Oliver 2009 Nice Overview

Seminars in Cardiothoracic and Vascular
Anesthesia
http://scv.sagepub.com/
Anticoagulation and Coagulation Management for ECMO

William C. Oliver
SEMIN CARDIOTHORAC VASC ANESTH 2009 13: 154
DOI: 10.1177/1089253209347384
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Anticoagulation and Coagulation

Management for ECMO
Seminars in Cardiothoracic
and Vascular Anesthesia
Volume 13 Number 3
September 2009 154-175
2009 The Author(s)
10.1177/1089253209347384
http://scv.sagepub.com
William C. Oliver, MD
Advances in extracorporeal membrane oxygenation
(ECMO) management have helped to reduce complications compared with its inception but they remain
high. The principal causes of mortality and morbidity
are bleeding and thrombosis. The nonbiologic surface
of an extracorporeal circuit provokes a massive inflammatory response leading to consumption and activation
of procoagulant and anticoagulant components. The
vast differences in neonatal and adult anticoagulation and transfusion requirements demands tremendous
ince the inception of extracorporeal membrane oxygenation (ECMO) in 1971,1 thousands of adults and pediatric patients have
been saved. Advances in ECMO have reduced morbidity and mortality compared with early experiences. However, mortality is still high with survival
rates of 77% for neonatal respiratory failure, 53% for
adult respiratory failure, 45% for pediatric cardiac
failure, and 32% for adult cardiac failure.2 The principal causes of mortality and morbidity remain
bleeding and thrombosis.3,4 Bleeding and thrombosis are related to contact of blood and its cellular
components with the nonbiologic surface of the
extracorporeal circuit (EC) used during ECMO that
results in a massive inflammatory and clotting
response. Consequently, anticoagulation is necessary to prevent thrombosis but it also increases the
risk of excessive bleeding especially as the duration
of ECMO increases. Excessive bleeding is the most
common reason for premature separation from
ECMO that may rob the cardiac and respiratory
From the Department of Anesthesiology, Mayo Clinic, Rochester,
Minnesota.
Address correspondence to: William C. Oliver, Department of
Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester,
MN 55905; e-mail: oliver.william@mayo.edu.
clinical knowledge to provide the best care. Increased

use of thrombelastogram will complement other methods currently being used to improved care. Methods to
recognize the level of thrombin formation at the bedside could help reduce neurologic complications. ECMO
requires a multidisciplinary team approach to achieve
the best outcomes.
Keywords: anticoagulation; transfusion; extracorporeal circuit; thromboelastogram; thrombosis
systems of an opportunity to rest and improve. The

aim of this article is to review the management of
anticoagulation and transfusion in pediatric and
adult patients that require ECMO.
Normal Coagulation
To successfully manage anticoagulation and transfusion in a patient on ECMO, a thorough knowledge of
the normal coagulation process for pediatric and
adult patients is essential. Knowledge of the coagulation system continues to evolve from early concepts
of zymogen clotting factors and cofactors activating
in sequence through two separate pathways, intrinsic
and extrinsic to generate fibrin for clotting, to a more
encompassing process that includes the vascular
endothelium, blood coagulation, prevention of clotting, and fibrinolysis. The fundamental principle
that governs the coagulation system is the unremitting drive to balance procoagulant and anticoagulant forces.
Normal coagulation consists of interactions
between the vascular endothelium and plasma proteins and platelets. A major advancement in the
understanding of coagulation is the enhanced appreciation for the role of the endothelium (Figure 1). It
is instrumental in maintaining the balance between
154
Anticoagulation and Coagulation Management for ECMO / Oliver 155
Figure 1. The endothelial cell membrane is involved in a variety of procoagulant activities. The extrinsic pathway is activated
by the expression of tissue factor (TF) at the endothelial cell
surface. TF complexed with factor VIIa stabilizes the VIIa site.
This results in the conversion of factor IX to factor IXa and
ultimately catalyzes the activation of factor X. With help of an
activated cell membrane and calcium (Ca2+), factor Xa catalyzes
the conversion of factor V to factor Va to convert prothrombin
(II) to thrombin (IIa).
procoagulant and anticoagulant activity. Its proper

functioning is better appreciated today than at any
time in the past.5
The negatively charged membranes of the
endothelium usually limit clotting unless an injury
or disruption occurs. At the site of endothelial injury,
blood contacts the subendothelium that contains
collagen, thromboxane, von Willebrand factor
(vWF), and other platelet attractants produced by the
endothelial cells exposing them to procoagulant proteins and nonactivated platelets. The platelet receptors attach to the subendothelial molecules, especially
vWF, causing platelet adhesion and formation of a
platelet plug. Continued recruitment of platelet agonists is necessary to achieve sufficient platelet activation to cause irreversible platelet aggregation,
thereby sustaining the platelet plug.
For the platelet plug to become a clot, it must be
reinforced by fibrin (Figure 2). The surfaces of activated platelets possess unique properties of the platelet membrane that strongly enhances activation
of blood coagulation to play a major role in thrombin
generation and fibrin production. With increasing
thrombin generation, platelet aggregation will continue to accelerate that not only strengthens the
platelet plug but also releases the platelets alpha and
Figure 2. GAG with AT inhibit excess thrombin.

Factors Va and VIIIa with slashes have been inactivated by APC
represented. Va and VIIIa with slashes indicate Va and VIIIa
inactivated by APC. Activated platelets and fibrin form a hemostatic plug.
NOTES: APC, activated protein C; AT antithrombin; GAG,
Glycosaminoglycans; PC, protein C; S, the cofactor of protein
C; T, thrombin; TF, tissue factor; TM, thrombomodulin.
Source: Reprinted with permission from Roberts HR, Monroe
DM, Escobar MA. Current concepts of hemostasis: implications
for therapy. Anesthesiology. 2004;100:722-730, figure 3.
Copyright 2004 American Society of Anesthesiologists, Lippincott
Williams & Wilkins.
dense granules. These granules contain compounds

necessary for clotting such as vWF, platelet factor 4,
factor V, fibrinogen, and a number of other platelet
agonists. The fibrin that changes the platelet plug to
clot is formed from the cleavage of the 4 peptide
bonds of fibrinogen, referred to as fibrinopeptides
A and B, by thrombin. The removal of the bonds
allows polymerization and subsequent clot formation. Thrombin also strengthens the clot by cleaving
factor XIII that establishes covalent bonds between
fibrin molecules.
Besides the endothelium, an integral membrane
protein called tissue factor (TF) is now more recognized as a major part of fibrin formation through the
blood coagulation pathways. Previously, the intrinsic
and extrinsic pathways of the blood coagulation system were believed to work separately to activate factor X, initiating the common pathway to thrombin
formation (Figure 3), but they are not independent
of one another because deficiencies of one pathway
are not compensated by the other pathway. Current
understanding suggests that TF complexes with trace
amounts of factor VII in the blood to activate factor
VII, but only in conjunction with a phospholipid
surface of a monocyte, platelet, or microparticles.
This forms the TF:VIIa complex6 so that VIIa activates factor X to reach the common coagulation pathway7 and factor IX of the intrinsic pathway to generate
thrombin and fibrin formation (Figure 1). Early in
156 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
Figure 3. Coagulation cascade consisting of the extrinsic,

intrinsic, and common pathways.
NOTES: PL, phospholipids; Ca2+ = calcium.
Source: Reprinted with permission from Hartmann M, Sucker
C, Boehm O, Koch A, Loer S, Zacharowski K. Effects of cardiac
surgery on hemostasis. Transfus Med Rev. 2006;20:230-241,
figure 3. Copyright 2006 Elsevier.
thrombin generation, it is the TF:VIIa complex that

