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Ann Thorac Surg 2002;73:1770-1777
© 2002 The Society of Thoracic Surgeons
a Department of Anesthesia, Children’s Hospital, Boston and Harvard Medical School, Boston, Massachusetts, USA
b Department of Cardiac Surgery, Children’s Hospital, Boston and Harvard Medical School, Boston, Massachusetts, USA
c Department of Biostatistics, Children’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA
Accepted for publication March 1, 2002.
* Address reprint requests to Dr Odegard, Cardiac Anesthesia Service, 300 Longwood Ave, Children’s Hospital, Boston, MA 02115, USA
e-mail: kirsten.odegard{at}tch.harvard.edu
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Abstract |
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Methods. Coagulation factors were assayed in 38 children (mean age 34.4 ± 15 months) immediately before the Fontan operation; 37 healthy children (mean age 33 ± 17 months) were assayed as controls. Concentration of factors II, V, VII, VIII, IX, and X and of antithrombin III, plasminogen, proteins C and S, fibrinogen, serum albumin, and liver enzymes were measured. Normal reference intervals based on the control patients were determined using 95% confidence limits. Patient demographic data, hemodynamic variables, and elapsed time after the Glenn procedure were evaluated as possible predictors of coagulation abnormalities.
Results. Concentrations of protein C; factors II, V, VII, and X; plasminogen; and antithrombin III were significantly lower before the Fontan operation compared with age-matched controls (p < 0.01); no specific hemodynamic variables were predictive of a pro- or anticoagulant deficiency. There were significant positive correlations between patients who had abnormally low factor VII, protein S, and protein C levels and a longer interval between the bidirectional Glenn procedure and the Fontan operation (p < 0.001).
Conclusions. Coagulation abnormalities that could predispose patients to increased risk for clotting or bleeding are evident early in the course of staged single-ventricle repair.
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Introduction |
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Thromboembolic events, in particular, may occur in the immediate postoperative period or some years later in patients with Fontan circulation. Both arterial and venous thromboses have been described. The frequency of thromboembolic events in patients with Fontan physiology is unknown, but it has been reported in three studies to be as high as 20% to 33% [3–5]. Coagulation abnormalities involving both pro- and anticoagulant factors have been described in patients with Fontan physiology [6–9]. Aspects of Fontan physiology that may contribute to abnormal hemostatic variables and increased thrombosis risk include increased venous pressure, stasis of flow through the right atrial baffle and pulmonary circulation, atrial dysrhythmias, hepatic dysfunction, and increased resting venous tone.
The bidirectional Glenn procedure (BDG) is an important interim staging operation before the Fontan operation for patients with single-ventricle defects. One benefit is that the volume load on the systemic ventricle is reduced, because the only source of pulmonary blood flow is through the superior vena cava to pulmonary artery anastomosis. Following the BDG procedure, adequate pulmonary blood flow is dependent on an elevated superior vena cava pressure. However, in contrast to the Fontan operation, inferior vena cava and hepatic venous pressures are low because venous return from these sites is to the lower-pressure common atrium. If factors other than the nature of the Fontan circulation and hepatic congestion contribute to coagulation abnormalities in patients with single-ventricle disease, coagulation abnormalities may also be evident in patients with BDG physiology before the Fontan operation.
In this single-center, prospective, cohort study, we measured pro- and anticoagulant factor levels in children with single-ventricle physiology who had undergone an earlier BDG procedure and who were presenting for the Fontan operation. Because coagulation factor concentrations and activities mature at varying rates, children of similar age without congenital heart disease were used as age-matched controls [10–13].
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Material and methods |
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Blood samples (8 mL) from all patients were obtained from a central venous catheter or an indwelling arterial catheter at two time points: immediately after induction of general anesthesia and 24 hours postoperatively in the intensive care unit. Measured variables included hemoglobin, hematocrit, platelet count, prothrombin time (PT), and activated partial prothrombin time (APTT). The circulating anticoagulant factors measured were protein C, protein S, plasminogen, and antithrombin III; the procoagulant factors measured were II, V, VII, VIII, IX, X, and fibrinogen.
