Effect of Heparin Loading During Congenital Heart
Operation on Thrombin Generation and Blood Loss
Sophronia O. Turner-Gomes, MB, ChB, Evan P. Nitschmann, BSc,
Geoffrey R. Norman, PhD, Maureen E. Andrew, MD, and William G. Williams, MD
Departments of Pediatrics and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, and University of Toronto,
Toronto, Ontario, Canada
Background. The heparin protocols used during cardio-
pulmonary bypass (CPB) in children undergoing surgical
repair for congenital heart disease are extrapolated from
adult data. Studies are needed that assess the optimal
heparin dosing in these children, whose heparin clear-
ance is increased compared with that in adults.
Methods. We assessed the effects of two commonly
used doses of heparin in the prime solution at the start of
CPB operation on plasma heparin levels, on thrombin
production (thrombin–antithrombin III complexes, pro-
thrombin fragment 1 1 2, D-dimer, and antithrombin
III), and on the risk of hemorrhage. Before CPB, 48
children with congenital heart disease received heparin
intravenously in a loading dose of 300 U/kg, followed by
either 1 U/mL of heparin in the prime (low-dose group:
22 patients—acyanotic, 9; cyanotic, 13) or 3 U/mL of
heparin in the prime (group: high-dose, 26 patients—
acyanotic, 15; cyanotic, 11).
Results. In all patients, CPB resulted in the generation
of thrombin. The duration of CPB was a significant
covariate factor for heparin levels (p 5 0.002), thrombin
production (p < 0.001), and postoperative blood loss (p <
C hildren with congenital heart disease (CHD) are at
increased risk for thromboembolism or hemor-
rhage after surgical repair involving cardiopulmonary
bypass (CPB) [1– 4]. Heparin is the mainstay of manage-
ment during CPB operation, as an important anticoagu-
lant and antithrombotic agent. Heparin protocols used in
children undergoing CPB operations are extrapolated
from adult data. However, we have observed that hepa-
rin clearance in children with CHD is increased com-
pared with that in adults [5]. At our institution, CHD
patients are given heparin in a loading dose of 300 U/kg,
with 1 U/mL given in the prime solution at the start of
CPB. Additional heparin is then given to keep the acti-
vated clotting time (ACT), measured using a Hemochron,
above 400 seconds. Other institutions use similar loading
doses of heparin, but they use higher doses (ie, 2–3
U/mL) in the prime solution (personal communications).
We have found in our patients that thrombin is gener-
Accepted for publication Sep 14, 1996.
Address reprint requests to Dr Turner-Gomes, Department of Pediatrics,
McMaster University Medical Centre, 1200 Main St W, Hamilton, ON,
Canada L8N 3Z5.
© 1997 by The Society of Thoracic Surgeons
Published by Elsevier Science Inc
0.001). In the patients in the high-dose group, the total
heparin dose and the plasma heparin levels were higher
(p 5 0.0005 and 0.005, respectively) and the D-dimer
levels tended to be lower (p 5 0.06). The postoperative
blood loss was higher in the cyanotic patients (p 5 0.02;
both high-dose and low-dose groups), with 2 cyanotic
patients (1 in low-dose group, 1 in high-dose group)
requiring reoperation, one of whom subsequently died.
The increased heparin dose had no significant effect on
the rate or volume of postoperative blood loss.
Conclusions. Increasing the heparin dose in the prime
solution from 1 to 3 U/mL increased the plasma heparin
levels and showed a trend toward reducing the postop-
erative laboratory values indicative of fibrinolysis.
Thrombin generation during CPB and the incidence of
postoperative hemorrhage were not significantly altered.
Larger randomized trials are needed to determine the
optimal heparin-dosing regimen in patients with congen-
ital heart disease.
