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PEDIATRIC ANESTHESIA

Clinical Measures of Heparin’s Effect and Thrombin Inhibitor Levels in Pediatric Patients with Congenital Heart Disease

Nina A. Guzzetta, MD^*, Bruce E. Miller, MD^*, Kathy Todd, RN, BA, CCRC, Fania Szlam, MMSc^*, Renee H. Moore, MS, Keith K. Brosius, MD^*, Elizabeth C. Wilson, MD^*, Anna M. Cohen, MD^*, and Steven R. Tosone, MD^*

From the *Department of Anesthesiology, Emory University School of Medicine; Cardiac Research Department, Children’s Healthcare of Atlanta at Egleston; and Department of Biostatistics, Emory University, Atlanta, Georgia.

Address correspondence and reprint requests to Nina A. Guzzetta, MD, Department of Anesthesiology, Children’s Healthcare of Atlanta at Egleston, 1405 Clifton Road, N.E., Atlanta, GA 30322. Address e-mail to nina_guzzetta{at}emoryhealthcare.org.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
In this investigation, we examined the relationship among three thrombin inhibitors, antithrombin III (ATIII), heparin cofactor II (HCII), and -2-macroglobulin (2M), and several clinical tests of heparin’s effect in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass. One hundred eighteen children were stratified into six age groups: <1 mo, 1–3 mo, 3–6 mo, 6–12 mo, 12–24 mo, and >10 yr. Baseline ATIII, HCII, and 2M values were measured. Baseline celite- and kaolin-activated clotting times (ACT) were also measured and repeated 3 min after a standard heparin dose of 400 U/kg. Differences in ACT values before and after heparin administration and a heparin dose–response relationship were calculated for each patient. Kaolin-activated ACT tests showed less variation after heparin administration than celite-activated tests. In contrast to what has been demonstrated in adults, ATIII showed no positive correlation with the clinical tests of heparin’s effect nor did the other thrombin inhibitors. Additionally, patients <1 mo old had unexpectedly low levels of 2M accompanying their expected low levels of ATIII and HCII. Our findings raise concerns about the ability of heparin to adequately anticoagulate these neonates during cardiopulmonary bypass and, consequently, challenge the accuracy of ACT prolongation to truly reflect the extent of their anticoagulation.

	Introduction

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
The coagulation system of infants begins its development during gestation and continues to evolve into the adult state in the postnatal period. There are distinct differences between the coagulation system of infants during the first 6 mo of life and that of adults, including quantitative and qualitative differences in most procoagulants and inhibitors, differences in the ability to generate thrombin, and differences in the ability to inhibit thrombin once it is formed (1). These differences are often further exaggerated in infants with altered physiologies, including those with congenital heart disease (CHD).

The differences in thrombin generation and inhibition are particularly relevant for pediatric patients undergoing cardiac surgery. The use of cardiopulmonary bypass (CPB) requires heparin administration to prevent clot formation within the extracorporeal circuit, and normal antithrombin III (ATIII) concentrations are required to effectively catalyze this antithrombotic action of heparin. Several studies in adult cardiac surgical patients confirm the correlation between the level of ATIII activity and the degree of the anticoagulant response to heparin administration before the institution of CPB (2,3). Indeed, in adult patients with subnormal ATIII activity, supplementation with ATIII concentrate results in the enhancement of heparin’s effect (4).

In neonates and infants, ATIII levels do not reach adult values until 3–6 mo of age (1,5,6). There is concern therefore regarding the ability to adequately anticoagulate ATIII-deficient pediatric patients who require CPB to correct a congenital heart defect. In fact, recent evidence suggests that the physiologically low ATIII levels in children may reduce the efficacy of heparin in neutralizing thrombin generation during CPB (7,8). Although ATIII is the main protease inhibitor of thrombin in adult plasma, other thrombin inhibitors, heparin-cofactor II (HCII) and -2-macroglobulin (2M), do exist but play lesser roles. However, in the ATIII-deficient plasma of neonates and infants, the relative contributions of HCII and 2M to thrombin inhibition may be quite different than that seen in adults. During the neonatal period and infancy of healthy children, -2-macroglobulin (2M) concentrations are twice as high as those of ATIII (1,9) and may be the inhibitor most quantitatively available to provide for the neutralization of thrombin. In this investigation, we examined the effects of heparin administration for CPB on conventional coagulation tests available in the operating room in several age-stratified groups of children undergoing cardiac surgery. We also explored differences in thrombin inhibitor levels and the relationship between these levels and the measured heparin responses among the different age groups.