The Coulter T 660 (Beckman Coulter, Inc, Miami, FL) automated hematology analyzer was used to measure hemoglobin, hematocrit, and platelets. Coefficients of variation (%) within and between assays at levels 1, 2, and 3 were 1.8, 1.0, and 0.9 for hemoglobin; 1.8, 1.2, and 1.5 for hematocrit; and 4.8, 2.7, and 1.8 for platelets, respectively.
The ACL 3000 plus (Automated Coagulation Laboratory, Beckman Coulter) was used to assay individual pro- and anticoagulant factors as well as the PT and APTT. The ACL contains two measuring systems: (1) nephelometry, which is used to detect clot formation as the endpoint; and (2) photometry, which is used for chromogenic substrate assays. Blood for these assays was collected in citrated plasma (3.2% buffered sodium citrate) from an indwelling cannula from which 10 mL of blood had been aspirated to remove residual heparin. The blood was immediately centrifuged at 13,000 revolutions per minute for 5 minutes and the plasma layer removed. The PT, APTT, and fibrinogen were measured immediately using nephelometry (coefficients of variation [%] for PT were 1.2 and 2.3; for APTT were 2.1 and 4.8; and for fibrinogen were 3.1 and 5.5, respectively). Remaining plasma was stored at -70°C in 200-µL aliquots for batch performance of the other coagulation assays, as described later.
Activity for both proteins C and S was measured using functional clotting assays. Protein C activity was determined based on the prolongation of the APTT using the Staclot Protein C kit (Diagnostica Stago, Asnieres-Sur-Seine, France) according to the manufacturer’s directions. In this assay, activated protein C inhibits factor V and VIII activity, thus prolonging the APTT of a system in which all the factors except protein C are present in excess; protein C is derived from the sample being tested (coefficients of variation [%]: 1.8 and 2.4).
Protein S activity was determined based on the principle of factor Va inhibition using the Staclot Protein S kit (Diagnostica Stago). The principle of the test is based on the cofactor activity of protein S, which enhances the anticoagulant action of activated protein C. This enhancement is reflected by the prolongation of the clotting time of a system enriched with factor Va (coefficients of variation [%]: 7.9 and 3.8).
Extrinsic coagulation factors (factors II, V, VII, and X) were each determined by performing a modified PT assay. Intrinsic coagulation factors (factors VIII and IX) were determined by performing a modified activated partial thromboplastin time. In these assays, correction of the clotting time of plasma specifically deficient in the factor being tested is proportional to the concentration (activity %) of that factor in the patient plasma, interpolated from a calibration curve. (Factor-deficient plasma factors II, V, VII, VIII, IX, and X obtained from Instrument Laboratory, Lexington, MA; coefficients of variation [%] were 2.3 and 2.7 for factor II; 3.3 and 2.3 for factor V; 2.5 and 2.2 for factor VII; 4.9 and 3.7 for factor VIII; 3.2 and 3.1 for factor IX; and 3.0 and 2.0 for factor X.)
Antitrombin III activity was determined using a synthetic chromogenic substrate assay based on factor Xa inactivation. (antithrombin III, Instrument Laboratory; coefficients of variation [%]: 4.3 and 2.8). Plasma plasminogen was activated through reaction with an excess of streptokinase in the presence of fibrinogen. Plasminogen content was then determined based on a synthetic chromogenic substrate assay according to the manufacturer’s directions (plasminogen, Instrument Laboratory; coefficients of variation [%]: 4.5 and 3.7).
Because altered hepatic dysfunction can contribute to coagulation factor abnormalities, serum alkaline phosphatase, 
-glutamyl transferase, alanine transaminase, aspartate transaminase, total bilirubin, albumin, and total protein were measured in all patients and compared to normal values for our laboratory.
Age-matched control coagulation measurements
With written informed parental consent, 37 healthy children (17 girls, 20 boys; mean age 33 ± 17.4 months [range 12 to 84 months]) undergoing minor day surgery procedures were studied. Blood was taken from each patient after induction of anesthesia and placement of an intravenous catheter and was collected into citrated plasma tubes (3.2% buffered sodium citrate). Blood samples were immediately centrifuged at 13,000 revolutions per minute for 5 minutes and the plasma stored at -70°C for subsequent batch analyses. Proteins C and S; plasminogen; fibrinogen; antithrombin III; and factors II, V, VII, VIII, IX, and X were analyzed as described earlier. No blood samples were taken 24 hours postoperatively in the control group.