(Ann Thorac Surg 1997;63:482– 8)
© 1997 by The Society of Thoracic Surgeons
ated during CPB [6]. Thrombin is a key enzyme in
hemostasis, because it cleaves fibrinogen so that a fibrin
clot can form. Thrombin further induces its own produc-
tion by means of the prothrombinase complex [7]. Hep-
arin acts as a catalyst in the inhibition of thrombin and
factor Xa by antithrombin III (ATIII) [8, 9]. We therefore
hypothesized on the basis of this information that higher
loading doses of heparin in the prime solution might
increase the initial amount of thrombin that would be
inhibited at the start of CPB. This would then decrease
the risk of further thrombin generation during CPB with-
out increasing the risk of hemorrhage.
Patients and Methods
Using a protocol approved in April 1992 by the Human
Subjects Committee at the Hospital for Sick Children,
Toronto, Ontario, we obtained informed consent from
parents of all patients before their inclusion in the study.
Children under 1 year of age were excluded. Forty-eight
consecutive patients with acyanotic or cyanotic CHD,
aged 1.1 to 15.7 years (median, 3.6 years; mean, 5 years),
were enrolled in the study. However, because of reser-
0003-4975/97/$17.00
PII S0003-4975(96)01215-5
Ann Thorac Surg
1997;63:482– 8
Table 1. Demographic Dataa
Low-Dose High-Dose
Heparin Heparin
Type of Defect n Age (y) n Age (y)
Acyanotic
Atrial septal defect 7 9.5 6 1.9 11 6.0 6 1.1
Ventricular septal defect 2 5.2 6 3.9 4 4.6 6 2.5
Total 9 7.8 6 2.5 15 6.0 6 1.8
Cyanotic
Tetralogy of Fallot 9 3.1 6 0.7 6 2.3 6 0.5
Univentricular heart 4 2.3 6 0.2 5 5.3 6 2.0
Total 13 3.5 6 0.8 11 3.3 6 0.6
a
Values are reported as mean 6 standard error of the mean. The
acyanotic children with congenital heart disease were older than the
cyanotic children (p , 0.05).
vations on the part of the attending physicians regarding
the potential for an increased risk of bleeding, we first
conducted a pilot study that involved 15 patients (10
low-dose heparin, 5 high-dose heparin). No major epi-
sodes of bleeding were observed during this initial phase
and we therefore continued the study, incorporating the
patients from the pilot study into the formal study.
Subsequent recruitment to the high-dose arm of the
study was attempted in all patients. In the event that a
child’s parents refused his or her admittance into the
high-dose arm (n 5 4), a request was then made to
include the patient as a control patient. At the end of the
study, 8 more patients were recruited as controls. In all,
22 patients were recruited as controls and 26 as high-dose
patients. The children’s diagnoses and demographic data
are summarized in Table 1. Cardiopulmonary bypass was
performed using a hollow-fiber membrane oxygenator
(Dideco 0.8 –3.5, Mirandola, Italy). The extracorporeal
circuit was primed with Ringer’s lactate, 5% albumin in
normal saline solution, mannitol, and heparin in a dose
of either 1 U/mL (22 patients: acyanotic, 9; cyanotic, 13) or
3 U/mL (26 patients: acyanotic, 15; cyanotic, 11). After the
induction of anesthesia, a loading dose of heparin (300
U/kg) was administered. Additional heparin was given to
maintain the ACT (Hemochron; International Techni-
dyne Corp., Edison, NJ) above 400 seconds. After CPB,
the effect of heparin was reversed with protamine in a
1.2:1 concentration. In accordance with our current prac-
tice, at the end of the surgical procedure, the tendency to
hemorrhage was assessed by the surgeon and additional
fresh frozen plasma and cryoprecipitate given if exces-
sive small-vessel bleeding was detected. Once the ster-
notomy was closed, mediastinal blood drainage was
recorded hourly throughout the patient’s stay in the
intensive care unit.
Collection of Samples
After the induction of anesthesia, preoperative blood
samples were drawn from freshly inserted arterial lines.
Blood samples were also obtained at five subsequent
time points: immediately after heparin loading, 5 min-
TURNER-GOMES ET AL 483
EFFECT OF HEPARIN LOADING ON THROMBIN FORMATION
utes after the start of CPB, at the end of hypothermia,
after heparin reversal with protamine, and 2 hours after
the patient’s return from the operating room. The sam-
ples were collected into 3.8% trisodium citrate and cen-
trifuged at 1,200 g at 4°C for 15 minutes. The supernatant
was then removed and centrifuged again. Multiple ali-
quots of plasma were frozen at 270°C until assayed.