	METHODS

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After obtaining IRB approval and written, informed parental consent, 118 children scheduled for elective cardiac surgical procedures requiring the use of CPB were enrolled in this prospective, observational study. Patients receiving preoperative anticoagulant therapy were excluded. Patients were stratified into six age groups: <1 mo, 1–3 mo, 3–6 mo, 6–12 mo, 12–24 mo, and >10 yr. Blood samples were drawn from an indwelling arterial line catheter after aspirating 5 mL of blood to insure that no heparin from the flush solutions was present in the collection sample. Baseline celite- and kaolin-activated clotting times (ACTs) (Hemochron Response, International Technidyne Corporation, Edison, NJ) were measured. Blood was also obtained to measure baseline ATIII (Coamatic Antithrombin, DiaPharma Group, West Chester, OH), HCII (Actichrome® Heparin Cofactor II, American Diagnostica, Greenwich, CT) and 2M (BN* II System, Dade Behring, Deerfield, IL) levels. Blood samples were placed into the appropriate prechilled tubes and centrifuged for 20 min. The resultant plasma was pipetted into cryovials (Sybron, Rochester, NY) for storage at –70°C until assayed within batches. A standard dose of porcine heparin, 400 U/kg, was administered in preparation for CPB. Three minutes after heparin administration, celite- and kaolin-ACTs were repeated. To measure heparin’s effectiveness, changes in the celite- and kaolin-ACT values resulting from heparin administration and a heparin dose–response relationship (HDRR), as described by Lemmer and Despotis (4), were calculated for each patient.

The HDRR was determined by dividing the change in ACT values before and after heparin administration by an estimate of the whole-blood heparin concentration. The HDRR-celite (HDRR-c) and the HDRR-kaolin (HDRR-k) were calculated using the changes in celite- and kaolin-ACT, respectively. As per Lemmer and Despotis (4), estimates of the whole-blood heparin concentration were obtained by dividing the total heparin dose in units by the patient’s blood volume in milliliters. Calculations of circulating blood volume were based upon the following averages: 85 mL/kg for patients <1 mo, 80 mL/kg for patients 1–12 mo, 75 mL/kg for patients 12–24 mo, and 70 mL/kg for the patients >10 yr (10–12).

For each age group, using the SAS GLM procedure, a means model was used to determine estimates of the means and standard deviations of baseline platelet counts, fibrinogen, and thrombin inhibitor levels and the results of the tests of heparin effect. The means model was then used to look for pairwise differences between the means of each variable among the different age groups. A Bonferroni adjustment was used for the 15 pairwise age comparisons making a P value <0.003 significant. Testing for overall linear association between age and thrombin inhibitor levels was conducted by Pearson correlation analyses. Likewise, Pearson correlation analyses were performed within each age group to determine linear association between thrombin inhibitor levels and heparin responses. Multivariable regression analyses were performed for HDRR-c and HDRR-k.

	RESULTS

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
A total of 118 patients presenting for elective cardiac surgery requiring CPB were enrolled in this study. Fifty-two percent of patients were female, and 48% were male. Patients were stratified into six age groups: <1 mo (n = 20), 1–3 mo (n = 19), 3–6 mo (n = 20), 6–12 mo (n = 19), 12–24 mo (n = 20), and >10 yr (n = 20). The cardiac defects in the children of each age group are delineated in Table 1. Distribution of preoperative platelet counts and fibrinogen levels for each age group are shown in Table 2.

The mean differences in celite- and kaolin-ACT values before and after heparin administration were compared among the age groups, as were the mean differences in the calculated HDRR-c and HDRR-k values (Table 3). When examining the mean change in celite-ACT, there were statistical differences between <1-mo-old and 1–3-mo-old patients as well as between 1–3-mo-old and 6–12-mo-old patients. With respect to the mean change in the kaolin-ACT, no statistical differences were noted among the different age groups. Comparisons of the mean HDRR-c among the different age groups showed statistical differences between patients <1 mo and patients in the 1–3 mo, 12–24 mo, and >10 yr age groups (Fig. 1A). There were no statistical differences among the mean HDRR-k values in the different age groups (Fig. 1B).