Potential hemodynamic factors
As part of the routine preoperative evaluation before the Fontan operation, all patients underwent elective echocardiography and cardiac catheterization. Ventricular morphology (morphologic right or left systemic ventricle), ventricular function, atrioventricular valve function, and semilunar valve function were assessed by preoperative echocardiography. Superior vena cava O2 saturation (SVO2), the ratio of pulmonary to systemic blood flow (QP/QS), common atrial pressure (CAP), superior vena cava pressure, pulmonary artery pressure, pulmonary vascular resistance, systemic ventricular end-diastolic pressure (EDP), and the presence of systemic ventricle outflow obstruction or aortic arch obstruction were assessed by preoperative cardiac catheterization. The length of time between the BDG and the Fontan operation was also examined as a potential variable contributing to coagulation abnormalities.
Statistical analysis
A power analysis indicated that a total sample of 72 patients (36 control and 36 Fontan patients) would provide 90% power to detect an effect size of 1.0 (mean difference/common standard deviation) with respect to each of the 11 coagulation factors and protein levels based on a two-sample Student’s t test and applying a Bonferroni-corrected alpha level of 0.005 (0.05/11). This sample size would also provide a statistical power exceeding 95% for comparisons between pre- and post-Fontan values based on paired t tests (version 4.0, nQuery Advisor, Statistical Solutions, Boston, MA). All 11 coagulation and protein variables were assessed for normality by the Kolmogorov-Smirnov goodness-of-fit test, and no significant departures were identified. Normal reference ranges were based on the empirical 95% confidence intervals and defined according to 2.5th and 97.5th percentiles [14]. Controls were compared to pre- and post-Fontan values using the two-sample Student’s t test. Changes between pre- and post-Fontan values were evaluated by paired t tests. Univariate and multiple stepwise logistic regression, using the likelihood ratio test to evaluate significance [15], were conducted to determine whether any patient, hemodynamic, or laboratory risk factors was predictive of a coagulation abnormality. Thirteen candidate variables considered in these analyses included sex, weight, prior procedure, ventricle morphology (left or right), EDP, SVO2, QP/QS ratio, CAP, pulmonary vascular resistance, ventricular function, atrioventricular valve regurgitation, serum albumin, and waiting time since BDG. Analysis of the data was performed using the SPSS (version 11.0, SPSS Inc, Chicago, IL) and SAS (version 6.12, SAS Institute, Cary, NC) software packages. Continuous variables are expressed in terms of the mean ± standard deviation. All reported p values are two-tailed.
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Results |
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The mean interval time between the BDG and the Fontan operation for our patients was 23 ± 11 months. To further evaluate the possible influence of a longer time interval between operations, patients were divided into two groups; group A (n = 25) underwent the Fontan within 24 months of the BDG, and group B (n = 13) waited longer than 24 months. A multivariate analysis was performed to determine if any variables (weight, hematocrit, albumin, diagnosis, right or left ventricle morphology, ventricular function, atrioventricular valve regurgitation, pulmonary vascular resistance, oxygen saturation, SVO2, QP/QS ratio, oxygen tension (PO2), superior vena cava pressure, CAP, pulmonary artery pressure, and EDP) could independently distinguish these groups. Considering each of these variables separately, differences between groups A and B were found in weight, EDP, and CAP. Group B patients weighed significantly more (14.5 ± 2.6 kg versus 11.5 ± kg, p < 0.01), had a higher EDP (9.9 ± 3.4 mm Hg versus 7.8 ± 2.8 mm Hg, p = 0.05), and higher CAP (8.4 ± 3.8 versus 5.6 ± 3.3 mm Hg, p = 0.03). There were no other significant differences between groups A and B with respect to the variables mentioned earlier (all p values > 0.20). Logistic regression led to the estimate that patients in group B had a risk of factor VII coagulation abnormality approximately 17 times higher than the risk for those who had a Fontan operation within 24 months of the BDG (odds ratio = 17.4, 95% CI = 4.0 to 76.5), a risk 4 times higher for protein C coagulation abnormality (odds ratio = 4.2, 95% CI = 1.5 to 15.0), and a risk 6 times higher for protein S coagulation abnormality (odds ratio = 6.0, 95% CI = 1.7 to 22.8). By means of logistic regression analysis, nonlinear equations were derived to estimate the probability of a protein S or protein C abnormality according to the waiting time interval between BDG and the Fontan operation (Figs 1 and 2).