Hemodilution During Cardiopulmonary Bypass
To assess the degree to which plasma proteins were
diluted by CPB, immunoglobulin G (IgG) levels were
assessed in all samples by rate nephelometry (Kallestad
Diagnostics, Chaskan, MN). As an additional measure of
hemodilution, hematocrit values were measured in the
preoperative and postoperative samples.
Thrombin Generation In Vivo
Thrombin–antithrombin III (TAT) complexes and levels
of prothrombin fragment 1 1 2 were assayed using Behring
enzyme-linked immunosorbent assay kits (Hoechst, Mon-
treal, Que, Canada) [10, 11]. D-dimer levels were assayed
using the enzyme-linked immunosorbent assay kit man-
ufactured by Diagnostica Stago (Wellmark Diagnostics,
Guelph, Ont, Canada) [12].
Additional Assays
The ATIII levels were measured functionally using a
chromogenic substrate [13]. Heparin levels were ana-
lyzed using the antifactor Xa assay of Teien and associ-
ates [14].
Statistical Analysis
Analyses of variance and covariance with repeated mea-
sures were used to analyze the data. The design included
two between-subject factors— cyanotic versus acyanotic
and high-dose heparin versus low-dose heparin—and a
within-subject factor—repeated factor of time. The fac-
tors of group and dose were adjusted for perioperative
differences in the IgG levels and the perioperative levels
of each assay. To correct for the effect of dilution, the
preoperative IgG level was used as the second covariate.
This analysis of covariance approach allowed for differ-
ences among patients before the administration of hep-
arin to be adjusted. The data for the TAT and D-dimer
assays were logged before analysis. Individual variations
in analysis are discussed in the results section. A p value
of less than 0.05 was considered significant.
Results
Patient Population
The ages and diagnoses in the patients receiving high-
dose and low-dose heparin were similar within the
acyanotic and cyanotic group of patients with CHD (see
Table 1). However, the acyanotic children were older
than the cyanotic children, which was a reflection of our
current surgical practice (p , 0.05). The median total time
on CPB was 45 minutes (14 –129 minutes) for the acya-
notic group and 132 minutes (95–264 minutes) for the
cyanotic group. There was no appreciable difference
484 TURNER-GOMES ET AL Ann Thorac Surg
EFFECT OF HEPARIN LOADING ON THROMBIN FORMATION 1997;63:482– 8

Fig 1. Mediastinal blood loss up to 24 hours after operation was

significantly less in the acyanotic than in the cyanotic children with
congenital heart disease (p , 0.05) but was not significantly differ- Fig 2. Plasma immunoglobulin G (IgG) values over time. Cardio-
ent between the high-dose and low-dose groups. Cardiopulmonary pulmonary bypass resulted in hemodilution of 41% to 51% in all
bypass (CPB) duration was a significant covariate factor for blood groups. There was no significant difference in the degree of hemodi-
loss up to 24 hours after operation (p , 0.001). lution in the groups. (CPB 5 cardiopulmonary bypass; hypoth 5 at
end of hypothermia; NS 5 not significant; post CPB 5 after start
of CPB; post-hep 5 after heparin loading; post-op 5 2 hours after
operation; post-prot 5 after protamine administration; Pre-op 5
between the total time on CPB between the high-dose post anesthesia.)
and low-dose patients (Fig 1). The total dose of heparin
received by the high-dose patients (median, 525 U/kg;
range, 399 – 656 U/kg) was higher than that received by modilution to changes in the plasma concentrations of
the low-dose patients (median, 403 U/kg; range, 325– 636 coagulation factors, the preoperative IgG values were
U/kg) (p 5 0.0005). No macroscopic thrombi were noted used as a second covariate for analysis of the coagulation
in the circuits during the CPB operation. All patients variables.
