafting: preoperative alterations and relations
to graft occlusion. Thromb Haemost 1994;72:335 42
25. Yavari M, Becker RC. Coagulation and fibrinolytic protein
kinetics in cardiopulmonary bypass. J Thromb Thrombolysis


26. van den Goor JM, Nieuwland R, Rutten PM, Tijssen JG, Hau
C, Sturk A, Eijsman L, de Mol BA. Retransfusion of pericardial blood does not trigger systemic coagulation during
cardiopulmonary bypass. Eur J Cardiothorac Surg 2007;31:
1029 36
27. Velan T, Chandler WL. Effects of surgical trauma and cardiopulmonary bypass on active thrombin concentrations and the
rate of thrombin inhibition in vivo. Pathophysiol Haemost
Thromb 2004;33:144 56
28. Kalweit G, Bach J, Huwer H, Winning J, Hellstern P. The
impact of cardiac ischemia and reperfusion on markers of
activated haemostasis and fibrinolysis during cardiopulmonary bypass: comparison of plasma levels in arterial and
coronary venous blood. Thromb Res 2005;116:339
29. Teufelsbauer H, Proidl S, Havel M, Vukovich T. Early activation of hemostasis during cardiopulmonary bypass: evidence
for thrombin mediated hyperfibrinolysis. Thromb Haemost
1992;68:250 2
30. Marx G, Pokar H, Reuter H, Doering V, Tilsner V. The effects
of aprotinin on hemostatic function during cardiac surgery.
J Cardiothorac Vasc Anesth 1991;5:46774
31. Raivio P, Kuitunen A, Suojaranta-Ylinen R, Lassila R, Petaja J.
Thrombin generation during reperfusion after coronary artery bypass surgery associates with postoperative myocardial
damage. J Thromb Haemost 2006;4:15239
32. de Haan J, Boonstra PW, Tabuchi N, van Oeveren W, Ebels T.
Retransfusion of thoracic wound blood during heart surgery
obscures biocompatibility of the extracorporeal circuit. J Thorac Cardiovasc Surg 1996;111:2725
33. de Haan J, Boonstra PW, Monnink SH, Ebels T, van Oeveren
W. Retransfusion of suctioned blood during cardiopulmonary
bypass impairs hemostasis. Ann Thorac Surg 1995;59:9017
34. De Somer F, Van Belleghem Y, Caes F, Francois K, Van
Overbeke H, Arnout J, Taeymans Y, Van Nooten G. Tissue
factor as the main activator of the coagulation system during
cardiopulmonary bypass. J Thorac Cardiovasc Surg 2002;123:
951 8
35. Eisses MJ, Seidel K, Aldea GS, Chandler WL. Reducing
hemostatic activation during cardiopulmonary bypass: a
combined approach. Anesth Analg 2004;98:1208 16
36. Raivio P, Lassila R, Petaja J. Thrombin in myocardial ischemiareperfusion during cardiac surgery. Ann Thorac Surg 2009;88:
318 25
37. Hemker HC, Beguin S. Thrombin generation in plasma: its
assessment via the endogenous thrombin potential. Thromb
Haemost 1995;74:134 8
38. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E,
Wagenvoord R, Lecompte T, Beguin S. Calibrated automated
thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4 15
39. Coakley M, Hall JE, Evans C, Duff E, Billing V, Yang L,
McPherson D, Stephens E, Macartney N, Wilkes AR, Collins
PW. Assessment of thrombin generation measured before and
after cardiopulmonary bypass surgery and its association
with post-operative bleeding. J Thromb Haemost 2010;9:
40. Eichinger S, Hron G, Kollars M, Kyrle PA. Prediction of
recurrent venous thromboembolism by endogenous thrombin
potential and D-dimer. Clin Chem 2008;54:2042 8
41. Campbell DJ. The kallikrein-kinin system in humans. Clin
Exp Pharmacol Physiol 2001;28:1060 5
42. Sharma JN. Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system. Arch Med Res 2006;37:
299 306
43. Sharma JN. Involvement of the kinin-forming system in the
physiopathology of rheumatoid inflammation. Agents Actions Suppl 1992;38:343 61
44. Schmaier AH, McCrae KR. The plasma kallikrein-kinin system: its evolution from contact activation. J Thromb Haemost
45. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Studies
on components of the plasma kallikrein-kinin system in
patients undergoing cardiopulmonary bypass. Adv Exp Med
Biol 1986;198:38591