View larger version (15K): [in this window] [in a new window]   Figure 1. Mean HDRR-c (Panel A) and mean HDRR-k (Panel B) values versus age. Values are expressed as mean ± sd. * P <0.003 vs 1–3 mo, 12–24 mo, and >10 yr.

In children <24 mo of age, we found significant correlations between age and thrombin inhibitor levels (P 0.01). We then compared levels of the different thrombin inhibitors (ATIII, HCII and 2M) among the various age groups (Fig. 2 and Table 4). Mean ATIII levels in patients <1 mo were significantly less than mean ATIII levels in all other groups. Mean HCII levels also trended lower in the neonatal group and showed a statistical difference when compared with patients of age 12–24 mo. Mean 2M levels in patients aged <1 mo were significantly less than levels in all other age groups except for the >10 yr group. Although the 2M levels in the children aged >10 yr trended lower than those in all children except the neonates, we found that these differences reached statistical significance only when compared with patients in the 1–3 mo (P < 0.003) and 6–12 mo (P < 0.003) age groups.

View larger version (15K): [in this window] [in a new window]   Figure 2. Thrombin inhibitor values versus age. Panel A: antithrombin III (ATIII), Panel B: heparin-cofactor II (HCII), Panel C: -2-macroglobulin (Á2M). Values are expressed as mean ± sd. * P < 0.003 vs. all other groups; P <0.003 vs. 12–24 mo; # P < 0.003 vs. 1–3 mo, 3–6 mo, 6–12 mo, and 12–24 mo.

To compare pediatric and representative adult values, we calculated the amount of each thrombin inhibitor present in the different age groups as a percentage of that in the >10 yr group (Table 4). In neonates, mean ATIII levels were 78.9%, mean HCII levels were 73.9%, and mean 2M levels were 85.5% of the levels observed in the children >10 yr old. Mean 2M levels in the other pediatric groups were far more than 100% of the >10 yr group.

We sought potential correlations between the thrombin inhibitors and the different heparin responses in each age group. In patients <1 mo, a significant negative correlation was found between 2M levels and all the measured heparin responses: change in celite-ACT (r = –0.47, P = 0.04), change in kaolin-ACT (r = –0.48, P = 0.03), HDRR-c (r = –0.45, P = 0.04; Fig. 3A) and HDRR-k (r = –0.47, P = 0.04; Fig. 3B). The only other significant correlations were in the 3–6 mo group between 2M levels and the change in kaolin-ACT (r = –0.45, P = 0.05) and the HDRR-k (r = –0.45, P = 0.05). No significant correlations were found between ATIII or HCII and the tests of heparin’s effect in any age group.

View larger version (16K): [in this window] [in a new window]   Figure 3. (A) Correlation between -2-macroglobulin (2M) and the heparin dose–response relationship with celite activation (HDRR-c); r = –0.45; P = 0.04. (B) Correlation between -2-macroglobulin (2M) and the heparin dose–response relationship with kaolin activation (HDRR-k); r = –0.47; P = 0.04.

Multivariable stepwise regression analysis revealed that significant factors in predicting HDRR-c include age, preoperative platelet count, and HCII levels (HDRR-c = 326 – 0.32 * age – 60 * HCII – 0.19 * platelet; P < 0.0001). Age, preoperative platelet count and preoperative fibrinogen levels were significant in predicting HDRR-k (HDRR-k = 388 – 0.27 * age – 0.40 * fibrinogen – 0.20 * platelet; P < 0.0001).

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
The purpose of this study was three-fold: to investigate the changes in tests of heparin’s effect after its administration before the institution of CPB to children of various age groups, to compare the levels of three thrombin inhibitors among these age groups, and to analyze the relationships between each thrombin inhibitor and the tests of heparin’s effect in each age group. After heparin administration, responses to kaolin-activated coagulation tests showed less variation among the different age groups than the responses seen with celite activation. Measured ATIII, HCII and 2M levels correlated with age, and were lowest in the neonatal group in comparison with the older children. Furthermore, 2M levels were found to be lower in our neonates with CHD than levels reported in the literature for otherwise healthy neonates (1,13). No significant positive correlations were found between any of the thrombin inhibitors and the measured heparin responses in any age group. In patients <1 mo old, however, 2M showed a consistent inverse correlation with all of the tests of heparin’s effect.