(except 2 acyanotic, 1 in the high-dose group) received
blood products in the first 2 hours as replacement for Coagulation Assays
mediastinal losses. There was no statistical difference heparin levels. The heparin concentrations in plasma
between the low-dose and high-dose groups in the determined by the antifactor Xa assay increased in all
volume of albumin or other blood products received patients after heparin loading (Fig 3). Increasing the
during the first 2 postoperative hours. Two patients with heparin dose in the prime solution raised the plasma
cyanotic CHD (patient 26 [high dose] and patient 44 [low
dose]) required further surgical exploration for excessive
small-vessel bleeding at 12 and 2 hours, respectively,
after operation. Patient 26 subsequently died as the result
of a low-output state at 20 hours after operation. The rate
and volume of blood loss over the first 24 hours after
operation were not significantly different between the
high-dose and low-dose groups but was significantly less
in the acyanotic than in the cyanotic children (p 5 0.02)
(see Fig 1). The duration of CPB was a significant covari-
ate factor for blood loss up to 24 hours after operation
(p , 0.001). The statistical interaction of time versus
group (p 5 0.003) indicated that the differences in blood
loss between the acyanotic and cyanotic groups were due
only in part to CPB duration.

Hemodilution During Cardiopulmonary Bypass

Plasma concentrations of IgG decreased from preopera-
tive values of 6.4 6 0.5 g/L to postoperative values of
3.3 6 0.2 g/L in the acyanotic patients and from 5.1 6 0.4
g/L preoperatively to 2.1 6 0.1 g/L postoperatively in the
cyanotic patients (Fig 2). On the basis of these measure-
ments, the degree of hemodilution occurring during CPB
was 41% to 51%. To determine the contribution of he-
Fig 3. Heparin levels over time at the same time points as those in
Figure 1. Increased heparin in the prime solution raised plasma hep-
arin levels above 3 U/mL after the start of cardiopulmonary bypass
(p 5 0.005). This concentration was better maintained throughout
operation in the acyanotic groups than in the cyanotic groups (p ,
0.001). (See Figure 2 for key to abbreviations.)
Ann Thorac Surg TURNER-GOMES ET AL 485
1997;63:482– 8 EFFECT OF HEPARIN LOADING ON THROMBIN FORMATION

Table 2. Preoperative Coagulation Dataa

Thrombin–
Antithrombin Prothrombin
No. of III Complex Fragment 1 D-Dimer Antithrombin III
Variable Patients (mg/L) 1 2 (nmol/L) (ng/L) (U/mL) Hematocrit

Pediatric range ,4 0.98 6 0.44 ,500 0.8 –1.0 0.33– 0.48

Acyanotic low dose 9 8.3 6 4.2 0.9 6 0.07 312.0 6 61.0 1.1 6 0.04 0.39 6 0.01
Acyanotic high dose 15 4.9 6 1.6 1.1 6 0.13 222.7 6 38.8 1.0 6 0.05 0.38 6 0.01
Cyanotic low dose 13 8.5 6 3.2 0.9 6 0.09 373.3 6 65.1 1.1 6 0.04 0.47 6 0.01
Cyanotic high dose 11 6.4 6 3.2 0.8 6 0.10 267.5 6 51.7 1.0 6 0.07 0.46 6 0.02
a
Values reported as mean 6 standard error of the mean.

heparin levels above 3 U/mL after the start of CPB (p 5 in the high-dose heparin groups than in the low-dose
0.005). This concentration was better maintained groups, but this difference did not reach statistical signif-
throughout operation in the acyanotic groups than in the icance (p 5 0.1).