actually primes thrombin generation but eventually
thrombin formation becomes independent of this
TF:VIIa complex.8 Despite beginning with the extrinsic pathway, thrombin formation is 50 times faster
via the intrinsic pathway activation.6
Unopposed clotting would be catastrophic, so
mechanisms exist to inhibit perpetual clot formation
as well as dissolve existing clot. Inhibition of sustained clot formation is primarily accomplished by
antithrombin (AT) by limiting activity once a complex is formed with the clotting protein. Produced
in the liver, AT can inhibit all serine proteases,
not only thrombin and factor X. AT is consumed
once it forms the complex with the serine protease.
Adequate AT concentration is very important to maintain the balance between procoagulant and anticoagulant activity, especially with exposure to an EC. AT
reaches adult levels in about 6 months after birth.9
Excess thrombin that is not complexed with AT is
bound by thrombomodulin derived from endothelial cells. This thrombinthrombomodulin complex
also activates protein C and in conjunction with its
cofactor, protein S inactivates factors Va and VIIIa.7
Finally, the endothelium produces tissue factor pathway inhibitor to stop clotting by complexing not only
with TF but also with factors VIIa and Xa.
The fibrinolytic systems function is to limit the
extent of clot growth and ultimately dissolve it.
Plasmin, a serine protease, is the primary effector
molecule. It not only dissolves clot by lysing fibrin
but also hydrolyzes fibrinogen, factors V, VIII, IX,
and XI to stop clotting. Plasmin is activated by clot
formation that stimulates the endothelium to produce tissue type plasminogen activator (tPA). To
prevent excessive fibrinolysis, -2-antiplasmin efficiently inactivates plasmin and thrombomodulin.
Plasmin formation generates plasminogen activating
inhibitor that inhibits plasmin completing the feedback loop.
The coagulation system for neonates, infants,
and children contains all the necessary components
for clotting but only in different concentrations compared with adults.10 Newborn clotting factors VII,
IX, X, XI, XII, prothrombin, prekallikrein, and high
molecular weight kininogen are approximately 50%
of adult levels whereas factors VIII, XIII, V, fibrinogen, and vWF approach or even exceed adult values
(Table 1).11 Clotting factor levels are not only a
function of the postnatal but also of gestational age.
A weakness in thrombin generation in the preterm
and term infant may reduce clotting capability when
combined with lower clotting factor and contact protein levels in this age range.12 Infant prothrombin
levels lag behind adult concentrations by 20% and a
weaker capacity to generate thrombin persists even
into childhood.9 Newborn platelets are hyporeactive
compared with adult platelets but achieve adult reactivity rapidly in 10 to 14 days. A majority of inhibitors
of clotting, AT and proteins C and S are also 50% of
adult levels at birth.9
The newborn coagulation system overall matures
over 6 months to adult levels and function even if
premature birth temporarily depresses its capabilities; however, maturation does not insure normal
concentrations of all clotting factors. Similarly, lower
concentrations may not indicate poor clotting capability. Miller et al13 demonstrated functional integrity
of the coagulation system of neonates and infants
with the thrombelastogram (TEG) even though maturation was not complete. In fact, a more coagulable state was reported based on TEG values in those
individuals 1 to 3 months of age compared with
adults despite the low clotting factor concentrations
normally present in this age range.11 In essence, it is
Table 1. Reference Values for Coagulation Tests in Healthy Full-term Infant During the First 6 Monthsa
Tests
PT (s)
APTT (s)
TCT (s)
Fibrinogen (g/L)
II (U/mL)
V (U/mL)
VII (U/mL)
VIII (U/mL)
vWF (U/mL)
IX (U/mL)
X (U/mL)
XI (U/mL)
XII (U/mL)
PK (U/mL)
HMW-K (U/mL)
XIIIa (U/mL)
XIIIb (U/mL)
Plasminogen
(CTA, U/mL)
Day 1 (n)
13.0
42.9
23.5
1.83
0.48
0.72
0.66
1.00
1.53
0.53
0.40
0.38
0.53
0.37
0.54
0.79
0.76
1.95
1.43
5.80
2.38
0.58
0.11
0.18
0.19
0.39
0.67
0.19
0.14
0.14
0.20
0.16
0.24
0.26
0.23
0.35
(61)*
(61)
(58)*
(61)*
(61)
(61)
(60)
(60)*
(40)
(59)
(60)
(60)
(60)
(45)
(47)
(44)
(44)
(44)
Day 5 (n)
12.4
42.6
23.1
3.12
0.63
0.95
0.89
0.88
1.40
0.53
0.49
0.55
0.47
0.48
0.74
0.94
1.06
2.17
1.46
8.62
3.07
0.75
0.15
0.25
0.27
0.33
0.57
0.19
0.15
0.16
0.18
0.14
0.28
0.25
0.37
0.38
(77)*
(76)
(64)
(77)*
(76)
(76)
(75)
(75)*
(43)
(75)
(76)
(74)
(75)
(51)
(63)
(49)*
(47)*
(60)
Day 30 (n)
11.8
40.4
24.3
2.70
0.68
0.98
0.90
0.91
1.28
0.51
0.59
0.53
0.49
0.57
0.77
0.93
1.11
1.98
1.25
7.42
2.44
0.54
0.17
0.18
0.24
0.33
0.59
0.15
0.14
0.13
0.16
0.17
0.22
0.27
0.36
0.36
(67)*
(67)
(53)*
(67)*
(67)
(67)
(67)
(67)*
(40)
(67)
(67)
(67)
(67)
(48)
(50)*
(44)*
(45)*
(52)
Day 90 (n)
11.9
37.1
25.1
2.43
0.75
0.90
0.91
0.79
1.18
0.67
0.71
0.69
0.67
0.73
0.82
1.04
1.16
2.48
1.15
6.52
2.32
0.68
0.15
0.21
0.26
0.23
0.44
0.23
0.18
0.14
0.21
0.16
0.32
0.34
0.37
0.37
(62)*
(62)*
(52)*
(60)*
(62)
(62)
(62)
(62)*
(40)
(62)
(62)
(62)
(62)
(46)
(46)*
(44)*
(44)*
(44)
Day 180 (n)

12.3
35.5
25.5
2.51
0.88
0.91
0.87
0.73
1.07
0.86
0.78
0.86
0.77
0.86
0.82
1.04
1.10
3.01
0.79
3.71
2.86
0.68
0.14
0.18
0.20
0.18
0.45
0.25
0.20
0.24
0.19
0.15
0.23
0.29
0.40
0.40
(47)*
(47)*
(41)*
(47)*
(47)
(47)
(47)
(47)
(46)
(47)
(47)
(47)
(47)
(43)
(48)*
(41)*
(41)*
(47)
Adult (n)
12.4
33.5
25.0
2.78
1.08
1.06
1.05
0.99
0.92
1.09
1.06
0.97
1.08
1.12
0.92
1.05
0.97
3.36
0.78
3.44
2.66
0.61
0.19
0.22
0.19
0.25
0.33
0.27
0.23
0.15
0.28
0.25
0.22
0.25
0.20
0.44
(29)
(29)
(19)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
(29)
NOTES: PT, prothrombin time; APTT, activated partial thromboplastin time; TCT, thrombin clotting time; vWF, von Willebrand factor; PK, prekallikrein; HMW-K, high molecular weight kininogen.
a
All factors except fibrinogen and plasminogen are expressed as units per milliliter (U/mL) where pooled plasma contains 1.0 U/mL. Plasminogen
units are those recommended by the Committee on Thrombolytic Agents (CTA). All values are expressed as mean standard deviation.
*Values that do not differ statistically from the adult values.
These measurements are skewed because of a disproportionate number of high values. The lower limit that excludes the lower 2.5th percentile of
the population has been given in the respective figures. The lower limit for factor VIII was 0.50 U/mL at all time points for the infant.
Source: Reprinted with permission from Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant.
Blood. 1997;70:165-172, table 2. Copyright 1997 American Society of Hematology (ASH).
difficult to reliably estimate the clotting capability of

pediatric patients based solely on the concentration
of clotting factors and platelets, so functional measures of clotting such as the TEG may provide
important information to guide diagnosis and treatment. However, the rarity of spontaneous hemorrhage and thrombosis in neonates and infants
suggests a balance between clotting and anticoagulation in normal circumstances.
Extracorporeal Circuit
and Hemostatic Activation
The inflammatory response and coagulation are
closely connected and readily return to equilibrium at
the local level. In contrast, exposure of the blood and
cellular components to a nonbiologic surface of an
EC provokes a massive inflammatory and thrombotic
response exceeding any contact activation experienced at a local level. The inflammatory response
activates cellular and enzymatic components that
interact with the activated coagulation system (Figure
4). A highly procoagulant state mediated primarily by
thrombin is counterbalanced by an excessive fibrinolytic response mediated by plasmin. The result is

consumption and activation causing clotting factor
deficiencies, impaired platelet function, thrombocytopenia, and fibrinolysis (Figure 5). To complete the
feedback loop, thrombin, factors Xa and VIIa also
activate the inflammatory responses directly or indirectly by complement activation.14 The ongoing nature
of the procoagulant (thrombin) and anticoagulant
(fibrinolysis) actions in concert with the elevated
inflammatory response that occurs during ECMO
creates opportunities for imbalance that heightens
the chance of thrombosis or more commonly excessive bleeding.15 Reduced postoperative bleeding associated with cardiopulmonary bypass (CPB) and
cardiac surgery was accomplished by efforts to block
the final complement pathway and therefore the
inflammatory response.16 However, the many arms of
the inflammatory response have limited the benefits
of targeted therapies. Furthermore, the inflammatory
response of neonates and infants is far greater than
adults exposed to EC17 and associated with greater
morbidity,18 so even stronger measures would be necessary to show any clinically significant benefit.
Figure 4. Cellular and plasmatic systems involved in the

inflammatory response induced by cardiopulmonary bypassinduced contact activation.
Source: Reprinted with permission from Mssinger H, Dietrich
W. Activation of hemostasis during cardiopulmonary bypass and
pediatric aprotinin dosage. Ann Thorac Surg. 1998;65(6 suppl):
S45-S51. Copyright 1998 The Society of Thoracic Surgeons,
Elsevier.
Contact between blood and a nonbiologic surface of an EC activates high molecular weight kininogen, plasma kallikrein, and factor XII to begin the
process of clotting. Within seconds of the bloods
contact with the surface of the EC, a layer of fibrinogen, vWF, and fibronectin is adsorbed that contains
the protein sequence responsible for strongly attracting platelet adhesive receptors such as GPIIa-IIIb
and GPIb (GP = glycoprotein). Platelets will initially
adhere to such a site but only with repeated platelet
stimulation, will they progress from a reversible
state of platelet adhesion to an irreversible state of
aggregation and platelet recruitment. This change is
reflected in pediatric patients after CPB when preCPB platelet aggregation fell as much as 77% by end
of surgery.19 Besides attracting platelets, surface proteins such as fibrinogen and factor XII affect other
cellular processes and interactions that promote a
procoagulant environment.
For infants during the first two hours of ECMO,
activated platelets catalyze increased thrombin formation, evidenced by rapid increases in concentration of
prothrombin fragments 1 + 2 (F1+2), thrombinantithrombin (TAT) complexes, and fibrin split products,
to generate fibrin to stabilize the platelet plug (Figure
Figure 5. Pathophysiology of hemostatic abnormalities with