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Transfusion requirements
According to institutional practice, the cardiopulmonary bypass circuit for all patients was primed with whole blood to achieve a hematocrit of approximately 30%. Patients received 2 mg/kg of heparin before aortic cannulation and an additional 2 mg/kg in the circuit prime. The initial activated clotting time on cardiopulmonary bypass was more than 500 seconds in all patients, despite a significantly lower antithrombin III level in the majority of the patients. Twenty-four patients received transfusions in the operating room with whole blood (mean volume 405 ± 218 mL), 23 with packed red blood cells (mean volume 266 ± 143 mL), 27 with platelets (mean volume 109 ± 65 mL), and 15 with cryoprecipitate (mean volume 58 ± 22 mL); no patient received fresh frozen plasma, and 1 patient did not receive any blood products in the operating room but received a transfusion postoperatively in the intensive care unit. An antifibrinolytic (tranexamic acid) was administered intraoperatively to 14 patients according to the surgeon’s preference.
The mean chest tube drainage at 24 hours in the intensive care unit was 447 ± 267 mL; 16 patients received transfusion with whole blood (mean volume 115 ± 104 mL) within 24 hours in the intensive care unit, 23 patients received packed red blood cells (mean volume 192 ± 137 mL), 7 patients received cryoprecipitate (mean volume 45 ± 29 mL), 13 patients received platelets (mean volume 132 ± 97 mL), and 8 patients received fresh frozen plasma (mean volume 134 ± 63 mL). There were no significant correlations detected between chest tube drainage volume and any of the coagulation variables pre- or post-Fontan (-0.25 < r < 0.25, all p values > 0.10).
Postoperative coagulation abnormalities
Coagulation factors were assayed in the intensive care unit 24 hours postoperatively. Levels of factors II, V, VII, and X; antithrombin III; plasminogen; protein C; and protein S were all significantly lower than in the age-matched controls; factor VIII was significantly higher (Table 6).
When pre- and post-Fontan levels were compared within the same patients, factors II, V, VII, and X; antithrombin III; plasminogen; protein C; and protein S were significant lower, and factor VIII was significantly higher than preoperative values (all p values < 0.001).
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No other patients demonstrated clinical evidence of thromboembolic events, and no intracardiac thrombus was detected by echocardiography performed routinely before discharge. The majority of the patients (34 of 38) were discharged on aspirin alone, and 4 patients were discharged on coumadin (2 patients who had undergone an extracardiac Fontan operation and 2 patients who developed a thromboembolic complication in the postoperative period).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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The cause of thromboembolic events after the Fontan operation seems to be multifactorial, and no consistent predisposing risk factors have been identified. Several authors have also described multiple coagulation factor abnormalities involving both pro- and anticoagulant proteins as a cause of a hypercoagulable state in children who have previously undergone the Fontan operation [6–9]. These studies have suggested that an imbalance between procoagulant and anticoagulant factors favors thrombus formation, and that one or more aspects of the Fontan physiology are responsible for the imbalance. However, these studies did not examine the full complement of coagulation factors, did not employ age-matched control subjects, and did not study patients earlier in their course of single-ventricle physiology to evaluate if there might be preexisting coagulation factor abnormalities before completing the cavopulmonary connection.