cyanotic groups (p , 0.001). The duration of CPB was a
statistically significant covariate factor for heparin levels association with patient morbidity. The data in those
over time (p 5 0.002). When age was used as the second patients who had excessive bleeding (n 5 2) were com-
covariate in analysis of covariance designs for heparin pared with the data in the patients without bleeding (n 5
levels, it was not found to have a statistically significant 46) (Table 3). Patient 26, aged 3.6 years, had a univen-
effect. However, this may be explained by the fact that no tricular connection and was a candidate for a Fontan
infants (ie, ,1 year of age) were included in the study and operation. He received high-dose heparin in the prime
the age ranges were 1.1 to 15.7 years (mean, 5.2 years) in solution. There was no significant difference in any of his
the low-dose group and 1.1 to 13.9 years (mean, 4.8 years) preoperative variables from those in other patients. The
in the high-dose group. Heparin was not detectable in duration of CPB was 120 minutes (the mean CPB dura-
any of the samples taken 2 hours after return of the tion for cyanotic patients with CHD in the high-dose
patient to the intensive care unit from the operating group was 134.7 minutes). At 12 hours after operation, his
room. Heparin levels were not found to be a statistically total mediastinal loss was 61 mL/kg (the mean total
significant covariate factor for blood loss during the first mediastinal loss at 12 hours for cyanotic CHD patients
24 hours after operation. who did not undergo reoperation for bleeding was 20.1 6
2.8 mL/kg [p , 0.001]). At reoperation, extensive oozing
thrombin generation. Preoperatively, plasma concen-
trations of TAT, prothrombin fragment 1 1 2, D-dimer,
and ATIII in CHD patients were within the normal range
for children (Table 2). During operation, plasma concen-
trations of D-dimer, prothrombin fragment 1 1 2, and
TAT increased significantly, and this could not be ac-
counted for by hemodilution (p , 0.01) (Figs 4, 5). The
duration of CPB was a statistically significant covariate
factor for the increases in the concentrations of TAT,
prothrombin fragment 1 1 2, and D-dimer (p , 0.001)
and in the decrease in the concentration of ATIII (p 5
0.03) occurring during CPB. When the effect of CPB
duration on the coagulation variables was removed, there
was no statistically significant difference in the TAT
levels between the acyanotic and cyanotic patients. How-
ever, the increase in the prothrombin fragment 1 1 2 and
D-dimer values and the expected decrease in the ATIII
values were less in the acyanotic group than in the
cyanotic group (p , 0.01, D-dimer and ATIII; p , 0.05,
prothrombin fragment 1 1 2). Increasing the dose of
standard heparin in the prime solution resulted in a Fig 4. Thrombin–antithrombin III (TAT) values are plotted logarith-
mically. Time points are the same as those in Figure 1. Levels were
trend toward lower D-dimer levels at the end of hypo-
lower in acyanotic than in cyanotic patients with congenital heart
thermia (p 5 0.06) (see Fig 5). However, the TAT and disease (p , 0.01), but this difference could be accounted for by the
prothrombin fragment 1 1 2 values during operation and difference in duration of cardiopulmonary bypass between the two
the D-dimer values at the end of operation did not differ groups. Increased heparin in the prime solution did not result in sta-
significantly between the high-dose and low-dose groups tistically significant differences in the thrombin–antithrombin III
(see Figs 4, 5). The ATIII levels also fell to a lesser degree levels (p 5 0.2). (See Figure 2 for key to abbreviations.)
486 TURNER-GOMES ET AL
EFFECT OF HEPARIN LOADING ON THROMBIN FORMATION
Fig 5. D-dimer values are plotted logarithmically. Time points are
the same as those in Figure 1. D-dimer levels increased to a lesser
degree in acyanotic than in the cyanotic patients with congenital
heart disease (p , 0.01), but the difference could not be accounted
for by the difference in duration of cardiopulmonary bypass between
the two groups. There was a trend toward lower D-dimer values in
the high-dose heparin than in the low-dose heparin group (p 5
0.06). (See Figure 2 for key to abbreviations.)