extracorporeal circulation. Contact activation via extracorporeal
circulation (ECC) refers to contact activation related to interface of blood with nonendothelial surface of the ECC. Pericardial
activation refers to activation of the hemostatic system via the
tissue factor pathway mediated by transfusion pericardial blood
containing tissue thromboplastin. Mechanical ECC refers to
shear forces imposed by some of the components of the ECC
circuit as listed (tPA = tissue plasminogen activator).
Source: Modified and reprinted with permission from Despotis
GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999;91:1122-1151. Copyright 1999
Lippincott Williams & Wilkins.
6).20 Activated platelets are far more attracted to the

surface of the oxygenator and endothelium than
resting ones but contact activation eventually slows
over the ensuing 48 hours as markers of thrombin
formation subside. The reason for less contact activation at this point may be a surface replete with
proteins and cellular components.20 Ongoing surface activation not only forms clot from thrombin
and factor XII formation, but also stimulates tPA to
generate plasmin to dissolve clot. Activated endothelial cells and platelets control the amounts of tPA to
try to maintain that balance between procoagulant
and anticoagulant forces.
Activation of the coagulation system occurs not
only on the surface of the EC but also within the
patients vasculature leading to either overt thrombosis or disseminated intravascular coagulation.21
Vascular endothelial cells in contact with activated
platelets and other procoagulant agonists, will produce thrombin, but resting endothelial cells express
little TF so that there is minimal thrombin and
clot.17 The role of the EC is not only to activate the
be appreciated but future findings may hold some

answers to better management of ECMO.
Anticoagulation
The goal of anticoagulation for ECMO is to prevent
life-threatening thrombosis and excessive bleeding.
Discerning the degree of anticoagulation to attenuate platelet and thrombin activation but provide sufficient clotting to prevent excessive bleeding is
difficult. It is made more difficult because the technology to accurately assess the degree of anticoagulation is not clinically available or developed currently.
Unidentified macroscopic clots cause a variety of
thromboembolic events in patients considered adequately anticoagulated.22 It appears that the effectiveness of anticoagulation worsens with the duration
of ECMO. A recent autopsy series of ECMO patients
reported unexpectedly high rates of systemic thromboemobolic events approaching 50% with an almost
linear increase with duration of ECMO (Figure 7).23
However, the study identified a median time of
6 days with freedom from these events. Current
management of anticoagulation for ECMO partially
derived from the experiences of CPB.24 Advancements
of anticoagulation in ECMO will likely remain limited because of the difficulty of conducting randomized trials compared with CPB. The ensuing
paragraphs will discuss the monitoring and dosing
for anticoagulation for ECMO.
Figure 6. A, Course of F1+2 (in nanomoles per liter). B, TAT (in
micrograms per liter). C, d-dimer (in nanograms per liter). A
steep increase of values is seen within the first 2 hours of
ECMO. Thereafter F1+2 and TAT values decrease, whereas d-dimer levels remain high. Values represent mean SEM. preEC,
Before start of ECMO (n = 6, asterisk; otherwise n = 7).
NOTES: F1+2, prothrombin fragments; TAT, thrombinantithrombin complexes; ECMO, extracorporeal membrane oxygenation; SEM, standard error of the mean.
Source: Reprinted with permission from Urlesberger B, Zobel G,
Zenz W, et al. Activation of the clotting system during extracorporeal membrane oxygenation in term newborn infants. J Pediatr.
1996;129:264-268, figure 1. Copyright 1996 Mosby.
endothelium to express TF, but it also causes a

change to occur in the endothelial membrane to
support the TF:VIIa complex, also known as the
prothrombinase complex (Figure 1). The importance
of the endothelium in clotting and anticoagulation
in patients undergoing ECMO is just now begun to
Monitoring for Anticoagulation

Identification of the level of anticoagulation is the
heartbeat of ECMO management. In the initial
years of cardiac surgery with CPB, a fixed dose of
heparin was administered without monitoring for
level of anticoagulation. The advent of anticoagulation monitoring was a great advancement to improve
care in cardiac surgery.
The earliest and most popular test to monitor
anticoagulation for EC was the activated clotting
time (ACT). It measures the integrity of the intrinsic
coagulation and common pathways. To perform an
ACT, whole blood is placed in a test tube with 1 of
2 activators of the contact pathway, celite (diatomaceous earth) or kaolin (clay). The celite ACT forms
clot that will disrupt the magnetic field of the magnetic detector by pulling iron away from it, thereby
halting the timer. The kaolin ACT has a plunger that
Figure 7. Time-dependent incidence of systemic thromboembolisms in ECMO patients based on autopsy findings.
NOTES: ECMO, extracorporeal membrane oxygenation; d,
days.
Source: Reprinted with permission from Rastan AJ, Lachmann N,
Walther T, et al. Autopsy findings in patients on postcardiotomy
extracorporeal membrane oxygenation (ECMO). Int J Artif Organs.
2006;29:1121-1131. Copyright 2006 Wichtig Editore.
actively rises and falls in whole blood until the rate

of the falling plunger is slowed by clot formation and
an optical sensor detects the change halting the
timer. The ACT is a functional test of anticoagulation. Bull et al25 were the first to explore the possibility of evaluating the degree of anticoagulation during
CPB with the ACT. To achieve good results, they
recognized that a dose response method was necessary to dose heparin during CPB because of the
great variability associated with the amount of heparin and the resulting ACT values among patients.
Bull et al25 obtained ACT values for numerous time
points generating a curve predicting the heparin
required to achieve adequate anticoagulation. ACT
management of anticoagulation was proclaimed successful without visible clots in the EC. The ACTs
that provided such conditions varied between 300
and 600 seconds. Soon after, Young et al26 challenged the accepted range of ACTs for adequate
anticoagulation. In a study of monkeys undergoing
CPB, significantly higher fibrin monomer levels
were found in animals below an ACT of 400 seconds
despite the absence of visible clot in the EC. This
not only changed the minimal acceptable ACT for
heparinization with EC, but more important, it dispelled the idea that the absence of overt clotting
Figure 8. Activated clotting time (ACT) versus heparin levels

(anti-factor Xa activity). The correlation of the ACT values and
plasma heparin levels was r = .38.
Source: Reprinted with permission from Chan AK, Leaker M,
Burrows FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost.
1997;77:270-277, figure 12. Copyright 1997 International Society
on Thrombostasis and Haemostasis.
indicated adequate anticoagulation. Subsequently,

more sensitive tests were developed and employed to
evaluate adequate anticoagulation during EC.
ACT remains the predominant test to manage
heparin anticoagulation during ECMO.27 However,
the ACTs capability to correctly measure the level
of anticoagulation has been questioned.28 Concern
about the ACTs ability to provide adequate anticoagulation is because the test results are affected by
patient characteristics, such as coagulopathy, immature coagulation system, platelet dysfunction, hypothermia, AT level, age, and hemodilution,29 as well as
technical factors, such as sample size, venous or arterial blood, and temperature.27 Even changes in the
use of a specific ACT device may result in unrecognized inadequate anticoagulation.30
A concern with the ACT for management of
anticoagulation with EC is its limited range of accuracy. The correlation coefficient of a laboratoryderived heparin concentration (anti-Xa level) to kaolin
ACT (r = .93) and celite ACT (r = .91) before initiation of EC is excellent,31 but deteriorates on EC (r =
.38) especially with neonates or infants (Figure 8).
Heparin levels < 2 u/mL have been reported despite
prolonged ACT values indicative of adequate anticoagulation.32 Ongoing thrombin generation is evident in adults, and especially children, undergoing
cardiac surgery and CPB despite acceptable ACT
Figure 9. A, Correlation of the kaolin activated clotting time

(ACT) to the chromogenically measured plasma anti-Xa activity.
B, Correlation of the plasma added modified kaolin ACT to the
chromogenically measured plasma anti-Xa activity.
Source: Reprinted with permission from Koster A, Despotis G,
Gruendel M, et al. The plasma supplemented modified activated
clotting time for monitoring of heparinization during cardiopulmonary bypass: a pilot investigation. Anesth Analg. 2002;95:26-30,
figure 1. Copyright 2002 International Anesthesia Research
Society, Lippincott Williams & Wilkins.
values supporting inadequate anticoagulation.29,33-35