Hemostasis and Cardiopulmonary Bypass

46. Campbell DJ, Dixon B, Kladis A, Kemme M, Santamaria JD.

Activation of the kallikrein-kinin system by cardiopulmonary
bypass in humans. Am J Physiol Regul Integr Comp Physiol
2001;281:R1059 70
47. Gallimore MJ, Jones DW, Winter M, Wendel HP. Changes in
high molecular weight kininogen levels during and after
cardiopulmonary bypass surgery measured using a chromogenic peptide substrate assay. Blood Coagul Fibrinolysis
2002;13:561 8
48. Cugno M, Nussberger J, Biglioli P, Alamanni F, Coppola R,
Agostoni A. Increase of bradykinin in plasma of patients
undergoing cardiopulmonary bypass: the importance of lung
exclusion. Chest 2001;120:1776 82
49. Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin
stimulates tissue plasminogen activator release in human
vasculature. Hypertension 1999;33:14315
50. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of
tissue-type plasminogen activator (t-PA) in vivo by infusion
of bradykinin. Thromb Haemost 1997;77:5225
51. Agostoni A, Cugno M. Influence of contact system deficiencies
during cardiopulmonary bypass. Thromb Haemost 2001;85:
52. Stavrou E, Schmaier AH. Factor XII: what does it contribute to
our understanding of the physiology and pathophysiology of
hemostasis & thrombosis? Thromb Res 2010;125:210 5
53. Burman J, Chung H, Lane D, Philippou H, Adami A, Lincoln
J. Role of factor XII in thrombin generation and fibrinolysis
during cardiopulmonary bypass. Lancet 1994;344:11923
54. Chung HI, Burman JF, Balogun BA, Lincoln JCR, Pepper JR.
Elevated fibrinolysis in cardiopulmonary bypass is factor XII
dependent. Fibrinolysis 1994;8:84 5
55. Braat EA, Dooijewaard G, Rijken DC. Fibrinolytic properties
of activated FXII. Eur J Biochem 1999;263:904 11
56. Zhao X, Courtney JM, Yin HQ, West RH, Lowe GD. Blood
interactions with plasticised poly (vinyl chloride): influence of
surface modification. J Mater Sci Mater Med 2008;19:7139
57. Chandler WL, Velan T. Secretion of tissue plasminogen
activator and plasminogen activator inhibitor 1 during cardiopulmonary bypass. Thromb Res 2003;112:18592
58. Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi
K. Alterations in coagulation and fibrinolysis associated with
cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181 8
59. Chandler WL, Fitch JCK, Wall MH, Verrier ED, Cochran RP,
Soltow LO, Spiess BD. Individual variations in the fibrinolytic
response during and after cardiopulmonary bypass. Thromb
Haemost 1995;74:12937
60. Booyse FM, Bruce R, Dolenak D, Grover M, Casey LC. Rapid
release and deactivation of plasminogen activators in human
endothelial cell cultures in the presence of thrombin and
ionophore A23187. Semin Thromb Hemost 1986;12:228 30
61. Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown
NJ. A pilot study indicating that bradykinin B2 receptor
antagonism attenuates protamine-related hypotension after
cardiopulmonary bypass. Clin Pharmacol Ther 2005;78:
477 85
62. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Aprotinin
in cardiopulmonary bypass: effects on the Hageman factor
(FXII) kallikrein system and blood loss. Blood Coagul Fibrinolysis 1992;3:99 104
63. Chandler WL, Alessi MC, Aillaud MF, Vague P, Juhan-Vague
I. Formation, inhibition and clearance of plasmin in vivo.
Haemostasis 2000;30:204 18
64. van den Goor JM, van Oeveren W, Rutten PM, Tijssen JG,
Eijsman L. Adhesion of thrombotic components to the surface
of a clinically used oxygenator is not affected by trillium
coating. Perfusion 2006;21:16572
65. Nishida H, Aomi S, Tomizawa Y, Endo M, Koyanagi H, Nojiri
C, Oshiyama H, Kido T, Yokoyama K. Comparative study of
biocompatibility between the open circuit and closed circuit
in cardiopulmonary bypass. Artif Organs 1999;23:54751
66. Chandler WL, Velan T. Plasmin generation and D-dimer
formation during cardiopulmonary bypass. Blood Coagul
Fibrinolysis 2004;15:58391