from suture sites as well as bleeding from a large medi-
astinal vessel were observed. The latter was occluded, the
thoracic cavity was emptied of large thrombi, and blood
loss was replaced with packed red blood cells, platelets
and fresh frozen plasma. Despite these measures, he died
at 20 hours of a low-output state. Patient 44, aged 2.2
years, has tetralogy of Fallot and was included in the
low-dose heparin group. There were no significant dif-
ferences in his preoperative coagulation variables or in
the duration of CPB (136 minutes; mean CPB duration in
the cyanotic CHD patients in the low-dose group, 162
minutes) from that of the other cyanotic patients. He was
returned to the operating room 2 hours after operation
because of excessive bleeding. His total mediastinal
blood loss at that time was 71 mL/kg (the 2-hour mean
total blood loss in cyanotic CHD patients without reop-
eration for bleeding was 8.9 6 1.9 mL/kg [p , 0.001]). At
reoperation, extensive oozing from suture sites and the
sternotomy incision was noted. No large-vessel bleeding
Table 3. Cardiopulmonary Bypass and Blood Lossa
Cardiopulmonary
No. of Bypass
Group Patients Duration (min)
Acyanotic, low dose 9 45.2 6 20 (median, 27)
Acyanotic, high dose 15 51.7 6 11 (median, 46)
Cyanotic, low dose 13 162 6 20 (median, 146)
Cyanotic, high dose 11 134.7 6 7 (median, 112)
a
Mediastinal blood loss up to 24 hours after operation was significantly less in the acyanotic than in the cyanotic children with congenital heart disease
(p , 0.05) but was not significantly different between the high-dose and low-dose groups. The duration of cardiopulmonary bypass was a significant
covariate for blood loss up to 24 hours after operation (p , 0.001).
Ann Thorac Surg
1997;63:482– 8
was identified. The hematoma was evacuated and medi-
astinal losses replaced with 5% albumin. His subsequent
course was unremarkable.
Comment
This study assessed the effect of two doses of heparin in
the CPB prime solution on plasma heparin levels, on
indices of thrombin generation, and on the risk of hem-
orrhage. In our analyses of the data, we used the preop-
erative IgG level as a covariate factor. By doing so, we
corrected for the influence of confounding factors, such
as preoperative polycythemia and the degree of hemodi-
lution during CPB. We identified that increasing the
heparin concentration in the prime solution resulted in
an increase in plasma heparin levels and tended to
decrease the D-dimer levels during CPB operation. The
increase in the plasma heparin levels was greater in the
acyanotic patients than in the cyanotic patients. How-
ever, increasing the heparin dose in the prime solution
did not significantly affect the rate or the volume of
mediastinal blood loss up to 24 hours after operation. The
duration of CPB was a significant covariate factor for
postoperative blood loss.
In adults undergoing cardiac procedures using CPB,
heparin levels of 2.5 to 4 U/mL in the prime solution are
considered adequate for producing antithrombotic ef-
fects [15, 16], with anticoagulation monitored during CPB
using the ACT. In our pediatric patients, however, a
heparin concentration of 3 U/mL in the prime solution
did not guarantee maintenance of the plasma heparin
levels at that concentration throughout operation, de-
spite ACT values above 400 seconds. Because ACT values
vary with therapeutic manipulations such as hemodilu-
tion and hypothermia, they are a suboptimal tool to
assess the effects of heparin during CPB [15, 16].
Heparin catalyzes the inhibition of thrombin by ATIII
and thus prevents continued thrombin production [8, 9].
Therefore, increasing the heparin dose in the prime
solution at the start of CPB and maintaining the level of
heparin above 3 U/mL would protect against further
thrombin production, because this would increase the
amount of thrombin inhibited by ATIII. A reduction in
the amount of thrombin generated would result in a
reduction in D-dimer and TAT levels and in the amount
of ATIII utilized to complex thrombin. We identified a
trend toward lower D-dimer and higher ATIII values
2-Hour Blood Loss 24-Hour Blood Loss
(mL/kg) (mL/kg)
2.5 6 0.6 17.2 6 5.2
4.5 6 0.8 17.5 6 2.2
12.9 6 5.2 28.9 6 2.7
11.8 6 3.6 38.5 6 7.8
Ann Thorac Surg
1997;63:482– 8
during operation, but the differences between the high-
dose and low-dose heparin groups did not reach statis-
tical significance. This failure to reach statistical signifi-
cance might be due to a type II error, as our numbers of
patients are small. Sample size calculation was also
difficult, because the study was complex and there were
many clinically interrelated variables. Selecting TAT,
D-dimer, and ATIII as dependent variables of interest
and, calculating as if for a t test, we concluded that our
numbers would only have detected an effect size of 1. We
would need to triple our numbers to conclusively prevent
a type II error (power, 0.8). We also did not expect
differences in the coagulation profiles between the high-
dose and low-dose heparin groups after operation, be-
cause, once heparin has been neutralized, the small
amounts of thrombin that might be present would induce
further thrombin production by means of the prothrom-
binase complex [7]. This would continue until thrombin
and clot lysis had been inhibited spontaneously [7–9].