Such poor correlations with the ACT and heparin
levels may be improved with more normal clotting
factor levels in the patient. The correlation of ACT
with anti-Xa derived heparin concentrations was
poor with crystalloid only hemodilution (Figure 9A)
but improved with same degree of hemodilution
(75%) as crystalloid but substituting fresh frozen
plasma (FFP; Figure 9b).36 Koster et al37 also found
poor correlation of the ACT with saline hemodilution, which improved by adding plasma during CPB
but besides a better correlation of the ACT with

heparin levels there was evidence of reduced thrombin generation, fewer d-dimers, and less neutrophil
activation. This suggests that ACT management
with ECMO may be improved if adequate clotting
factor levels are maintained. Unfortunately, increasing complexities associated with ECMO patients also
worsen the correlation of ACT to heparin dosing
causing more uncertainty for the clinician with this
form of monitoring.
The popular range for the ACT with heparin during ECMO has been 180 to 220 seconds.38 Recently,
a retrospective review of 604 consecutive pediatric
ECMO patients at a single institution were analyzed
for factors that affected outcome.27 The mean ACT
for all patients was 227 50 seconds but the range
of 158 to 620 seconds was very broad. Using regression analysis to determine the correlation of survival
with heparin dosing and ACT values, it was higher
heparin dosing and not the ACT that was predictive
of survival independent of other variables (P < .0001).
Figure 10 shows a moderate correlation coefficient
(r = .48) between ACT and heparin dosing (units/
kg/h) but when survival was plotted, the greatest
survival was in the right upper quadrant of the graph
with the higher heparin dosing. All the data suggest
increased survival with increasing heparin dosing.27
Furthermore, higher heparin dosing was also associated with increased survival in patients who had
prior surgery and required ECMO. Survivors had
significantly shorter ECMO times but significantly
greater heparin doses adjusted for body weight per
hour. ACTs were not different between survivors
and nonsurvivors.
Although the celite and kaolin ACT tests are the
most popular types of anticoagulation monitoring
tests, there are other types of ACT tests such as the
i-STAT (Abbott Laboratories, Abbott Park, IL) ACT.
Although the results are shorter compared with traditional ACT there may be some value in its use
during ECMO where rapid ACT is often required.39
There are also efforts to replace the traditional
ACT with an ACT derived from point-of-care (POC)
instruments such as the sonoclot,40 and the TEG
with TF activation41 but they have not become popular at this time.
Despite the continued use of the ACT, it alone
may be too insensitive to achieve consistent adequate anticoagulation during ECMO so the addition
of other coagulation tests may prove beneficial. The
measurement of heparin concentration is an option
Figure 10. Scatterplot shows the moderate positive linear correlation between heparin dose and ACT (r = .48, P < .001).
Similar moderate correlations were observed in both survivors
(open triangles; r = .52, P < .001) and nonsurvivors (filled triangles; r = .43, P < .001). Regression line (solid line) based on
all patients is drawn according to the derived linear equation for
estimating ACT from heparin dose: y = 0.95x + 180.
NOTES: ACT, activated clotting time; ECMO, extracorporeal
membrane oxygenation.
Source: Reprinted with permission from Baird CW, Zurakowski
D, Robinson B, et al. Anticoagulation and pediatric extracorporeal membrane oxygenation: impact of activated clotting time
and heparin dose on survival. Ann Thorac Surg. 2007;83:912919, figure 1. Copyright 2007 The Society of Thoracic Surgeons,
Elsevier.
to manage anticoagulation. Laboratory derived heparin concentration is the gold standard but is not
easily or quickly obtained for patients on ECMO.
A relatively accurate point-of-care heparin concentration is obtained with the technique of heparin/
protamine titration. The Hepcon (Medtronic
Perfusion Systems, Minneapolis, MN) is able to provide heparin concentrations that have relatively
good correlation to the laboratory-derived anti-Xa
plasma heparin measurements.31 These tests do not
however, actually measure the anticoagulant properties of heparin, so they are not functional tests,
such as the ACT, but still depend on clotting to
determine the concentration.
Heparin concentration monitoring for anticoagulation is more frequent in cardiac surgery with CPB
especially when severe hemodilution or hypothermia
is anticipated. Heparin concentration monitoring
with the Hepcon has demonstrated superior capability to achieve adequate anticoagulation in adults and
especially children undergoing cardiac surgery and
CPB compared with the ACT.33,34 Codispoti and

Mankad35 compared heparin concentration management for pediatric and adult CPB finding not
only more adequate anticoagulation but also
increased heparin dosing and reduced bleeding and
transfusion requirements compared with ACT management. Better platelet preservation with higher
than lower heparin concentrations in patients
undergoing CPB28 may be advantageous with ECMO
as bleeding due to thrombocytopenia and poor platelet function is a major problem. More important,
unlike the ACT, use of heparin concentrations have
the benefit of being less sensitive to changes in the
patients platelet and clotting factor levels so better
management of anticoagulation is possible.
Studies of heparin concentration monitoring for
anticoagulation during ECMO are few compared to
the ACT so target heparin levels have not been determined. In 1990, a study of heparin clearance during
ECMO unintentionally discovered heparin concentrations of 0.1 to 0.3 u/mL associated with ACTs of
110 to 220 seconds.42,43 Urlesberger et al20 noted that
the heparin concentrations remained surprisingly
steady in term newborn infants requiring ECMO
compared with the ACT with heparin dosing during
a 48-hour period (Figure 11). Similar to the studies
by Green et al,42,43 this study shows a similar range
of heparin concentration of 0.2 to 0.4 u/mL during
ECMO, but unfortunately there are no other studies
to confirm the findings. Uncertainty regarding the
target heparin concentration during ECMO has limited its use.
The use of viscoelastic tests for anticoagulation
is not totally new. Several centers have incorporated
the TEG into their management of ECMO.44 It is a
major part of anticoagulation and transfusion therapy in our institution. The TEG is a device that
measures the viscoelastic properties of the blood
to examine the whole clotting system instead of isolated parts.45 It provides ongoing coagulation profiles looking at not only the initiation of clotting but
also the strength and dissolution of the clot as in the
case of fibrinolysis. Figure 12 shows the parameters
of the TEG.
To manage anticoagulation with the TEG, the
reaction time, r, is the most important value because
it represents the time for initial fibrin formation. It
is affected by severe hypofibrinogemia, hypercoagulability, and heparin. In fact, the TEG is so sensitive
to the effects of heparin that as little as 0.3 u/mL will
prolong the r time and 1 u/mL will greatly suppress
Figure 11. A, Heparin concentration (in international units

per milliliter). B, Activated clotting time (ACT; in seconds). The
ACT values increased at the start of ECMO, whereas heparin
concentration has a stable course. Values represent mean
SEM. preEC, Before the start of ECMO (n = 6, asterisk; otherwise n = 7).
NOTES: ACT = activated clotting time; ECMO, extracorporeal
membrane oxygenation; SEM, standard error of the mean.
Source: Reprinted with permission from Urlesberger B, Zobel G,
Zenz W, et al. Activation of the clotting system during extracorporeal membrane oxygenation in term newborn infants. J Pediatr.
1996;129:264-268, figure 2. Copyright 1996 Mosby.
clotting so that only a flat line occurs. This makes it

impractical for management of anticoagulation during CPB, but not ECMO because heparin levels
usually do not exceed 1 u/mL.
The value of the TEG for ECMO and CPB has
become more recognized over the last decade with
the application of additives such as heparinase, TF,
and kaolin to expand its capabilities. The addition of
kaolin to the TEG (kTEG) sample gives a more rapid
result. The addition of heparinase to the TEG
(hTEG) permits a fully formed tracing to be generated and so allows a view of hemostatic capability
Figure 12. Quantification of native thromboelastogram (TEG)

variables. Analysis of the thrombelastograph. r = reaction time
(time from sample placement in the cuvette until TEG tracing
amplitude reaches 2 mm; normal range, 6-8 min). This represents the rate of initial fibrin formation and is related functionally to plasma clotting factor and circulating inhibitor activity
(intrinsic coagulation). Prolongation of the r time may be a
result of coagulation factor deficiencies, anticoagulation (heparin), or severe hypofibrinogenemia. A small r value may be present in hypercoagulability syndromes. K = clot formation time
(normal range, 3-6 min); measured from r time to the point
where the amplitude of the tracing reaches 20 mm. The coagulation time represents the time taken for a fixed degree of viscoelasticity to be achieved by the forming clot, as a result of
fibrin build up and cross linking. It is affected by the activity of
the intrinsic clotting factors, fibrinogen and platelets. Angle
(normal range, 50-60) = greatest amplitude on the TEG trace
and is a reflection of the absolute strength of the fibrin clot. It
is a direct function of the maximum dynamic properties of fibrin
and platelets. Platelet abnormalities, whether qualitative or
quantitative, substantially disturb the maximum amplitude
(MA). A60 (normal range, MA-5 mm) = amplitude of the tracing
60 min after MA is achieved. It is a measure of clot lysis or
retraction. The clot lysis index (CLI; normal range >85%) is
derived as A60/MA 100 (%). It measures the amplitude as a
function of the time and reflects loss of clot integrity as a result
of lysis.
Source: Reprinted with permission from Mallett SV, Cox DJ.
Thrombelastography. Br J Anaesth. 1992;69:307-313, figure 2.
Copyright 1992 Oxford University Press.
even with a heparin infusion (Figure 13). Because the

TEG r is sensitive to certain many factors, the best
diagnostic option is to perform a hTEG and kTEG
simultaneously46 especially during ECMO. Simulta
neous TEGs will provide a measure of the degree of
anticoagulation. If the kTEG r time and the hTEG r
time are similar in length, then very little systemic
heparin is present. We like to maintain a kTEG r of
more than 20 minutes as a baseline for anticoagulation. If the kTEG r time exceeds 90 minute, then
anticoagulation may be too great possibly increasing
bleeding.
Figure 13. Thromboelastogram with heparinase and native

whole blood samples. The difference in the r time and angles are
especially notable.
Source: Reprinted with permission from Agati S, Ciccarello G,
Salvo D, Turla G, Undar A, Mignosa C. Use of a novel anticoagulation strategy during ECMO in a pediatric population:
single-center experience. ASAIO J. 2006;52:513-516, figure 2.
Copyright 2006 Lippincott Williams & Wilkins.
The TEG is not only useful for determining

anticoagulation but is also able to characterize hypercoagulability. This information is relevant when managing the anticoagulation from birth to adulthood.
The concentration of procoagulant and anticoagulant compounds vary in amount from birth to adulthood; however, the ability to assess this functionally
with a POC test is beneficial. Miller et al13 found that
most coagulable infants are 1 to 3 months of age
whereas neonates are similar to infants 6 months of
age in terms of coagulability with the TEG. The TEG
of infants demonstrates that even with lower plasma
levels than adults they clot effectively. Kinetics may
explain the low levels despite functional equivalency
compared with adults.
A new type of TEG, the rotational TEG (RoTEG)
may be helpful in the future in ECMO patients and
is gaining rapid popularity in Europe because of its
simplicity compared with the native TEG (Figure 14).
The device still evaluates whole blood viscoelastic
properties but is mechanistically different from the
TEG and the parameters are defined differently. The
RoTEG is not yet available in the United States.
Activated Partial Thromboplastin Time

