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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.
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
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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).
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156 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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
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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)
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).
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
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158 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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
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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.
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160 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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.
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162 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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
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164 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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
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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
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
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166 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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168 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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.
<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.
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
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170 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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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.
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172 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009
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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