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PEDIATRIC ANESTHESIA

Low Preoperative Antithrombin Activity Causes Reduced Response to Heparin in Adult but not in Infant Cardiac-Surgical Patients

Wulf Dietrich, MD^*, Siegmund Braun, MD, Michael Spannagl, MD, and Joseph A. Richter, MD^*

*Department of Anesthesiology and Institute of Clinical Chemistry, German Heart Center, Munich, Germany, and the Department of Hematology, University Clinic, Munich, Germany

Address correspondence and reprint requests to Wulf Dietrich, MD, Department of Anesthesiology, German Heart Center Munich, Lazarettstr. 36, 80636 Munich/Germany. Address e-mail to dietrich{at}dhm.mhn.de

	Abstract

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We evaluated the interaction of preoperative antithrombin (AT) activity and intraoperative response to heparin in cardiac surgery. Heparin anticoagulation is essential during cardiopulmonary bypass (CPB). Heparin itself has no anticoagulant properties, however it causes a conformational change of the physiologic plasma inhibitor AT that converts this slow-acting serine protease inhibitor into a fast acting one. Thus, adequate AT activity is a prerequisite for sufficient heparin anticoagulation. AT activity is reduced by long-term heparin therapy. This prospective, observational study investigated 1516 consecutive cardiac-surgical patients (1304 patients >1 yr (Group A) and 212 patients 1 yr (Group I)). AT activity was measured the day before surgery by a chromogenic substrate assay. The celite-activated activated clotting time (ACT) was used to guide intraoperative heparin administration. Heparin sensitivity was calculated and the postoperative blood loss and perioperative blood requirement was recorded. Infant patients had significantly less preoperative AT activity compared with older patients: 84 (33)% vs 97 (17)%, median (interquartile range) (P < 0.05). The subgroup of patients aged <1 mo (n = 64) demonstrated a preoperative AT activity of 56 (27)% as compared with 90 (23)% in infant patients between one month and one year (n = 148). In adult patients, preoperative AT activity depended predominantly on preoperative heparin treatment: 62% of the patients with an AT activity <80% were pretreated with heparin. Five minutes after heparin but before CPB the ACT was 587 (334) s in Group A patients with AT activity 80%, and 516 (232) in patients with AT activity 80% (P < 0.05). The target ACT of 480 s was achieved in 70% of patients with normal AT activity in Group A compared with only 54% of patients with AT activity <80% (P < 0.05). In Group A patients with decreased AT activity, 18% demonstrated an inadequate ACT response—defined as ACT <400 s—to the first bolus injection of heparin. In Group I, preoperative AT activity did not influence the ACT response (ACT 5 min after heparin: 846 [447] s in patients with AT activity 80% vs 1000 [364] s in patients with decreased AT activity). The heparin sensitivity was 2.4 (1.1) s/unit heparin/kg compared with 1.5 (0.8) s/unit heparin/KG in group A (P < 0.05). These results suggest that preoperative diminished AT activity causes reduced response to heparin in adult but not in infant patients. Infant patients demonstrate a higher heparin sensitivity despite lower preoperative AT activity. Measurement of preoperative AT activity identifies adult patients at risk of reduced sensitivity to heparin.

Implications: In patients less than one year of age, low antithrombin (AT) activity is caused by the immature coagulation system. Despite low AT activity, these young patients demonstrate a normal or increased response to heparin anticoagulation before cardiopulmonary bypass (CPB). In contrast, in patients older than one year of age and adult patients decreased preoperative AT activity is mainly caused by preoperative heparin therapy and causes insufficient response to heparin anticoagulation with a standard heparin dosage. Measurement of preoperative AT activity identifies patients at risk of inadequate anticoagulation during CPB.

	Introduction

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The nonphysiologic stimulus of cardiopulmonary bypass (CPB) causes massive activation of the hemostatic system. To prevent this activation, heparin is used for anticoagulation during CPB. Heparin is a glycosamino-glycan composed of chains of D-glucosamine and uronic acid, and has no direct anticoagulant potency. The anticoagulant effect of heparin is accounted for by a high-affinity binding sequence to the physiologic thrombin inhibitor antithrombin (AT). The serine protease inhibitor AT is a single-chain glycoprotein with a molecular weight of 58,000 Dalton (1). The plasma protein AT is a relatively poor inhibitor of thrombin. However, hereditary human AT deficiency has been associated with thrombosis (2,3). A reduction of AT activity <70% is associated with thrombotic events during percutaneous coronary revascularization (4), but a "normal" level of AT has not yet been defined. The thrombin-inhibitory potency of AT is increased 1000-fold in the presence of heparin. Heparin binds to lysine sites on AT and produces a conformational change at the arginine reactive center, thus converting AT from a slow to a rapid inhibitor of thrombin. After binding to AT and thrombin heparin is dissociated from the complex and can react with other molecules (5). In addition to thrombin, AT interacts with several plasma proteases, such as kallikrein, factors IXa, Xa, XI, and XIIa (6).