The activated partial thromboplastin time (APTT)
is universally recognized as a standard monitor for
heparin therapy except when high heparin dosing
is required as in CPB. The APTT is performed on
Figure 14. Typical tracings of viscoelastic point-of-care coagulation devices. Top, Thrombelastograph (TEG) tracing: r =
reaction time; K = kinetics; = slope between r and K; MA =
maximum amplitude; CL = clot lysis. Bottom, Rotation thrombelastography (ROTEM) tracing: CT = clotting time; CFT = clot
formation time; = slope of tangent at 2 mm amplitude;
MCF = maximal clot firmness; LY = lysis.
Source: Reprinted with permission from Ganter MT, Hofer CK.
Coagulation monitoring: current techniques and clinical use of
viscoelastic point-of-care coagulation devices. Anesth Analg.
2008;106:1366-1375, figure 3A. Copyright 2008 International
Anesthesia Research Society, Lippincott Williams & Wilkins.
recalcified citrated plasma and represents the intrinsic and common pathways.47 Its reagent contains
phospholipids that act as platelets for clotting to
occur. The wide variety of reagents results in some
occasional sensitivity to various clotting factor deficiencies. The activator for the APTT influences the
clotting time as well so that APTT results between
institutions may not be comparable.
In situations that do not require high heparin
dosing, such as ECMO, the APTT is a valuable tool
to assess anticoagulation. Although both ACT and
APTT are prolonged with heparin, there is poor correlation between the ACT and the APTT. In a comparison between laboratory APTT and five bedside
devices for monitoring heparin therapy, including the
celite and kaolin ACT, the ACT was found to correlate poorly with the APTT.48 Furthermore, in very
ill patients requiring continuous infusions of heparin the ACT could not delineate between low and
moderate levels of anticoagulation compared with the
APTT (Figure 15).49
The APTT that will prevent thrombus extension
with heparin has been reported as 1.5 times baseline
APTT. This APTT corresponds to a heparin level of
0.2 to 0.3 u/mL and does correlate moderately well
with heparin concentrations.50 The APTT is sensitive
Infants who received FFP as a prime had lower postCPB APTT values of 99.2 41.7 seconds, which did
not quite reach statistical significance but demonstrated the impact of hemodilution on the APTT.
Significant hemodilution may occur with the early
stages of ECMO or during circuit changes, so it is
important to be aware of this problem. The ACT,
although affected by hemodilution, is less susceptible
to it than the APTT.
Anticoagulation Therapy
Figure 15. ACT at different levels of heparin anticoagulation.

Group 1 APTT < 60 seconds; group 2 APTT 60 to 90 seconds;
group 3 APTT > 90 seconds. All 3 groups differed statistically
from one another (P < .001). Only Group 3 was the mean ACT
(192 39.1 seconds) significantly higher than the other mean
ACT values for groups 1 and 2.
NOTES: ACT, activated clotting time; APTT, activated partial
thromboplastin time.
Source: Reprinted with permission from De Waele JJ, Van
Cauwenberghe S, Hoste E, Benoit D, Colardyn F. The use of
the activated clotting time for monitoring heparin therapy in
critically ill patients. Intensive Care Med. 2003;29:325-328,
figure 2. Copyright 2003 Springer-Verlag.
over a heparin range of 0.1 to 1.0 u/mL. When the

heparin level gets much more than 1 u/mL, the APTT
becomes markedly prolonged. For ECMO anticoagulation, the APTT is another measure to manage anticoagulation, not only to prevent thrombus formation
but also to avoid excessive hemorrhage. In general,
we have found that an APTT of 50 to 80 seconds
complements the kTEG r time for anticoagulation.
Because of the APTT sensitivity, it will take priority
over the ACT when there is a discrepancy between
the two measurements. For infants and children, the
APTT may be prolonged in response to hemodilution
without any measurable heparin. This is demonstrated
in a trial looking at the use of FFP in infants that
underwent CPB.51 The APTT of control infants before
CPB was 35.2 6.8 seconds compared with 117
42.3 seconds after CPB and heparin neutralization.
Heparin continues to dominate anticoagulation therapy for ECMO because it is rapidly acting, easily
reversible, inexpensive, widely available, and well
tolerated by pediatric and adult patients. It is a glycosaminoglycan composed of chains of alternating
residues of d-glucosamine and an uronic acid. Its
unique pentasaccharide present in only one third of
the molecule has a strong affinity to bind with AT.
This binding causes a conformational change at the
lysine site of AT that converts a slow inhibitor of serine proteases, to one up to 10 000 times faster than
normal depending on the enzyme. Serine proteases
such as kallikrein and factors Xa, IXa, XIa, and XIIa
are inhibited to a much weaker degree than factor
Xa and thrombin, the most sensitive to AT. Thrombin
bound to clot or surfaces of the circuit is not capable
of being inhibited by the ATheparin complex.6 As a
result, bound thrombin will further activate clotting
and thrombin generation resulting in greater heparin needs. The action of heparin is not solely limited
to thrombin but also to TF inhibition by stimulating
tissue factor pathway inhibitor.
Once heparin is injected, it immediately binds to
plasma proteins such as platelet factor 4, fibronectin, vWF, and others, which reduces its bioavailability
especially at low doses.50 Heparin also binds to macrophages and the endothelium further complicating its pharmacokinetics. Its anticoagulant activity is
heterogeneous because of its variant size, clearance,
and molecular format. Biologic activity varies between
30 minutes and 6 hours depending on the systemic
heparin concentration. The half-life is affected so
much by the dose that the anticoagulant response is
not linear. It is metabolized in the reticuloendothelial system as well as the liver and 50% will be excreted
unchanged by the kidneys.50 Clearance of heparin is
greater for children with congenital heart disease than
for adults.52
Anticoagulation for ECMO is based on the need

to prevent thrombus formation in the EC and patient;
however, complete inhibition of thrombin would
cause excessive bleeding. Depending on the history
of the patient prior to ECMO, profound coagulation
abnormalities may exist as with cardiac surgery. If a
patient is bleeding or is likely to bleed after placement on ECMO, anticoagulation may be held and
coagulation abnormalities corrected until the bleeding is controlled. The use of a heparin-coated circuit
and good cardiac outputs are recommended. Once
bleeding has been controlled to a degree, heparin will
be given.
Heparin dosing for adults and pediatric patients
is different for several reasons. The larger blood
volume/weight ratios in neonates compared with
adults require greater heparin dosing. The more rapid
metabolic rates with neonates and infants may allow
greater excretion by the kidneys and therefore affects
heparin dosing. Heparin elimination half-life is also
dependent on the initial dose as well as the temperature. However, there is evidence that heparin clearance
in infants is less after ECMO than before initiation.42 Therefore, the actual heparin clearance after
initiation of ECMO is only speculation, hence heparin dosing must depend on laboratory tests.
Differences in heparin dosing for adults and pediatric patients may also derive from differences in
thrombin generation. There is evidence that neonates have greater thrombin generation even before
the start of CPB compared with older children.53
However, even with higher heparin dosing during
CPB, neonates had more evidence of thrombin generation than younger children based on increased F
1 + 2 and fibrinopeptide A concentrations. The idea
of heparin resistance or sensitivity in neonates has
been debated. Dietrich et al54 suggested that the
neonate is sensitive to heparin even though AT levels
are below adult for at least 6 months. On the contrary, however, Guzzetta et al53 have shown that the
study by Dietrich et al was focused on the wrong
endpoint, to reach such a conclusion. The research
seems to point to neonates are more resistant to
heparin and require greater amounts of heparin to
inhibit thrombin that has implications for ECMO
management. Additionally, neonates from cardiac
surgery may have increased heparin needs as there
is increased circulating thrombin because of greater
clot-bound thrombin that is caused by the catheters
and other nonbiologic items often placed in these
neonates prior to initiation of ECMO.
Traditionally, heparin dosing ranges between 20