December 2011 Volume 113 Number 6

67. de Haan J, van Oeveren W. Platelets and soluble fibrin

promote plasminogen activation causing downregulation of
platelet glycoprotein Ib/IX complexes: protection by aprotinin. Thromb Res 1998;92:1719
68. Michelson AD, Barnard MR. Plasmin-induced redistribution
of platelet glycoprotein Ib. Blood 1990;76:200510
69. Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman
R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991;75:388 93
70. Slaughter TF, Sreeram G, Sharma AD, El-Moalem H, East CJ,
Greenberg CS. Reversible shear-mediated platelet dysfunction during cardiac surgery as assessed by the PFA-100
platelet function analyzer. Blood Coagul Fibrinolysis 2001;12:
71. Velik-Salchner C, Maier S, Innerhofer P, Kolbitsch C, Streif W,
Mittermayr M, Praxmarer M, Fries D. An assessment of
cardiopulmonary bypass-induced changes in platelet function using whole blood and classical light transmission aggregometry: the results of a pilot study. Anesth Analg
72. Ray MJ, Marsh NA, Hawson GAT. Relationship of fibrinolysis and platelet function to bleeding after cardiopulmonary
bypass. Blood Coagul Fibrinolysis 1994;5:679 85
73. Freyburger G, Janvier G, Dief S, Boisseau MR. Fibrinolytic
and hemorheologic alterations during and after elective aortic
graft surgery: implications for postoperative management.
Anesth Analg 1993;76:504 12
74. Lu H, Du Buit C, Soria J, Touchot B, Chollet B, Commin PL,
Conseiller C, Echter E, Soria C. Postoperative hemostasis and
fibrinolysis in patients undergoing cardiopulmonary bypass
with and without aprotinin therapy. Thromb Haemost 1994;72:
438 43
75. Rifon J, Paramo JA, Panizo C, Montes R, Rocha E. The
increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aortocoronary bypass surgery. Br J Haematol 1997;99:2627
76. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S71520
77. Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent
C, Darzi AW, Athanasiou T. The inflammatory response to
cardiopulmonary bypass. Part 1. Mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009;23:22331
78. Warren OJ, Watret AL, de Wit KL, Alexiou C, Vincent C,
Darzi AW, Athanasiou T. The inflammatory response to
cardiopulmonary bypass. Part 2. Anti-inflammatory therapeutic strategies. J Cardiothorac Vasc Anesth 2009;23:384 93
79. Levy JH. Anti-inflammatory strategies and hemostatic agents:
old drugs, new ideas. Hematol Oncol Clin North Am 2007;21:
89 101
80. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory
response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97:21552
81. Shibamiya A, Tabuchi N, Chung J, Sunamori M, Koyama T.
Formation of tissue factor-bearing leukocytes during and
after cardiopulmonary bypass. Thromb Haemost 2004;92:
124 31
82. Chung J, Suzuki H, Tabuchi N, Sato K, Shibamiya A, Koyama
T. Identification of tissue factor and platelet-derived particles
on leukocytes during cardiopulmonary bypass by flow cytometry and immunoelectron microscopy. Thromb Haemost
2007;98:368 74
83. Johnell M, Elgue G, Thelin S, Larsson R, Siegbahn A. Cell
adhesion and tissue factor upregulation in oxygenators used
during coronary artery bypass grafting are modified by the
Corline Heparin Surface. Scand Cardiovasc J 2002;36:3517
84. Barstad RM, Ovrum E, Ringdal MA, Oystese R, Hamers MJ,
Veiby OP, Rolfsen T, Stephens RW, Sakariassen KS. Induction
of monocyte tissue factor procoagulant activity during coronary artery bypass surgery is reduced with heparin-coated
extracorporeal circuit. Br J Haematol 1996;94:51725
85. Tabuchi N, Shibamiya A, Koyama T, Fukuda T, van Oeveren
W, Sunamori M. Activated leukocytes adsorbed on the surface of an extracorporeal circuit. Artif Organs 2003;27:591 4



86. el Habbal MH, Carter H, Smith LJ, Elliott MJ, Strobel S.

Neutrophil activation in paediatric extracorporeal circuits:
effect of circulation and temperature variation. Cardiovasc
Res 1995;29:1027
87. Gillinov AM, Bator JM, Zehr KJ, Redmond JM, Burch RM, Ko
C, Winkelstein JA, Stuart RS, Baumgartner WA, Cameron DE.
Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators. Ann
Thorac Surg 1993;56:84753
88. Shen M, Horbett TA. The effects of surface chemistry and
adsorbed proteins on monocyte/macrophage adhesion to
chemically modified polystyrene surfaces. J Biomed Mater
Res 2001;57:336 45
89. Parratt R, Hunt BJ. Direct activation of factor X by monocytes
occurs during cardiopulmonary bypass. Br J Haematol
1998;101:40 6
90. Hattori T, Khan MM, Colman RW, Edmunds LH Jr. Plasma
tissue factor plus activated peripheral mononuclear cells
activate factors VII and X in cardiac surgical wounds. J Am
Coll Cardiol 2005;46:70713
91. Sturk-Maquelin KN, Nieuwland R, Romijn FP, Eijsman L,
Hack CE, Sturk A. Pro- and non-coagulant forms of non-cellbound tissue factor in vivo. J Thromb Haemost 2003;1:1920 6
92. Philippou H, Adami A, Davidson SJ, Pepper JR, Burman JF,
Lane DA. Tissue factor is rapidly elevated in plasma collected
from the pericardial cavity during cardiopulmonary bypass.
Thromb Haemost 2000;84:124 8
93. Weiler H. Regulation of inflammation by the protein C
system. Crit Care Med 2010;38:S18 25
94. Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ. The
protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010;115:
95. Musial J, Niewiarowski S, Rucinski B, Stewart GJ, Cook JJ,
Williams JA, Edmunds LH Jr. Inhibition of platelet adhesion
to surfaces of extracorporeal circuits by disintegrins: RGDcontaining peptides from viper venoms. Circulation 1990;82:
96. Tsai WB, Grunkemeier JM, McFarland CD, Horbett TA.
Platelet adhesion to polystyrene-based surfaces preadsorbed
with plasmas selectively depleted in fibrinogen, fibronectin,
vitronectin, or von Willebrands factor. J Biomed Mater Res
2002;60:348 59
97. Niimi Y, Ichinose F, Ishiguro Y, Terui K, Uezono S, Morita S,
Yamane S. The effects of heparin coating of oxygenator fibers
on platelet adhesion and protein adsorption. Anesth Analg
98. Gorbet MB, Sefton MV. Biomaterial-associated thrombosis:
roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 2004;25:5681703
99. Gemmell CH, Ramirez SM, Yeo EL, Sefton MV. Platelet
activation in whole blood by artificial surfaces: identification
of platelet-derived microparticles and activated platelet binding to leukocytes as material-induced activation events. J Lab
Clin Med 1995;125:276 87
100. Grunkemeier JM, Tsai WB, Horbett TA. Hemocompatibility
of treated polystyrene substrates: contact activation, platelet
adhesion, and procoagulant activity of adherent platelets.
J Biomed Mater Res 1998;41:65770
101. Gemmell CH. Assessment of material-induced procoagulant
activity by a modified Russell viper venom coagulation time
test. J Biomed Mater Res 1998;42:611 6
102. Zillmann A, Luther T, Muller I, Kotzsch M, Spannagl M,
Kauke T, Oelschlagel U, Zahler S, Engelmann B. Plateletassociated tissue factor contributes to the collagen-triggered
activation of blood coagulation. Biochem Biophys Res Commun 2001;281:6039
103. Khuri S, Wolfe J, Josa M, Axford TC, Szymanski I, Assousa S,
Ragno G, Patel M, Silverman A, Park M, Valeri CR. Hematologic changes during and after cardiopulmonary bypass and
their relationship to the bleeding time and nonsurgical blood
loss. J Thorac Cardiovasc Surg 1992;104:94 107