The anticoagulant response to bolus injection of heparin shows a wide variability (6). The response to heparin is correlated to plasma AT activity (7). With long-term heparin therapy, plasma AT activity declines progressively over several days. More complete anticoagulation has been achieved by administration of AT concentrate in vivo (7,8) and in vitro (9). Patients with preoperative heparin therapy undergoing open-heart operations showed increased intraoperative prothrombotic activation, despite larger heparin dosages, when compared with patients without heparin treatment (10).

There are substantial differences in the postnatal hemostatic system compared with the mature adult system (11). AT is a late-developing protein with low activities at term (12), which reaches near-normal levels by 6 months of age (11). Only limited information is available about the effect of low AT activity in infants on heparin response during CPB.

The aim of the present study was to investigate the interaction of preoperative AT activity and intraoperative heparin requirement in adult and infant cardiac surgical patients.

	Methods

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With IRB approval, patients undergoing cardiac surgery were included in this prospective, observational study. Patients in this data set were categorized in groups of more than (Group A) or less than 1 yr of age (Group I). Because children and adolescents did not demonstrate differences in the hemostatic variables, these patients were included in Group A. Group I was stratified in subgroups of patients younger or older than 1 month of age.

Patients with impaired liver function, treatment with phenprocoumon (a warfarin analog), or with a preoperative thromboplastin time with an international normalized ratio >1.5 were excluded from the analysis as well as patients receiving AT concentrate or fresh frozen plasma intraoperatively. AT activity was measured the day before surgery in all patients with a thrombin-based chromogenic assay (Roche Diagnostics, Mannheim, Germany) in citrated plasma (1:9, vol/vol) on an automated clinical chemistry analyzer (Hitachi 911; Roche Diagnostics). The measurement was performed within 2 h after sampling according to the manufacturer’s specifications. The interassay imprecision determined with a commercial control plasma (PreciChrom 1; Roche Diagnostics) is currently 1.83% at a mean AT activity of 84% (n = 29). Heparin anticoagulation for CPB was achieved by a bolus injection of 375 U/kg porcine mucosa heparin (Liquemin; Roche, Grenzach, Germany). The celite-activated activated clotting time (ACT) (Hemochron 800; Intern Technidine Corp., Edison, NJ) was used to guide heparin anticoagulation. It was measured 5 min after the heparin administration (before the commencement of CPB and aprotinin administration), 5 min after start of CPB, and after rewarming. ACT values more than 1000 s were truncated to 1000 s. All calculations were done with these truncated values. An ACT <480 s was indication for a repeat bolus injection of 125 U/kg heparin. Heparin sensitivity was calculated as ACT increase 5 min after heparin bolus in seconds per unit of heparin/kg. All patients received large-dose aprotinin intraoperatively: adult patients approximately 6 x 10⁶ KIU during the entire operation, infants and children: a bolus injection of 30,000 KIU/kg before CPB, and an additional bolus of 30,000 KIU/kg (but at least 0.5 x 10⁶ KIU) to the prime of the heart-lung machine (13). Aprotinin therapy was started after the heparin administration and blood collection for the ACT measurement.

A standard anesthesia technique with midazolam, sufentanil, and pancuronium was used. Inhaled anesthetics—either isoflurane or desflurane—were added occasionally during sternotomy. The membrane oxygenator was primed with 1800 mL of crystalloid solution in adults and according to the body weight in pediatric patients. Heparin (5,000 U in adult or 1000 U in infant patients) was added to the pump prime of the heart-lung machine. In all patients with a body weight <10 kg the oxygenator was primed with 250 mL packed cells, 250 mL fresh frozen plasma, and 100–300 mL of crystalloid solution. CPB was conducted with moderate hypothermia of 30–32°C (rectal temperature) and a flow rate of 2.4 L/min/m² for adults. Infant patients were operated on either in hypothermia with a rectal temperature of 24°C and a blood flow between 2.4 L/min/m² and 1.2 L/min/m² or in deep hypothermic circulatory arrest with a rectal temperature of 20°C or less.