and 70 u/kg/h for ECMO. The difference in heparin
anticoagulant responsiveness between individuals is
evident by the wide range of heparin dosing response
slopes in both normal (median 92, 95% confidence
interval [CI] 77-117 s/u/mL) and cardiac patients
(median 79, 95% CI 58-114 s/u/mL).55 Heparin dosing for ECMO for adults and pediatric patients may
differ but is often derived from the guidelines for
patients with thromboembolic disease.21 Most agree
that the APTT should be 1.5 to 2.5 times the control.
The most recent studies of heparin concentration
suggest a value of 0.3 to 0.7 u/mL.21 The use of
APTT in neonates on ECMO must be considered for
prolongations because of hemodilution and not heparin. However, even in adults the APTT is prolonged
without circulating heparin, because of hemodilution.56 It is in this situation of hemodilution that the
ACT may be more accurate with respect to circulating heparin than the APTT. Otherwise, the APTT
should provide excellent heparin monitoring. It is
not unusual to see heparin dosing change during
the ECMO duration in a patient. When monitoring
anti-Xa levels, heparin concentration increases with
time on ECMO.57 The cause may be a decrease in
AT or maybe ECMO bound heparin is removed from
the surface to increase the amount of circulating
heparin.
Heparin dosing and effective anticoagulation are
closely connected with AT concentration. Reduced
heparin responsiveness is called heparin resistance.
As mentioned earlier, for effective inhibition of thrombin, adequate levels of AT are required with heparin.
The major cause of heparin resistance is acquired
deficiency of AT often associated with severe hemodilution, liver abnormalities, preoperative heparin use,
or consumption during EC. Heparin infusions will
continue to deplete the AT level. However, the management of AT during ECMO is undecided. Arnold et
al58 found a mean AT level of 27% in neonates undergoing ECMO with some levels as low as 19%. This
level of AT was also associated with a 30% incidence
of neurologic bleeding. With the continuous administration of AT to normalize the AT level to 100% in
another study of neonates, reduced bleeding was
demonstrated during ECMO.44 From a cardiac surgical bleeding aspect, Hashimoto et al59 demonstrated
that supplementation with AT in pediatric patients to
maintain preoperative levels suppressed activation
of the coagulation system based on the extent of
fibrin formation. Because complete suppression of
thrombin is not the goal of ECMO anticoagulation, it

is difficult to make recommendations regarding the
proper practice. It is clear that prolonged durations of
ECMO will lead to consumption of AT and the
patient may not be capable of maintaining the level.
It is our practice to monitor AT daily during ECMO
but replacement is an individual preference.
Transfusion and ECMO

The morbidity and mortality associated with hemorrhage during ECMO is known. Stronger anticoagulation to lessen thrombotic complications will
inevitably lead to greater bleeding and transfusion of
blood products.60 Unlike in the past, the morbidity
associated with blood transfusion is currently related
to immunomodulation and increased inflammatory
response that occurs with excessive blood transfusion rather than infectious transmission. Repeated
transfusions compounded by a profound inflammatory response associated with EC greatly increase
the risk of sepsis. Therefore, efficient and appropriate transfusion to minimize bleeding and transfusion requirements may contribute greatly to reducing
morbidity and mortality associated with ECMO.
Bleeding and transfusion with ECMO usually
take 2 different forms. Serious hemorrhage in the
neonate with respiratory distress syndrome who
needs ECMO is primarily related to injury of the
central nervous system at the intracranial level.60
Intracranial hemorrhage may occur in 15% of neonates61 and lead to premature discontinuation of
ECMO or serious morbidity after separation. The
risk of bleeding for neonates on ECMO is heightened by the knowledge that up to 70% of neonates
and infants have preexisting coagulation abnormalities prior to initiation of ECMO.61 However, it is not
apparent that coagulopathy is the major cause for
bleeding as other factors such as prolonged hypoxia,
ischemia, acidosis, carotid ligation, and changes in
the cerebral blood flow may play a role. In contrast,
hemorrhage in other group of patients that require
ECMO, especially postcardiac surgical patients, is
about massive blood loss and transfusion that may
continue indefinitely and also require premature separation from ECMO. A prospective study of autopsies
of ECMO patients found a mean of 45 u of packed
red blood cells (PRBCs) per patient, massive transfusion of nonred cell blood products and reexploration rates in the range of 40% to 80% in adult
postcardiotomy patients.23 Caring for patients on

ECMO entails the ability to manage both types of
vastly different hemorrhagic conditions.
In general, the approach to transfusion in ECMO
patients includes assessment and maintenance of
coagulation mechanisms that may prevent or reduce
catastrophic bleeding and its complications.44,58 Some
of the key factors that may contribute to hemorrhage
and merit examination for management of ECMO
are clotting factor and platelet production, endothelial injury, consumption, fibrinolysis, systemic illness,
and multisystem organ dysfunction. Full correction
of coagulation abnormalities may be unwarranted
depending on the risk of thrombosis and the amount
ongoing hemorrhage. Unfortunately, the partial
degree of anticoagulation maintained during ECMO
causes consumption of clotting factors and platelet
activation that will necessitate repeated transfusions
until separation from the EC.
Optimal transfusion management during ECMO
requires an array of scheduled tests that repeatedly
assess hemostatic capability such as platelet count
(PC) AT, prothrombin time (PT), APTT, and TEG,
and hemoglobin requirements. Additional tests that
influence transfusion decisions include liver function
tests, inflammatory markers, and measures of cell
disruption.
Profound reduction in coagulation components
of neonates and infants occur with initiation of
ECMO compared with adults (Table 2).58 Table 2
illustrates the low coagulation concentrations produced from priming the EC with PRBC and albumin.
These levels persist over the next 24 hours despite
transfusion of blood products to correct the deficiencies. Factors V, VII, and VIII start to recover the fastest after initiation of ECMO. Factor V concentration
is lower than predicted based on hemodilution during the initiation of ECMO58 similar to neonates on
CPB.62 In contrast, McManus et al61 found that the
addition of 20% of the prime with FFP attenuated
some of the major factor deficiencies associated
with ECMO but not all. An FFP prime is especially
important if excessive bleeding is ongoing prior to
initiation of ECMO. With excessive bleeding, falls in
coagulation levels will likely exceed those in Table 3
with initiation of ECMO. Although it has been recommended to reach normal coagulation status at
least once during the early period of ECMO,58 optimal factor levels to maintain during the entire duration of ECMO are indeterminate but depend strongly
on the amount of bleeding.
Table 2. Median and Range at 4 Time Periods for Each of 6 Clotting Factors and ATIII (rel, Relative to Normal
Adult Plasma Levels of 100%) and for Fibrinogen and Platelets (Normal Those Described for a Healthy 1-Day-Old
Term Neonate With Values Encompassing 95% of the Population)

Prior to ECMO
Immediately
on ECMO
6 h
24 h
Normal
Median
Range
Median
Range
Median
Range
Median
Range
Mean
95% Range
ATIII (rel)
Fibrinogen (g/L)
Factor II (rel)
Factor V (rel)
Factor VII (rel)
Factor VIII (rel)
Factor IX (rel)
Factor X (rel)
Platelets (109/L)
ACT (s)a
PT (s)b
APPT (s)c
30*
1.85*
22*
28*
39.5*
82.5
30*
30.5
141*
125*
24*
54*
18-85
1.05-4
7-71
10-74
13-82
43-176
12-109
7-112
26-291
87-175
14-45
31-250
19*
0.5*
14*
8*
16*
24.5*
16.5*
14.5*
39*
999*
43*
250*
3-49
0.1-1.8
3-39
3-30
10-38
9-78
10-51
4-48
16-105
284-999
21-170
210-250
28*
1.45*
24.5*
20*
30.5*
39.5*
26.5
29
94*
216*
27*
250*
17-46
1.05-2.9
12-46
9-32
12-49
23-76
12-62
16-55
52-148
128-331
20-40
170-250
33.5*
2.3
29*
32*
42.5*
68.5
30.5
31
126*
214*
21*
250*
15-51
1.2-3
16-64
17-52
16-70
39-174
18-137
13-63
106-137
196-263
17-37
224-250
63
2.83
48
72
66
100
53
40
>150
80-120
13
43
39-87
2.167-3.99
26-70
34-108
28-104
50-178
15-91
12-68
10-16
31-55
NOTES: ECMO, extracorporeal membrane oxygenation; ACT, activated clotting time; PT, prothrombin time; APTT, activated partial thromboplastin.
*Significant number of values outside the normal range (P < .05).
a
Population data for platelets or ACT is not adequate to make this comparison.
b
PT values greater than 170 recorded at 170.
c
APTT values greater than 250 recorded at 250.
Source: Reprinted with permission from Arnold P, Jackson S, Wallis J, Smith J, Bolton D, Haynes S. Coagulation factor activity during
neonatal extra-corporeal membrane oxygenation. Intensive Care Med. 2001;27:1395-1400, table 2. Copyright 2001 Springer.
Table 3. Kaolin-Activated Thrombelastograph Reference Valuesa