104. Shigeta O, Kojima H, Jikuya T, Terada Y, Atsumi N, Sakakibara Y, Nagasawa T, Mitsui T. Aprotinin inhibits plasmininduced platelet activation during cardiopulmonary bypass.
Circulation 1997;96:569 74
105. Diago MC, Garcia-Unzueta MT, Marcano G, Merino J, Salas E,
Amado JA. Serum soluble selectins in patients undergoing
cardiopulmonary bypass: relationship with circulating blood
cells and inflammation-related cytokines. Acta Anaesthesiol
Scand 1997;41:72530
106. Vallely MP, Bannon PG, Bayfield MS, Hughes CF, Kritharides
L. Quantitative and temporal differences in coagulation,
fibrinolysis and platelet activation after on-pump and offpump coronary artery bypass surgery. Heart Lung Circ
107. Lo B, Fijnheer R, Castigliego D, Borst C, Kalkman CJ, Nierich
AP. Activation of hemostasis after coronary artery bypass
grafting with or without cardiopulmonary bypass. Anesth
Analg 2004;99:634 40
108. Johnell M, Elgue G, Larsson R, Larsson A, Thelin S, Siegbahn
A. Coagulation, fibrinolysis, and cell activation in patients
and shed mediastinal blood during coronary artery bypass
grafting with a new heparin-coated surface. J Thorac Cardiovasc Surg 2002;124:32132
109. Kongsgaard UE, Hovig T, Brosstad F, Geiran O. Platelets in
shed mediastinal blood used for postoperative autotransfusion. Acta Anaesthesiol Scand 1993;37:265 8
110. Fabre O, Vincentelli A, Corseaux D, Juthier F, Susen S, Bauters
A, Van Belle E, Mouquet F, Le Tourneau T, Decoene C, Crepin
F, Prat A, Jude B. Comparison of blood activation in the
wound, active vent, and cardiopulmonary bypass circuit. Ann
Thorac Surg 2008;86:537 41
111. Koster A, Bottcher W, Merkel F, Hetzer R, Kuppe H. The more
closed the bypass system the better: a pilot study on the
effects of reduction of cardiotomy suction and passive venting on hemostatic activation during on-pump coronary artery
bypass grafting. Perfusion 2005;20:285 8
112. Skrabal CA, Khosravi A, Choi YH, Kaminski A, Westphal B,
Steinhoff G, Liebold A. Pericardial suction blood separation
attenuates inflammatory response and hemolysis after cardiopulmonary bypass. Scand Cardiovasc J 2006;40:219 23
113. Takayama H, Soltow LO, Chandler WL, Vocelka CR, Aldea
GS. Does the type of surgery effect systemic response following cardiopulmonary bypass? J Card Surg 2007;22:30713
114. Ferraris VA, Ferraris SP, Singh A, Fuhr W, Koppel D, McKenna
D, Rodriguez E, Reich H. The platelet thrombin receptor and
postoperative bleeding. Ann Thorac Surg 1998;65:352 8
115. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC,
Taylor KM. Clinical inhibition of the seven-transmembrane
thrombin receptor (PAR1) by intravenous aprotinin during
cardiothoracic surgery. Circulation 2004;110:2597 600
116. Niewiarowski S, Senyi AF, Gillies P. Plasmin-induced platelet
aggregation and platelet release reaction: effects on hemostasis. J Clin Invest 1973;52:164759
117. de Haan J, Schonberger J, Haan J, van Oeveren W, Eijgelaar A.
Tissue-type plasminogen activator and fibrin monomers synergistically cause platelet dysfunction during retransfusion of
shed blood after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:101723
118. Mao Y, Jin J, Daniel JL, Kunapuli SP. Regulation of plasmininduced protease-activated receptor 4 activation in platelets.
Platelets 2009;20:191 8
119. Quinton TM, Kim S, Derian CK, Jin J, Kunapuli SP. Plasminmediated activation of platelets occurs by cleavage of
protease-activated receptor 4. J Biol Chem 2004;279:18434 9
120. van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L,
Wildevuur CR. Aprotinin protects platelets against the initial
effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg
1990;99:788 96
121. Huang H, Ding W, Su Z, Zhang W. Mechanism of the
preserving effect of aprotinin on platelet function and its use
in cardiac surgery. J Thorac Cardiovasc Surg 1993;106:11 8
122. Soslau G, Horrow J, Brodsky I. Effect of tranexamic acid on
platelet ADP during extracorporeal circulation. Am J Hematol