Heparin requirement, postoperative blood loss, and perioperative allogeneic blood requirement were recorded. Because a generally accepted lower limit for normal AT activity has not been defined, we arbitrarily chose an AT activity of two standard deviations below the AT activity of adult patients not pretreated with heparin (AT activity 99 ± 10%). Thus, patients were divided into groups with preoperative AT activity <80% and 80%.

Continuous variables were analyzed with the Student’s t-test for normally distributed variables and with the Mann-Whitney U-test for non-normally distributed variables. Repeated measurements of continuous variables were analyzed by analysis of variance, and the Newman-Keuls procedure was used to evaluate differences between groups. The ² test was used for analysis of discrete variables. Results are given as median and interquartile range. P < 0.05 was considered statistically significant.

	Results

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Two hundred twelve infant patients (Group I) and 1304 patients greater than one year of age (Group A) undergoing various cardiac surgical procedures were included in this investigation. In Group I 30% (n = 64) of the patients were neonates 1 mo of age. Demographic data and types of operation are presented in Tables 1 and 2. Patients in Group I had a significantly reduced preoperative AT activity, 84 (33)% vs 97 (17)% in Group A, respectively (median [interquartile range]) (P < 0.05). In Group A, no differences in preoperative AT activity were detected between children, adolescents, or adults.

In Group A, pretreatment with heparin influenced preoperative AT activity; 62% of the patients with an AT activity <80% were pretreated with heparin. Only 9% of the patients in Group A without heparin pretreatment demonstrated preoperative AT activity <80%, whereas 27% (n = 44) of the patients with subcutaneous heparin administration and 46% (n = 39) with IV application of heparin showed reduced AT activity (P < 0.05). In contrast, heparin pretreatment was not the cause of low AT activity in Group I; actually, none of the patients in this group received preoperative heparin therapy. AT activity correlated with age in Group I (Fig. 1 ): neonates aged less than 1 month showed an AT activity of 56 (27)% compared with 90 (23)% in the remaining patients in this group (P < 0.05). However, despite the low AT activity, the ACT after heparin was even higher in neonates compared with infants (1000 [376] s vs 834 [435] s) (P < 0.05).

View larger version (17K): [in this window] [in a new window]   Figure 1. Correlation between antithrombin (AT) activity and age in Group I. After 150 days there was no patient with an AT activity <60%. Activity was in the lower-normal range after 150 days, but demonstrated a wide variation as a sign of the severity of the underlying disease.

	Discussion

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The results of the present study in a large patient population demonstrate reduced heparin sensitivity in patients with diminished preoperative AT activity. This difference was not evident in infants; in these patients, the preoperative AT activity was low, whereas the anticoagulant effect of heparin was more pronounced compared with that seen in adults.

In adult patients, preoperative AT activity is predominantly reduced as a consequence of heparin therapy (14). Sixty-two percent of the patients with low AT activity were pretreated with heparin. Patients with IV heparin therapy showed an increased reduction in AT activity compared with subcutaneous administration. It is conceivable that the larger dosage of heparin given therapeutically compared with prophylactically administered heparin caused this more pronounced reduction. A considerable number of patients with decreased AT developed an inadequate response to heparin anticoagulation. It is most likely that anticoagulation in these patients was incomplete with an increased risk of prothrombotic activation (15).

This study was not designed to investigate clinical outcome with different preoperative AT activities. Although allogeneic blood requirement showed significant differences, the postoperative blood loss was not different. With the given sample size, our study had a power of 80% to detect a difference of 70 mL in blood loss. The difference in blood loss found by others (8) would have been detected with a power of 99% by the present study.

Heparin anticoagulation has certain biophysical limitations (16). Preoperative heparin therapy reduces the anticoagulant activity of AT and is therefore associated with increased intraoperative thrombin generation during cardiac surgery (17). Because thrombin plays the central role in the activation of hemostasis (18), this procoagulatory process leads to platelet activation (19) and the activation of other cellular and plasmatic systems (20). More accurate anticoagulation by monitoring the heparin concentration and by use of larger heparin dosages leads to a better preservation of the coagulation system with the consequence of reduced use of blood products (21). From these results it can be hypothesized for the present study that a larger heparin dosage and better monitoring of anticoagulation would be more beneficial to patients with reduced ACT response to heparin.

An in vitrostudy (9) demonstrated a linear relationship between AT activity and ACT response to heparin. The higher the in vitro activity of AT, the greater the ACT prolongation was. The same study also showed an in vivo inverse relationship between AT activity and fibrinopeptide A level at the end of CPB. However, prothrombin-fragment F_1.2 as a marker for thrombin generation did not show significant correlation to the AT activity. Levy et al. (22) demonstrated in an in vitro model that plasma of patients receiving preoperative heparin had decreased AT activity compared with controls (68% vs 92%; P < 0.01). The reduced ACT response in these patients could be increased after purified AT supplementation. The results of the present study are consistent with these results.