The hemostatic system of a newborn is dynamic and well-balanced, yet it is distinctly different from that of an adult. Previous studies have shown that levels of certain thrombin inhibitors, namely ATIII and HCII, are lower at birth than those in adults, whereas levels of other inhibitors such as 2M are elevated well above adult values (1,13). Investigators have suggested that in neonatal plasma the increased levels of 2M compensate to some extent for the decreased levels of ATIII (8,14,15). Ling et al. (16) demonstrated that 2M may inhibit up to 49% of generated thrombin in ATIII-deficient neonatal cord plasma. Similar studies comparing the relative importance of 2M and ATIII on the inhibition of radio-labeled thrombin confirmed that 2M contributed more to the inhibition of thrombin in neonatal and infant plasma than in adult plasma, leading these investigators to conclude that 2M is at least as important a thrombin inhibitor as ATIII in these patients (17).

Although our results confirm low levels of ATIII in neonates, we found much lower levels of 2M in our neonates with CHD than would be expected in otherwise healthy neonates. These findings are similar to those of Shah et al. (18), who also observed that levels of ATIII and 2M were significantly lower in the plasma from "sick" neonates compared with healthy age-matched controls and that, although thrombin generation was the same in both groups, the inhibition of thrombin was significantly impaired in the "sick" neonates. Shah et al.’s study defined "sick" as the presence of respiratory failure requiring mechanical ventilation. Our study shows that neonates with CHD presenting for cardiac surgery may also be considered sick because they too were found to be deficient in both ATIII and 2M. Additionally, neonatal plasma levels of other inhibitor proteins, such as protein C, protein S, and tissue factor pathway inhibitor, are also reduced in healthy neonates compared with adults and may be further reduced in sick neonates. There is concern therefore that neonates requiring CPB may have an impaired ability to inhibit thrombin and thus are perhaps more prothrombotic than we might otherwise anticipate. The cumulative deficiencies of these thrombin inhibitor proteins may lay the foundation for the thrombotic occlusion of major vessels often seen in many sicker neonates who undergo physiologically challenging surgeries and long postoperative recovery times.

This concern however seems to be refuted by the measures of heparin’s effect that we observed in our neonates. We found a statistically significant prolongation of celite-ACTs and steeper HDRR-c slopes in the neonatal group, even with low levels of thrombin inhibitors. Kaolin-ACTs and HDRR-k slopes, though not significantly different, also trended higher in the neonatal group, suggesting that these neonates are actually more anticoagulated by heparin. This observation may be explained either by a decreased ability of neonates to generate thrombin or by the fact that the ACT is a poor indicator of heparin-induced thrombin inhibition in neonates during cardiac surgery. Although healthy neonates have decreased levels of prothrombin and other procoagulants, which limit their ability to generate thrombin, neonates presenting for cardiac surgery are capable of producing large amounts of thrombin in the perioperative period (8,19). Unlike healthy neonates, they undergo preoperative events, such as the placement of indwelling umbilical or central lines and interventional manipulations in the cardiac catheterization laboratory, that perhaps trigger hemostatic activation. Therefore, it is difficult to presume that the prolonged ACTs seen in neonates are due to depressed thrombin-generating activity. The limitations of the ACT as an indicator of heparin’s effect may provide a more likely explanation. Because the ACT does not detect thrombin as a specific end-point, and is subject to the effect of other variables, it may not accurately reflect heparin-induced anticoagulation, especially during neonatal cardiac surgery. First, ACT values do not necessarily correlate with plasma heparin levels during CPB. Interpretation of the celite-ACT response to high-dose heparin is complicated by the loss of a linear dose–response curve at ACT values more that 600 s (20). Even in the linear portion of the dose–response curve, there is considerable variation in single-measurement ACT responses to heparin administration in adult cardiac surgical patients (21). Second, confounding variables, such as hypothermia and hemodilution, that are particularly prevalent in the pediatric realm further hinder the ability of the ACT to provide accurate information regarding plasma heparin levels (20). Third, the immature coagulation systems found in neonatal patients, specifically a paucity of contact activation factors (factors XII and XI, prekallikrein, and high-molecular-weight kininogen), complicates the interpretation of prolonged ACT values (22). Lastly, prostaglandin E1, a frequently used pharmacologic adjunct during the neonatal period, and a notable inhibitor of platelet aggregation, again may enhance ACT prolongations without accurately reflecting plasma heparin activity (23). These points suggest that the ACT may be a poor determinant of adequate thrombin inhibition in neonates during cardiac surgery, thus raising concerns about monitoring anticoagulation for neonates during often-prolonged periods of CPB using the ACT test as the sole measure of heparin’s effect. Monitoring of heparin levels may provide a more accurate guide for the administration of heparin during neonatal CPB, and deserves further study.