Hemostasis and Cardiopulmonary Bypass

123. Khan MM, Hattori T, Niewiarowski S, Edmunds LH Jr,

Colman RW. Truncated and microparticle-free soluble tissue
factor bound to peripheral monocytes preferentially activate
factor VII. Thromb Haemost 2006;95:462 8
124. Weerwind PW, Lindhout T, Caberg NE, De Jong DS. Thrombin generation during cardiopulmonary bypass: the possible
role of retransfusion of blood aspirated from the surgical
field. Thromb J 2003;1:3
125. Chung JH, Gikakis N, Rao AK, Drake TA, Colman RW,
Edmunds LH. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93:2014 8
126. Aldea GS, Soltow LO, Chandler WL, Triggs CM, Vocelka CR,
Crockett GI, Shin YT, Curtis WE, Verrier ED. Limitation of
thrombin generation, platelet activation, and inflammation by
elimination of cardiotomy suction in patients undergoing
coronary artery bypass grafting treated with heparin-bonded
circuits. J Thorac Cardiovasc Surg 2002;123:74255
127. Westerberg M, Bengtsson A, Jeppsson A. Coronary surgery
without cardiotomy suction and autotransfusion reduces the
postoperative systemic inflammatory response. Ann Thorac
Surg 2004;78:54 9
128. Nakahira A, Sasaki Y, Hirai H, Matsuo M, Morisaki A,
Suehiro S, Shibata T. Cardiotomy suction, but not open
venous reservoirs, activates coagulofibrinolysis in coronary
artery surgery. J Thorac Cardiovasc Surg 2011;141:1289 97
129. Wang G, Bainbridge D, Martin J, Cheng D. The efficacy of
an intraoperative cell saver during cardiac surgery: a
meta-analysis of randomized trials. Anesth Analg 2009;109:
320 30
130. Belway D, Rubens FD. Currently available biomaterials for
use in cardiopulmonary bypass. Expert Rev Med Devices
131. Ranucci M, Mazzucco A, Pessotto R, Grillone G, Casati V,
Porreca L, Maugeri R, Meli M, Magagna P, Cirri S, Giomarelli
P, Lorusso R, de Jong A. Heparin-coated circuits for high-risk
patients: a multicenter, prospective, randomized trial. Ann
Thorac Surg 1999;67:994 1000
132. Mangoush O, Purkayastha S, Haj-Yahia S, Kinross J, Hayward
M, Bartolozzi F, Darzi A, Athanasiou T. Heparin-bonded
circuits versus nonheparin-bonded circuits: an evaluation of
their effect on clinical outcomes. Eur J Cardiothorac Surg
2007;31:1058 69
133. Gunaydin S. Emerging technologies in biocompatible surface
modifying additives: quest for physiologic cardiopulmonary
bypass. Curr Med Chem Cardiovasc Hematol Agents 2004;2:
134. De Somer F, Francois K, van Oeveren W, Poelaert J, De Wolf
D, Ebels T, Van Nooten G. Phosphorylcholine coating of
extracorporeal circuits provides natural protection against
blood activation by the material surface. Eur J Cardiothorac
Surg 2000;18:602 6
135. Ereth MH, Nuttall GA. Biocompatibility of Trillium Biopassive Surface-coated oxygenator versus uncoated oxygenator
during cardiopulmonary bypass. J Cardiothorac Vasc Anesth
136. Pappalardo F, Della Valle P, Crescenzi G, Corno C, Franco A,
Torracca L, Alfieri O, Galli L, Zangrillo A, DAngelo A.
Phosphorylcholine coating may limit thrombin formation
during high-risk cardiac surgery: a randomized controlled
trial. Ann Thorac Surg 2006;81:886 91
137. Zimmermann AK, Weber N, Aebert H, Ziemer G, Wendel
HP. Effect of biopassive and bioactive surface-coatings on the
hemocompatibility of membrane oxygenators. J Biomed Mater Res B Appl Biomater 2007;80:4339
138. Ranucci M, Balduini A, Ditta A, Boncilli A, Brozzi S. A systematic review of biocompatible cardiopulmonary bypass circuits
and clinical outcome. Ann Thorac Surg 2009;87:13119
139. Fromes Y, Gaillard D, Ponzio O, Chauffert M, Gerhardt
MF, Deleuze P, Bical OM. Reduction of the inflammatory
response following coronary bypass grafting with total
minimal extracorporeal circulation. Eur J Cardiothorac
Surg 2002;22:52733