The increased heparin loading did not affect the rate
and volume of blood loss up to 24 hours after operation.
Two patients experienced major postoperative bleeding,
but as found in a previous study [6], there was no
appreciable difference in the preoperative variables be-
tween those patients with bleeding leading to reopera-
tion and those who did not require reoperation for
bleeding. The postoperative bleeding in these 2 patients
could be due to the relatively decreased capacity to
generate thrombin after CPB operation, as opposed to
the better preserved capacity to inhibit thrombin produc-
tion described by us previously [6].
Significant differences in the responses to increased
heparin levels in the prime solution were observed
between the acyanotic and cyanotic groups. The acya-
notic groups had higher heparin levels, and these were
associated with lower TAT and D-dimer values and
higher ATIII levels. We have identified that heparin
clearance is faster in the younger cyanotic child [5]. The
patients in the cyanotic group were younger than those in
the acyanotic group as the result of differences in the
diagnoses and in the ages at which the appropriate
surgical procedures were performed. Data analysis did
not identify age as a statistically significant covariate
factor for the changes in heparin levels. However, this
may have been due to the fact that the number of young
children in this study was small (7 #2 years of age). Data
analysis also identified that the presence of cyanotic
CHD was a significant covariate factor for heparin levels
over time. The presence of cyanosis might therefore help
explain the differences that are seen in the heparin levels
between the acyanotic and cyanotic groups.
The duration of CPB was a significant covariate factor
for thrombin generation and postoperative blood loss.
This is not surprising, because it is contact activation by
the extracorporeal membrane that starts the coagulation
process [17–19], followed by the further induction of
thrombin production by means of the prothrombinase
complex [7]. The difference in the CPB duration between
the acyanotic and cyanotic groups is due to the different
complexities of the surgical procedures performed and
TURNER-GOMES ET AL 487
EFFECT OF HEPARIN LOADING ON THROMBIN FORMATION
may explain the differences seen in thrombin generation
and blood loss between the two groups.
In summary, during CPB operations in pediatric CHD
patients, the use of 3 U/mL of heparin in the prime
solution was found to lead to an increase in the plasma
heparin levels without either an increase in the risk of
hemorrhage or a decrease in the postoperative blood
loss, as compared with the findings in patients receiving
1 U/mL in the prime solution. There was also a trend
toward less generation of thrombin and less fibrinolysis
during CPB. Further, younger cyanotic CHD patients
have lower plasma heparin levels during CPB operation
and are most at risk for subsequent thromboembolic or
hemorrhagic complications. Although the ACT is of
value in maintaining anticoagulation, recently developed
high-dose heparin bedside assays may also be of value
[20]. The heparin dosing during CPB in pediatric patients
with CHD needs to be individualized, but increasing the
heparin dose in the prime solution from 1 to 3 U/mL
contributes to a reduction in the indices of subclinical
consumptive coagulopathy without any change in mor-
bidity. A larger randomized trial would be invaluable in
determining the optimal regimen of heparinization dur-
ing CPB in pediatric patients with CHD.
We gratefully acknowledge the assistance of Ms Mary Lou
Schmuck, BA, Research Assistant, McMaster University, in the
analysis of the data from this study. The assistance of the
technologists at McMaster University Medical Centre is also
greatly appreciated.
Supported by grant XG91-003 from the Hospital for Sick Chil-
dren Foundation.
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