R (min)
K (min)
()
MA (mm)
LY30 (%)
<1 yr
n = 24
13M/11F
7.7
1.8
66.5
67.2
3.8
(4.5-11.6)
(1.2-2.3)
(58.8-73.4)
(60.7-73.2)
(0.3-8.4)
1-5 yr
n = 24
12M/12F
8.3
2.0
63.6
65.2
3.0
(5.7-10.9)
(1.4-3.3)
(53.8-70.3)
(57.6-71.3)
(0.2-7.8)
6-10 yr
n = 26
12M/14F
7.8
2.0
63.9
65.0
3.3
(5.3-11.0)
(1.4-2.8)
(54.3-70.7)
(57.3-72.8)
(0.2-6.2)
11-16 yr
n = 26
13M/13F
6.9
1.9
65.1
66.5
3.7
(3.8-11.1)
(1.2-2.9)
(54.9-73.2)
(56.8-74.4)
(0.5-8.0)
Adults
n = 25
12M/13F
7.5
2.0
64.3
63.0
4.3
(5.3-9.3)
(1.4-3.5)
(48.8-72.2)
(55.3-69.3)
(0.8-8.6)
NOTES: M, males; F, females; R, reaction time; K, coagulation time; , measure of the rate of clot formation; MA, maximum amplitude; LY30, percentage lysis 30 min post-MA.
a
Results are expressed as the mean and boundary encompassing 95% of the population.
Source: Reprinted with permission from Chan K-L, Summerhayes RG, Ignjatovic V, Horton SB, Monagle PT. Reference values for
kaolin-activated thromboelastography in healthy children. Anesth Analg. 2007;105:1610-1613, table 1. Copyright 2007 International
Anesthesia Research Society, Lippincott Williams & Wilkins.
It is generally necessary to administer platelet

and clotting factor products to obtain the hemostasis needed to remain on ECMO. For bleeding in
pediatric63,64 and adult56 patients after separation
from CPB, routine coagulation tests (RCTs) have
been beneficial to appropriately treat bleeding and
are recommended for ECMO management. The PC
is readily measured with other RCT.
To determine clotting factor needs, specific factor levels are not clinically available during ECMO;
however, the PT may arguably be the best test.58 PT
assesses the extrinsic and common pathway integrity by measuring clotting of recalcified plasma in
the presence of tissue thromboplastin.47 PTs sensitivity for clotting factor deficiencies depends on the
choice of thromboplastin. The fibrinogen level is
also important with its role to reinforce the platelet

plug but often requires time to obtain the result.
POC fibrinogen levels have yet to provide the accuracy to substitute for the laboratory-derived fibrinogen levels. Because the APTT is affected by both
heparin and hemodilution, it is the least useful of
the RCTs to determine clotting factor levels and so
guide transfusion.
The TEG complements the use of RCT in the
management of transfusion during ECMO because it
examines not only the initiation but also the strength
of clotting. It is valuable because it simultaneously
examines three critical parts of the coagulation system, platelet function, clotting factors, and fibrinolysis. This is possible because the TEG is conducted
in whole blood, not plasma. The endpoint for the
plasma-based RCTs is the start of fibrin strand formation, but the TEG runs until clot formation and
dissolution occur.
The TEG has greatly expanded its capabilities
as a POC coagulation test with previously described
changes. The activated TEG has enabled clinicians
to make more rapid decisions about transfusion
resulting in more timely administration of blood
products. Although TEG studies have been conducted with three activators, kaolin, celite, and TF,
kaolin is the only commercially available activator.
The kTEG produces a result 20 to 30 minutes sooner
than the 1 hour necessary for a native TEG. TF
added to the TEG can produce clot in 6.5 minutes.65
It is very important to realize that the normal
ranges of the native TEG are changed with activators
but the patterns remain similar. Typically, the r and
K values are most affected and shorten significantly
with activation compared with the native TEG. Clot
strength is increased so the maximum amplitude
(MA) and angle are appreciably bigger. However,
each activator may change the normal range of
the native TEG slightly different from one another.
Miller et al65 looked at neonates and infants undergoing CPB with the celite- and TF-activated TEG to
identify any correlation between a faster TEG with
activators and RCT. These activators shortened time
to clotting but did not change the MA and angle
much. It is important to recognize the differences
in the TEG ranges with activation, but a working
knowledge of the native TEG values and patterns45
is just as important to manage transfusion during
ECMO. Many times TEG pattern recognition of the
traces will aid in determination of fibrinolysis or platelet dysfunction before values are known.
Age also affects the normal range of both native

and activated TEG values. In individuals younger
than 12 months of age, all the normal ranges for the
TEG differ from adult values.13 In fact, differences
exist between birth and 12 months. Miller et al66
reported differences in the normal ranges during
these ages <30 days, 1 to 3 months, 3 to 6 months,
6 to 12 months, and 1 to 2 years in a study of pediatric patients undergoing cardiac surgery. Recently,
the reference values of the kTEG were reported in
100 healthy children from 1 month to 16 years and
25 adults (Table 3).67 Even with studies that report
TEG values, each hospital may have slightly different normal ranges for the TEG. It is important to
verify the normal ranges with the hospitals reference laboratory to published values to insure accurate
interpretation of the TEG.65,66
In 1994, Tuman et al68 used the hTEG to provide
a fully formed tracing during CPB and demonstrated
the impact of heparin on not only the r but also the
K, MA, and angle of the TEG. Heparinase cannot
completely restore the TEG to its original form if large
systemic doses of heparin are present.68 The lower
systemic amounts of heparin favor the use of the
hTEG in management of transfusion during ECMO.
Another benefit of the TEG for ECMO management relates to its sensitivity to detect fibrinolysis
compared with RCT. The RCT, such as d-dimer
levels are not specific for fibrinolysis during EC, but
its detection is very important because excessive
bleeding has been highly correlated with it in cardiac patients with CPB.65 More compelling was the
difference in the incidence of fibrinolysis in pediatric and adult patients of 14% and 1%, respectively,
with the hTEG.
Transfusion requirements associated with ECMO
may be very high.3,23 Improvements in perioperative
transfusion management of both adults and children
undergoing cardiac surgery with CPB have resulted
in less bleeding and lower transfusions with utilization of algorithm-based transfusion practice.56,65,69
Unfortunately, there is no evidence for algorithmbased transfusion during ECMO in part because
anticoagulation is maintained instead of reversed
and potential subjects are few compared with cardiac
surgery and CPB. The following recommendations
for transfusion with ECMO will be a compilation of
opinion, anecdotal information and generalization
from experience with CPB.
Platelet transfusion represents a major part of
management of ECMO patients. The effect of EC
on platelet function and number has been well

documented.32,62,70-73 Severe thrombocytopenia consistently occurs with the onset of ECMO especially
in neonates and infants but often increases after 24
hours on ECMO.58 Moreover, many patients are
placed on ECMO after cardiac surgery so that platelet function and number are poor prior to ECMO. If
bleeding is excessive on ECMO, platelet transfusion
is largely based on PC. The degree of thrombocytopenia that triggers platelet transfusion varies
among institutions and physicians. The more critically ill the patient, the more likely platelets have
been given. In our institution, the PC is maintained
in a range of 45 to 65 109/L in concert with minimal
to mild bleeding. The PC is important as reported by
Muntean,21 who found a significant relationship
between PC and bleeding complications on ECMO
especially in neonates.
Following CPB, platelets are no longer exposed
to the effects of surface activation and heparin activation so that indications to guide platelet transfusions have developed.56 In contrast with ECMO,
platelets are constantly exposed to activation from
the EC and heparin resulting in recurrent platelet
dysfunction. This is expressed during ECMO by frequent platelet transfusions even with normal PC.74
Although PC may largely direct platelet transfusion,
determination of platelet function may be beneficial.
The measurement of platelet function during CPB
and ECMO is imperfect because the gold standard
of platelet function, a platelet aggregation study, is
not clinically available. Consequently, the TEG has
been incorporated as a POC measure of platelet
function. It has been recognized by The Society of
Thoracic Surgeons and Society of Cardiovascular
Anesthesiologists as an important test to obtain in
post-CPB patients prior to platelet transfusion to
improve care.75
The value of TEG for transfusion of platelets is
its ability to measure the integrity of platelet activity
and number and the beginning of the fibrinplatelet
interactions. The TEG angle also measures the rate
of clot formation that reflects platelet and fibrinogen
interaction. Finally, the MA of the TEG represents
the summation of fibrinogen and platelets interacting with factors XIII and VIII.13
To evaluate platelet function during ECMO,
both the kTEG and hTEG are run simultaneously in
a scheduled fashion throughout its duration. A fully
formed kTEG will be generated in contrast to CPB
with higher heparin dosing. The hTEG will generate
a TEG unaffected by heparin. Depending on the MAs,

angles and current PC and PT values, differences
between the values are attributed to some degree of
platelet dysfunction. Differences between tracing
with respect to clotting factors is more difficult to
discern, so a PT is used to estimate the role of factor
deficiency.56 We would refrain from transfusion of
platelets with a PC of 45 to 65 109/L if the angle
of the hTEG was >25 or MA of the hTEG >40 mm.
The combination of TEG, PC, and PT may minimize
platelet transfusions based on PC alone and therefore extend the life of the oxygenator.
Transfusion of clotting factors is more frequently
based on PT and fibrinogen levels than the TEG.
Although the level of factors to achieve clotting in
general has been acknowledged to be 25% to 30%, it
may not apply during ECMO. We use the international normalized ratio (INR) to guide the transfusion of clotting factors attempting to maintain it
at 1.3. Although FFP contains most of the clotting factors, it is not concentrated in any of them.
This is nicely demonstrated by the finding of significantly greater bleeding after CPB with FFP than
cryoprecipitate in infants randomize to FFP or cryoprecipitate for excessive bleeding.63 The inability of
FFP to raise factor levels during ECMO without
large volumes was similarly demonstrated.21 However,
if bleeding is minimal, FFP may play a role during
ECMO as it provides enough volume to maintain
adequate flow with the EC and maintain good osmolality to minimize edema. However, it should not be
used as volume replacement if the coagulation tests
are normal.
Fibrinogen, although one of the clotting factors,
is discussed separately because it is intimately connected to clot formation with platelets and so is very
critical to clot formations. Its importance compared
with other clotting factors was nicely demonstrated
in an animal model where 65% of the blood volume
was replaced with a gelatin solution.76 Normalization
of the RoTEG values, representing the integrity of
the coagulation, was achieved rapidly with 50% less
bleeding by the addition of fibrinogen alone despite
the reduced levels of other factors.
Laboratory determination of fibrinogen is important for management of transfusion during ECMO.
Levels of fibrinogen < 50 mg/dL commonly occur in
neonates and infants during CPB62 and ECMO.58
Muntean21 has recommended maintaining a
fibrinogen level of 100 mg/dL during ECMO. A
higher concentration may be needed depending on
prior cardiac surgery or refractory bleeding. These