December 2011 Volume 113 Number 6

140. Rahe-Meyer N, Solomon C, Tokuno ML, Winterhalter M,

Shrestha M, Hahn A, Tanaka K. Comparative assessment of
coagulation changes induced by two different types of heartlung machine. Artif Organs 2010;34:312
141. Biancari F, Rimpilainen R. Meta-analysis of randomised trials
comparing the effectiveness of miniaturised versus conventional cardiopulmonary bypass in adult cardiac surgery.
Heart 2009;95:964 9
142. Zangrillo A, Garozzo FA, Biondi-Zoccai G, Pappalardo F,
Monaco F, Crivellari M, Bignami E, Nuzzi M, Landoni G.
Miniaturized cardiopulmonary bypass improves short-term
outcome in cardiac surgery: a meta-analysis of randomized
controlled studies. J Thorac Cardiovasc Surg 2010;139:11629
143. Halkos ME, Puskas JD. Off-pump coronary surgery: where do
we stand in 2010? Curr Opin Cardiol 2010;25:583 8
144. Casati V, Gerli C, Franco A, Della Valle P, Benussi S, Alfieri O,
Torri G, DAngelo A. Activation of coagulation and fibrinolysis during coronary surgery: on-pump versus off-pump
techniques. Anesthesiology 2001;95:11039
145. Untch BR, Jeske WP, Schwartz J, Botkin S, Prechel M, Walenga JM, Bakhos M. Inflammatory and hemostatic activation
in patients undergoing off-pump coronary artery bypass
grafting. Clin Appl Thromb Hemost 2008;14:141 8
146. Ballotta A, Saleh HZ, El Baghdady HW, Gomaa M, Belloli F,
Kandil H, Balbaa Y, Bettini F, Bossone E, Menicanti L, Frigiola A,
Bellucci C, Mehta RH. Comparison of early platelet activation in
patients undergoing on-pump versus off-pump coronary artery
bypass surgery. J Thorac Cardiovasc Surg 2007;134:132 8
147. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC,
Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach ME,
McCall SA, Petersen RJ, Bailey DE, Weintraub WS, Guyton
RA. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life
outcomesa randomized trial. JAMA 2004;291:18419
148. Garvin S, Fitzgerald D, Muehlschlegel JD, Perry TE, Fox AA,
Shernan SK, Collard CD, Aranki S, Body SC. Heparin dose
response is independent of preoperative antithrombin activity in
patients undergoing coronary artery bypass graft surgery using
low heparin concentrations. Anesth Analg 2010;111:856 61
149. Hirsh J. Current anticoagulant therapy: unmet clinical needs.
Thromb Res 2003;109:S1 8
150. Lobato RL, Despotis GJ, Levy JH, Shore-Lesserson LJ, Carlson
MO, Bennett-Guerrero E. Anticoagulation management during cardiopulmonary bypass: a survey of 54 North American
institutions. J Thorac Cardiovasc Surg 2010;139:1665 6
151. Fitzgerald DJ, Patel A, Body SC, Garvin S. The relationship
between heparin level and activated clotting time in the adult
cardiac surgery population. Perfusion 2009;24:93 6
152. Brister SJ, Ofosu FA, Buchanan MR. Thrombin generation
during cardiac surgery: is heparin the ideal anticoagulant?
Thromb Haemost 1993;70:259 62
153. Koster A, Fischer T, Praus M, Haberzettl H, Kuebler WM,
Hetzer R, Kuppe H. Hemostatic activation and inflammatory
response during cardiopulmonary bypass: impact of heparin
management. Anesthesiology 2002;97:837 41
154. Despotis GJ, Joist JH, Hogue CWJ, Alsoufiev A, Kater K,
Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M,
Lappas DG. The impact of heparin concentration and activated clotting time monitoring on blood conservation: a
prospective, randomized evaluation in patients undergoing
cardiac operation. J Thorac Cardiovasc Surg 1995;110:46 54
155. Slight RD, Buell R, Nzewi OC, McClelland DB, Mankad PS. A
comparison of activated coagulation time-based techniques
for anticoagulation during cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2008;22:4752
156. Khuri SF, Valeri CR, Loscalzo J, Weinstein MJ, Birjiniuk V,
Healey NA, MacGregor H, Doursounian M, Zolkewitz MA.
Heparin causes platelet dysfunction and induces fibrinolysis
before cardiopulmonary bypass. Ann Thorac Surg 1995;60:
1008 14
157. Kemme MJ, Burggraaf J, Schoemaker RC, Kluft C, Cohen AF.
Quantification of heparin-induced TFPI release: a maximum
release at low heparin dose. Br J Clin Pharmacol 2002;54:62734