Some of our data may explain previous thromboelastogram findings of increased coagulability in young infants noted by other authors (24,25). Depending on the concentration of ATIII in the surrounding plasma, 2M can exert an anticoagulant or a procoagulant action. In the ATIII-deficient plasma of neonates, 2M functions, primarily as a thrombin inhibitor. However, as ATIII levels approach a more physiologic range and ATIII becomes the preferential thrombin inhibitor, excess 2M is available to interact with activated protein C, thereby suppressing the formation of the activated protein C anticoagulant complex (26). Consequently, 2M now exerts a procoagulant action. Our data show an increase in ATIII activity to a physiologic range in patients of 1–3 mo of age and, at the same time, 2M levels remain increased. At this age, 2M may begin to function more as a procoagulant than an anticoagulant, thus explaining thromboelastogram findings of a more coagulable state in this age group.

In our study, the change in celite-ACT values in response to heparin administration prior to CPB shows significant variability among the different age groups. The HDRR-c, being a calculated number using the change in celite-ACT, also shows significant variability among the age groups. Conversely, the change in kaolin-ACT and, consequently, the HDRR-k, show a more consistent response among the age groupings. Changes in kaolin-ACT values in response to high-dose heparin administration for CPB in adult cardiac surgical patients have also been shown to demonstrate greater consistency than celite-mediated responses (27–29). Our data suggest that the kaolin-ACT may be more appropriate than the celite-ACT in measuring heparin’s effect for CPB in pediatric patients.

Cardiac surgery involving CPB is a powerful activator of the hemostatic system. Effective anticoagulation with unfractionated heparin is used to prevent not only grossly visible clot formation but also microemboli. In adult cardiac surgical patients, heparin’s anticoagulant effects are intimately dependent on ATIII activity. Consequently, low levels of ATIII plasma activity impair heparin’s ability to provide adequate anticoagulation, as demonstrated by both a decreased HDRR and a decreased ability to prevent excessive thrombin generation (2,30). In this pediatric study, however, we found no correlation between ATIII levels and the change in ACT with heparin administration, or between ATIII levels and the HDRR. None of the thrombin inhibitors showed a positive correlation with the clinical measures of heparin’s effect. Conversely, 2M showed a statistically significant inverse correlation with all the heparin responses in patients <1 mo of age. The meaning of this negative correlation remains to be elucidated. Multivariable regression analysis demonstrated that both patient age and preoperative platelet count were significant and consistent predictors of celite- and kaolin-activated heparin responses in our patients. This finding may alert us to patient populations where the change in ACT after heparin administration may not be a true indicator of the degree of anticoagulation.

In summary, our investigation demonstrates that kaolin-ACTs of heparin’s effect in children with CHD show less variable results than coagulation tests activated by celite. Our data also reveal that neonates with CHD are distinct from healthy neonates and from older pediatric patients with CHD, in that neonates with CHD may be deficient in all three of the major thrombin inhibitors. Although deficiencies in thrombin inhibitor levels may help explain the recent findings of excess thrombin formation in neonates presenting for cardiac surgery (8), they oppose this study’s other finding of increased heparin effect as measured by the ACT in these same neonates. This inconsistency makes us question the accuracy of the ACT test in assessing heparin-induced anticoagulation for CPB in neonates. Further research is needed to help explain these discrepancies.

	Footnotes

 
Accepted for publication July 27, 2006.

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