Use of age-matched controls is essential because the hemostatic system matures over the first several years of life [12, 13], leading to important differences in factor and activity measurements between children and adults. In general, values of most pro- and anticoagulant factors are lowest in neonates and infants and increase toward adult values at varying rates. One study of 246 children aged 1 year to 16 years demonstrated that the mean values of seven procoagulants were significantly lower than adult values, with levels increasing with age. Values for three circulating inhibitors also differed from adults, with protein C in particular being significantly lower compared with adult values [12]. Despite these observed differences, there is no evidence that infants are at greater risk for hemorrhagic or thrombotic problems compared with adults, suggesting that the neonatal and infant system is in "functional balance" at lower concentrations of most factors.
Despite the significant reduction in both pro- and anticoagulant factor levels in our patients, no hemodynamic or laboratory predictors of thromboembolic or hemorrhagic complications or of prolonged chest tube drainage could be identified. Whether the coagulation factor abnormalities (compared to age-matched controls) we measured in our patients are attributable to delayed maturation secondary to cyanosis, low cardiac output, or possibly a genetic predisposition is speculative. It is also unknown whether children with congenital heart disease per se have pro- and anticoagulant abnormalities. To answer this question we would need to compare coagulation factors in healthy age-matched controls with children who have two-ventricle congenital cardiac defects (both cyanotic and acyanotic).
A recent study by Ravn and colleagues [16] reported lower concentrations of coagulation factors II, VII, VIII, and X and of anticoagulants protein C, protein S, and antithrombin III in 24 patients who had undergone a cavopulmonary operation (14 Fontan, 10 BDG). Our data confirm their findings in the BDG patients. However, there are important differences. They reported only 10 BDG patients, and although they did not specify the age range for the BDG patients, the age range reported for all their patients (median 11 years, range 4 to 22 years) was considerably older than that of our patients. Therefore, their BDG patients had possibly been exposed to a longer period of cyanosis, and prior surgical procedures were not specified. Ravn and colleagues [16] evaluated a small number of hemodynamic variables (superior vena cava pressure, inferior vena cava pressure, pulmonary artery and aortic saturation) and were unable to demonstrate any significant correlation between these variables and factor abnormalities. We also were unable to correlate specific hemodynamic variables from echocardiography and cardiac catheter studies with coagulation factor abnormalities.
The likelihood of abnormalities in protein C and protein S levels with increasing time interval between the BDG and Fontan operation is a new finding. We were unable to determine specific reasons for delayed surgery in some of our patients. Although the CAP and EDP were significantly elevated in patients who waited longer between surgeries, no other anatomic, hemodynamic, or laboratory factors were different between the two groups. The reason why a longer period with Glenn physiology increases the likelihood of coagulation abnormalities is unknown. Nevertheless, earlier rather than delayed completion of the Fontan circulation may be advantageous.
Interpretation of coagulation factor abnormalities 24 hours after cardiac surgery is problematic because of changes in the plasma concentration of coagulation proteins from hemodilution during cardiopulmonary bypass, consumption coagulopathy, the acute phase response, use of antifibrinolytic agents, and transfusion of blood products. In particular, immediate postoperative increases in the concentrations of fibrinogen and factor VIII as reported here are difficult to interpret because they are well-described acute phase reactants [17, 18]. A high plasma level of factor VIII is associated with an increased risk for venous thrombosis [19]. Whether changes in these two variables represent an acute phase reaction or reflect the development of a hypercoagulable state [9] cannot be determined.
In contrast to previous studies that suggested that pro- and anticoagulant factor abnormalities are the result of the Fontan operation and physiology, our current study indicates that abnormalities that could predispose to a risk for clotting or bleeding are present earlier in the course of staged single-ventricle repair. Other than a longer time interval between the BDG and Fontan operations, we could not demonstrate specific hemodynamic or hepatic variables that correlated with coagulation abnormalities. Further, in a separate cohort of infants with single-ventricle physiology we have recently reported that lower levels of specific coagulation factors are present before the BDG procedure [20]. Taken together, these data suggest that numerous abnormalities in circulating coagulation factors are present at various stages of single-ventricle operations and may not be related specifically to Fontan physiology. Furthermore, it is not at all clear that these changes have a significant influence on the propensity to develop thrombosis (or hemorrhage). To more fully assess these issues, a prospective, longitudinal evaluation of changes in coagulation throughout the surgical stages in a cohort of patients with the same diagnosis (hypoplastic left heart syndrome) is currently under way.
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