158. Sandset PM, Bendz B, Hansen JB. Physiological function of

tissue factor pathway inhibitor and interaction with heparins.
Haemostasis 2000;30:48 56
159. Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic
complications in the perioperative setting: an update on
heparin-induced thrombocytopenia. Anesth Analg 2007;105:
570 82
160. Levy JH, Winkler AM. Heparin-induced thrombocytopenia
and cardiac surgery. Curr Opin Anaesthesiol 2010;23:74 9
161. Sniecinski RM, Hursting MJ, Paidas MJ, Levy JH. Etiology
and assessment of hypercoagulability with lessons from
heparin-induced thrombocytopenia. Anesth Analg 2011;112:
46 58
162. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76:212131
163. Gluckman TJ, Segal JB, Schulman SP, Shapiro EP, Kickler TS,
Prechel MM, Conte JV, Walenga JM, Shafique I, Rade JJ,
Menicanti L, Frigiola A. Effect of anti-platelet factor4/heparin antibody induction on early saphenous vein graft
occlusion after coronary artery bypass surgery. J Thromb
Haemost 2009;7:1457 64
164. Van De Car DA, Rao SV, Ohman EM. Bivalirudin: a review of
the pharmacology and clinical application. Expert Rev Cardiovasc Ther 2010;8:1673 81
165. Koster A, Yeter R, Buz S, Kuppe H, Hetzer R, Lincoff AM,
Dyke CM, Smedira NG, Spiess B, Menicanti L, Frigiola A.
Assessment of hemostatic activation during cardiopulmonary
bypass for coronary artery bypass grafting with bivalirudin:
results of a pilot study. J Thorac Cardiovasc Surg 2005;129:
1391 4
166. Smedira NG, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu
T, McCarthy HL II, Lincoff AM, Spiess BD, Aronson S.
Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF
study. J Thorac Cardiovasc Surg 2006;131:686 92
167. Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL
II, Kirshner R, Lincoff AM, Spiess BD. A comparison of
bivalirudin to heparin with protamine reversal in patients
undergoing cardiac surgery with cardiopulmonary bypass:
the EVOLUTION-ON study. J Thorac Cardiovasc Surg
168. Martin ME, Kloecker GH, Laber DA. Argatroban for anticoagulation during cardiac surgery. Eur J Haematol 2007;78:161 6
169. Smith AI, Stroud R, Damiani P, Vaynblat M. Use of argatroban
for anticoagulation during cardiopulmonary bypass in a patient
with heparin allergy. Eur J Cardiothorac Surg 2008;34:1113 4
170. Follis F, Filippone G, Montalbano G, Floriano M, Lobianco E,
DAncona G, Follis M. Argatroban as a substitute of heparin
during cardiopulmonary bypass: a safe alternative? Interact
Cardiovasc Thorac Surg 2010;10:592 6
171. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral
thrombin inhibitor. Circulation 2011;123:1436 50
172. Zaidan JR, Johnson S, Brynes R, Monroe S, Guffin AV. Rate of
protamine administration: its effect on heparin reversal and
antithrombin recovery after coronary artery surgery. Anesth
Analg 1986;65:377 80
173. Ranucci M, Ditta A, Boncilli A, Cotza M, Carboni G, Brozzi S,
Bonifazi C, Tiezzi A. Determinants of antithrombin consumption in cardiac operations requiring cardiopulmonary bypass.
Perfusion 2004;19:4752
174. Okita Y, Takamoto S, Ando M, Morota T, Yamaki F, Matsukawa R, Kawashima Y. Coagulation and fibrinolytic system in
aortic surgery under deep hypothermic circulatory arrest
with aprotinin: importance of adequate heparinization. Circulation 1997;96:II-376 81
175. Slaughter TF, Mark JB, El-Moalem H, Hayward KA, Hilton
AK, Hodgins LP, Greenberg CS. Hemostatic effects of antithrombin III supplementation during cardiac surgery: results
of a prospective randomized investigation. Blood Coagul
Fibrinolysis 2001;12:2531
176. Sniecinski R, Szlam F, Chen EP, Bader SO, Levy JH, Tanaka
KA. Antithrombin deficiency increases thrombin activity after
prolonged cardiopulmonary bypass. Anesth Analg 2008;106:
713 8


177. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi

S. Postoperative antithrombin levels and outcome in cardiac
operations. Crit Care Med 2005;33:355 60
178. Garvin S, Muehlschlegel JD, Perry TE, Chen J, Liu KY, Fox
AA, Collard CD, Aranki SF, Shernan SK, Body SC. Postoperative activity, but not preoperative activity, of antithrombin is associated with major adverse cardiac events after
coronary artery bypass graft surgery. Anesth Analg 2010;111:
179. Koster A, Fischer T, Gruendel M, Mappes A, Kuebler WM,
Bauer M, Kuppe H. Management of heparin resistance during
cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac
Vasc Anesth 2003;17:1715
180. Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD,
Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK,
Despotis GJ. Recombinant human antithrombin III restores
heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary
bypass. J Thorac Cardiovasc Surg 2005;130:10713
181. Levy JH, Despotis GJ, Szlam F, Olson P, Meeker D, Weisinger
A, Menicanti L, Frigiola A. Recombinant human transgenic
antithrombin in cardiac surgery: a dose-finding study. Anesthesiology 2002;96:1095102
182. Rossi M, Martinelli L, Storti S, Corrado M, Marra R, Varano C,
Schiavello R, Menicanti L, Frigiola A. The role of antithrombin III in the perioperative management of the patient with
unstable angina. Ann Thorac Surg 1999;68:2231 6
183. Williams MR, DAmbra AB, Beck JR, Spanier TB, Morales DL,
Helman DN, Oz MC. A randomized trial of antithrombin
concentrate for treatment of heparin resistance. Ann Thorac
Surg 2000;70:8737
184. Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM,
Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina
M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ. A phase
III, double-blind, placebo-controlled, multicenter study on
the efficacy of recombinant human antithrombin in
heparin-resistant patients scheduled to undergo cardiac
surgery necessitating cardiopulmonary bypass. Anesthesiology 2005;102:276 84
185. Conley JC, Plunkett PF, Menicanti L, Frigiola A. Antithrombin III in cardiac surgery: an outcome study. J Extra Corpor
Technol 1998;30:178 83
186. Mannucci PM, Levi M. Prevention and treatment of major
blood loss. N Engl J Med 2007;356:230111
187. Ozier Y, Bellamy L. Pharmacological agents: antifibrinolytics and desmopressin. Best Pract Res Clin Anaesthesiol
188. Henry DA, Carless PA, Moxey AJ, OConnell D, Stokes BJ,
McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use
for minimising perioperative allogeneic blood transfusion.
Cochrane Database Syst Rev 2007;4:CD001886
189. Brown JR, Birkmeyer NJ, OConnor GT. Meta-analysis
comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:
190. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks
of aprotinin and tranexamic acid in cardiac surgery: a oneyear follow-up of 1188 consecutive patients. Anesth Analg
191. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the
aprotinin saga: current perspective on antifibrinolytic therapy
in cardiac surgery. J Anesth 2010;24:96 106
192. Kang HM, Kalnoski MH, Frederick M, Chandler WL, Menicanti L, Frigiola A. The kinetics of plasmin inhibition by
aprotinin in vivo. Thromb Res 2005;115:327 40
193. Levy JH, Sypniewski E. Aprotinin: a pharmacologic overview. Orthopedics 2004;27:s653 8
194. Segal H, Sheikh S, Kallis P, Cottam S, Beard C, Potter D,
Townsend E, Bidstrup BP, Yacoub M, Hunt BJ. Complement
activation during major surgery: the effect of extracorporeal
circuits and high-dose aprotinin therapy. J Cardiothorac Vasc
Anesth 1998;12:5427


Hemostasis and Cardiopulmonary Bypass

195. Longstaff C. Studies on the mechanisms of action of aprotinin

and tranexamic acid as plasmin inhibitors and antifibrinolytic
agents. Blood Coagul Fibrinolysis 1994;5:537 42
196. Rossi M, Storti S, Martinelli L, Varano C, Marra R, Zamparelli
R, Possati G, Schiavello R. A pump-prime aprotinin dose in
cardiac surgery: appraisal of its effects on the hemostatic
system. J Cardiothorac Vasc Anesth 1997;11:8359
197. Ray MJ, Marsh NA. Aprotinin reduces blood loss after
cardiopulmonary bypass by direct inhibition of plasmin.
Thromb Haemost 1997;78:1021 6
198. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C,
Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA,
Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger
M, Wells G, Clinch J, Pretorius R. A comparison of aprotinin and
lysine analogues in high-risk cardiac surgery. N Engl J Med
2008;358:2319 31
199. Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, Tait
G, Beattie WS. The risk-benefit profile of aprotinin versus
tranexamic acid in cardiac surgery. Anesth Analg 2010;110:219

December 2011 Volume 113 Number 6

200. Perry TE, Muehlschlegel JD, Body SC. Genomics: risk and
outcomes in cardiac surgery. Anesthesiol Clin 2008;26:399 417
201. Shore-Lesserson L, Reich DL. A case of severe diffuse venous
thromboembolism associated with aprotinin and hypothermic circulatory arrest in a cardiac surgical patient with factor
V Leiden. Anesthesiology 2006;105:219 21
202. Podgoreanu MV, Schwinn DA. New paradigms in cardiovascular medicine: emerging technologies and practices
perioperative genomics. J Am Coll Cardiol 2005;46:196577
203. Welsby IJ, Podgoreanu MV, Phillips-Bute B, Mathew JP,
Smith PK, Newman MF, Schwinn DA, Stafford-Smith M.
Genetic factors contribute to bleeding after cardiac surgery.
J Thromb Haemost 2005;3:1206 12
204. Clements RT, Smejkal G, Sodha NR, Ivanov AR, Asara JM,
Feng J, Lazarev A, Gautam S, Senthilnathan V, Khabbaz KR,
Bianchi C, Sellke FW. Pilot proteomic profile of differentially
regulated proteins in right atrial appendage before and after
cardiac surgery using cardioplegia and cardiopulmonary
bypass. Circulation 2008;118:S24 31