low fibrinogen levels may carry even greater significance in those younger than 12 months of age because
there is a functional immaturity compared with
adults.77 This is supported by the significantly
reduced bleeding after CPB in infants that received
cryoprecipitate instead of FFP.63 The donated cryoprecipitate contained mature fibrinogen to replace
the immature fibrinogen of infants.
Apart from the laboratory fibrinogen test, the
TEG is useful test to determine fibrinogen requirements. A prolonged r with the kTEG cannot distinguish between low fibrinogen and heparin, but a
prolonged r with hTEG is consistent with low fibrinogen. Recently, TEG abnormalities in infants following CPB have shown a tendency to correlate better
with fibrinogen level than PC.77 Soon, availability
of the RoTEG, may greatly improve the ability to
separate out effects on the TEG tracing between
low fibrinogen and platelets with a special technique
unique to the RoTEG.69
It is important to be cognizant with transfusion
of blood products during ECMO, administration of
cryoprecipitate with platelet concentrates may greatly
increase the risk of thrombus and thromboembolic
complications so should be given separately at different times.
If bleeding during ECMO is refractory to administration of blood products, other forms of therapy
may be cautiously considered. Fibrinolysis is a known
risk factor for excessive bleeding. Antifibrinolytics
have been used successfully following CPB with the
onset of fibrinolysis and excessive bleeding to significantly reduce bleeding compared with control.78
There are not studies that evaluate antifibrinolytic
treatment for new onset of fibrinolysis during
ECMO. It is essential that one use the TEG for
diagnosis, as RCTs are not specific. The initiation of
an antifibrinolytic during ECMO is risky and has
resulted in massive thrombosis and death.79
Prothrombin complex concentrates have not only
been effective with excessive bleeding in cardiac
surgery but have also resulted in fatal thrombosis
during ECMO.80 We do not recommend prothrombin complex concentrates even if the levels of vitamin K factors are low. Finally, recombinant activated
factor VII (rVIIa) (Novoseven; NovoNordisk,
Copenhagen, Denmark) has recently been used off
label to control refractory bleeding following cardiac
surgery.81 Although the mechanism of action is indeterminate, it appears to enhance hemostasis at the
site of injury without activating systemic coagulation. It may bind to TF on cells at the site of injury
that then stimulate thrombin generation at the
bleeding sites. Recombinant activated factor VII can
initiate thrombin generation without TF on the surface of platelets, which also arrive at sites of injury.
The efficacy of rVIIa for intractable bleeding during CPB has been mixed.81-83 Agarwal et al81 studied
46 neonates and infants, who had cardiac surgery
and severe bleeding, over a period of 5 years. A total
of 96% of the patients responded with significantly reduced mediastinal chest tube drainage and
transfusion requirements. Chest tube drainage was
reduced by 60% after rVIIa and the PT fell from
19.9 1.6 to 13.5 1.9 seconds (P < .001) and
PRBCs were significantly reduced. Others have found
no reduction in transfusion or reduced time to close
the chest.82 The administration of rVII during ECMO
has been successful in anecdotal and case series to
control refractory bleeding.84,85
Dosing of rVIIa for cardiac surgery has been
established at 90 g/kg whereas for ECMO it is 50
to 60 g/kg, in part to reduce the risk of widespread
thrombosis.81 Unlike CPB patients, 70% of pediatric and ECMO patients were treated successfully
with one dose. The overall dosing was almost half of
the conventional dosing especially lower doses were
given in the ECMO patients. The authors suggested
30 to 50 g/kg for each dose every 2 to 4 hours to
control serious refractory bleeding.
The concern for massive clotting with the use of
rVIIa and ECMO is great as the risk of thrombosis
is high for ECMO even without administration of
rVIIa. The occurrence of fatal thrombosis with rVIIa
during ECMO is well described.86 However, in a
recent retrospective study looking specifically at congenital heart surgical patients that required ECMO,83
rVIIa was well tolerated and significantly affected
persistent hemorrhage without evidence of thrombosis. Another retrospective unmatched case control
study with 46 neonates and infants over a period of
5 years that had cardiac surgery with severe bleeding
reported 10% of the patients developed serious
thrombosis compared with controls.81 One can postulate that the availability of TF and platelets during
ECMO may be very high and continue to rise such
that there may be a high circulating level of TF
beyond the TF primarily located on the ECMO surface. Therefore, with the administration of rVIIa,
both the intravascular space and the surface of circuit clot instantaneously.
The risk of thrombosis with rVIIa during ECMO

must be evaluated in the context of other procoagulant factors. The risk may greatly increase if other
procoagulant treatments are combined with it such
as antifibrinolytics or prothrombin complex concentrates.80 If rVIIa is given during ECMO, the circuit
before and after administration must be examined to
detect any new clots that may predispose to a more
serious thrombosis. High pressures in the circuit
after rVIIa should immediately cause alert for major
clotting in the oxygenator. Recently, there is evidence
that the RoTEG may be used to monitor rVIIa in
these situations providing some ability to monitor the
situation before it becomes life threatening.40
Finally, the transfusion or PRBC is a complicated topic that requires a definition for the critical
hemoglobin. The critical hemoglobin for transfusion of PRBC during ECMO is influenced by the
level of bleeding, congenital heart disease, myocardial function, preoperative hemoglobin, ECMO flow,
neurologic status, and a host of other factors. The
management of PRBC transfusion is beyond the scope
of this article but is an important part of transfusion
management.
Future of ECMO
Management of anticoagulation and transfusion
for ECMO continues to evolve but very slowly.
Randomized trials and studies to find the best practice are unlikely for the reasons given earlier. New
technology is being used increasingly but again studies to confirm efficacy are difficult. Unfortunately,
treatment for bleeding is easier to diagnose and treat
compared with thromboembolic events. Improved
methods to recognize the level of thrombin formation at the bedside would improve the care of these
patients and possibly prevent neurologic injury. ECMO
is a major commitment of resources to a patient complicated by a number of problems that require a
multidisciplinary team approach to achieve the best
outcomes.
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Seminars in Cardiothoracic and Vascular

Anticoagulation and Coagulation Management for ECMO

Anticoagulation and Coagulation

clinical knowledge to provide the best care. Increased

systems of an opportunity to rest and improve. The

Anticoagulation and Coagulation Management for ECMO / Oliver 155

procoagulant and anticoagulant activity. Its proper

Figure 2. GAG with AT inhibit excess thrombin.

dense granules. These granules contain compounds

Figure 3. Coagulation cascade consisting of the extrinsic,

thrombin generation, it is the TF:VIIa complex that

Anticoagulation and Coagulation Management for ECMO / Oliver 157

Day 180 (n)

difficult to reliably estimate the clotting capability of

thrombin is counterbalanced by an excessive fibrinolytic response mediated by plasmin. The result is

Figure 4. Cellular and plasmatic systems involved in the

Figure 5. Pathophysiology of hemostatic abnormalities with

6).20 Activated platelets are far more attracted to the

Anticoagulation and Coagulation Management for ECMO / Oliver 159

be appreciated but future findings may hold some

endothelium to express TF, but it also causes a

Monitoring for Anticoagulation

actively rises and falls in whole blood until the rate

Figure 8. Activated clotting time (ACT) versus heparin levels

indicated adequate anticoagulation. Subsequently,

Anticoagulation and Coagulation Management for ECMO / Oliver 161

Figure 9. A, Correlation of the kaolin activated clotting time

values supporting inadequate anticoagulation.29,33-35

but besides a better correlation of the ACT with

CPB compared with the ACT.33,34 Codispoti and

Anticoagulation and Coagulation Management for ECMO / Oliver 163

Figure 11. A, Heparin concentration (in international units

clotting so that only a flat line occurs. This makes it

Figure 12. Quantification of native thromboelastogram (TEG)

even with a heparin infusion (Figure 13). Because the

Figure 13. Thromboelastogram with heparinase and native

The TEG is not only useful for determining

Activated Partial Thromboplastin Time

Anticoagulation and Coagulation Management for ECMO / Oliver 165

Figure 15. ACT at different levels of heparin anticoagulation.

over a heparin range of 0.1 to 1.0 u/mL. When the

Anticoagulation for ECMO is based on the need

Traditionally, heparin dosing ranges between 20

Anticoagulation and Coagulation Management for ECMO / Oliver 167

thrombin is not the goal of ECMO anticoagulation, it

Transfusion and ECMO

postcardiotomy patients.23 Caring for patients on

Table 3. Kaolin-Activated Thrombelastograph Reference Valuesa

It is generally necessary to administer platelet

Anticoagulation and Coagulation Management for ECMO / Oliver 169

also important with its role to reinforce the platelet

Age also affects the normal range of both native

on platelet function and number has been well

a TEG unaffected by heparin. Depending on the MAs,

Anticoagulation and Coagulation Management for ECMO / Oliver 171

prior cardiac surgery or refractory bleeding. These

The risk of thrombosis with rVIIa during ECMO

3. Green TP, Payne NR, Steinhorn RH. Determinants of

Anticoagulation and Coagulation Management for ECMO / Oliver 173

cardiopulmonary bypass is overestimated by current monitoring techniques. Arch Surg. 2000;135:1042-1047.

63. Miller BE, Mochizuki T, Levy JH, et al. Predicting and

Anticoagulation and Coagulation Management for ECMO / Oliver 175