In contrast to adults, the infant patients demonstrated increased heparin sensitivity despite decreased preoperative AT activity. Neonates, especially <1 month of age, showed prolonged ACT values despite significantly reduced AT activity. This difference to older patients is not attributed to the different degree of hemodilution during CPB or the different heparin priming of the oxygenator because the ACT increase was measured before CPB.

The hemostatic system in neonates has unique features compared with that of adults: all components of this system are diminished in the postnatal period and most of them achieve adult values by six months of life (11,23,24). The ratio of pro- and anticoagulatory factors—arbitrarily set to 1 for adults—is 1:1.5 in newborns (25). Despite decreased AT activity, the prothrombotic activity is even more reduced (25). The results of the present study are in accordance with these findings: the AT activity was found near normal by 6 months of age. Newborns are both resistant to heparin and excessively sensitive to heparin (12). None of the infants in our study demonstrated resistance to heparin. On the contrary, infants were significantly more sensitive to heparin compared with adults. Therefore, the question arises whether a tendency to overdose heparin exists in commonly practiced infant heparin dosage schemes.

In adults, substitution with purified AT also increases in vivo the response to heparin and leads to better anticoagulation (8,26). Subclinical plasma coagulation as measured by fibrinopeptide A was reduced by supplementation of 1000 U AT concentrate in a small group of pediatric patients (7). Rossi et al. (8) evaluated the effectiveness of AT administration to improve anticoagulation in patients with unstable angina under heparin treatment undergoing coronary artery bypass grafting. Purified AT substitution attenuated the activation of hemostasis as measured by prothrombin-fragment F_1.2 and a small, but significant, reduction in chest tube drainage was observed with AT supplementation. In the present study, low AT activity was not associated with increased blood losses. In a pig model of septic shock, large dose substitution of AT concentrate led to modulation of the procoagulatory state and generated a beneficial antiinflammatory effect (6). Further studies have to elucidate whether reduced response to heparin anticoagulation during cardiac surgery may be an indication for human (7) or transgenic (27) AT concentrate.

It is not justified to draw far-reaching clinical conclusions from this observational study without further investigation. It is questionable if patients with and without preoperative heparin therapy are comparable because the patients received preoperative heparin as a result of their underlying disease, which was not present in patients without heparin. Also, this study did not investigate clinical outcomes of patients with different degrees of hemostatic activation during CPB. No attempts were made to correct decreased preoperative AT activity. Although the allogeneic blood requirement was different in adults with low versus AT activity 80%, prospective studies must elucidate the clinical implication of this finding. The oxygenator is primed with a relatively larger heparin dose in infants compared with adults theoretically leading to increased heparin plasma levels. However, calculation of heparin sensitivity was performed with the ACT before CPB and is not affected by this potential bias. Because heparin administration was guided by the celite ACT, which is generally prolonged by aprotinin therapy (28), our data may underestimate the effect of heparin on the ACT during CPB.

Increased hemostatic activation during CPB leads to increased intra- and postoperative bleeding tendency (8,10). Therefore, adequate anticoagulation is mandatory. Heparin anticoagulation has its limitations. Because heparin anticoagulation is predominantly mediated by the binding of heparin to AT, the measurement of preoperative AT activity predicts the intraoperative response to heparin. A larger initial heparin dosage may be advantageous in adult patients with low preoperative AT activity, i.e., patients with preoperative heparin therapy. Substitution of AT concentrate may be a physiologic strategy for improvement of anticoagulation in patients with very low AT activity. In contrast, even with low AT activity, our data suggest that AT administration may not be advantageous in infant patients to improve heparin sensitivity. Further studies must elucidate whether a smaller heparin regimen is adequate in infant cardiac patients.

	CONCLUSION

Top Abstract Introduction Methods Results Discussion CONCLUSION References

 
We conclude that preoperative diminished AT activity causes reduced response to heparin in adult patients but not in infant patients. In adults, reduced AT activity is primarily caused by preoperative heparin treatment. These patients are at risk of inadequate anticoagulation during CPB. Measurement of preoperative AT activity identifies patients at risk of reduced sensitivity to heparin. In contrast, infant patients demonstrate an increased heparin sensitivity despite lower preoperative AT activity because of their immature hemostatic system.

	Footnotes

 
The results of the study were partly presented at the 1999 SCA meeting in Chicago.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999