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CARDIOVASCULAR ANESTHESIA

Anticoagulation for Cardiac Surgery in Patients Receiving Preoperative Heparin: Use of the High-Dose Thrombin Time

Linda Shore-Lesserson, MD^*, Heather E. Manspeizer, MD, Maria Bolastig, MD^*, Donna Harrington, RN^*, Frances Vela-Cantos, RN^*, and Marietta DePerio, RN^*

*Department of Anesthesiology, Mount Sinai Medical Center; and Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York

Address correspondence and reprint requests to Linda Shore-Lesserson, MD, Department of Anesthesiology, One Gustave L. Levy Place, Box 1010, New York, NY 10029.

	Abstract

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Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy.

Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.

	Introduction

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Adequate anticoagulation, most commonly achieved with large doses of heparin, is essential prior to the initiation of cardiopulmonary bypass (CPB) for cardiac surgery. The laboratory test most frequently used to confirm appropriate levels of heparinization during CPB is the activated clotting time (ACT). However, the ACT has been shown to be highly susceptible to variation, and does not correlate well with anti-Xa measures of heparin activity, or with heparin concentration, especially during the hypothermia and hemodilution commonly associated with CPB (1,2). Despotis et al. (1) showed a weak correlation between ACT and anti-Xa heparin concentration during CPB, most likely related to the influence of reduced hematocrit and temperature on the ACT. Similarly, in a study by Culliford et al. (3), ACT did not accurately reflect plasma heparin levels during CPB. Metz and Keats (4) also demonstrated the lack of correlation between ACT and heparin levels at various sampling time intervals during CPB.

Cardiac surgery patients receiving heparin preoperatively frequently exhibit "resistance" to systemic heparin, or a diminished ACT response to heparin. Possible explanations for this include antithrombin III (ATIII) deficiency, enhanced Factor VIII activity, and the presence of activated platelets (5–7). These patients often require additional heparin for CPB to maintain a minimum threshold ACT level, and it is unknown if these additional doses are necessary for safe anticoagulation. If a fixed-ratio protamine dosage scheme was used, large doses of protamine would be given and may result in post-CPB coagulopathy, excess blood loss, and increased transfusion of blood products.

The ACT measures the integrity of the intrinsic coagulation pathway and the final common coagulation pathway. The thrombin time (TT), a measure of thrombin conversion of fibrinogen to fibrin, is a more specific measure of thrombin inhibition, but is rendered unclottable by the high concentrations of heparin used for CPB. The high-dose TT (HiTT) is a modification of the TT and has been used to measure anticoagulation for CPB. HiTT has been shown to more closely correlate with heparin concentrations than the ACT in cardiac surgery patients (2).

The purpose of this study was to evaluate the HiTT as a monitor of anticoagulation for CPB in patients receiving and not receiving preoperative heparin. Using standard ACT monitoring, we also sought to determine if the "heparin resistance," seen in patients receiving preoperative heparin, is also characterized by a reduced HiTT response to heparin. Measures of thrombin formation and activity were analyzed for evidence of continuing subclinical coagulation in these patients.

	Methods

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This research protocol was approved by our institutional review board, and all patients gave informed consent to participate. Adult patients undergoing coronary artery bypass grafting (CABG) were consecutively recruited for study. Patients were excluded from enrollment if they had significant preexisting hepatic disease (transaminase levels greater than two times control), renal disease requiring dialysis, or if they required preoperative inotropic support. Patients receiving preoperative heparin infusion (Group H) were grouped and compared with those not receiving heparin. Since certain physicians discontinue heparin infusion prior to the start of surgery, criteria for entry into Group H was documentation of IV infusion of heparin of at least 48 h. The infusion had to be present at the time of surgery or discontinued not more than 8 h before surgery. The group of patients not receiving heparin was the reference group (REF).

CPB was conducted using moderate hypothermia, membrane oxygenator, and an arterial line filter. Anticoagulation for CPB was accomplished with bovine lung heparin (Fujisawa USA, Inc., Deerfield, IL) 300 units/kg administered into the right atrium by the surgeon. ACT > 400 s was accepted as adequate anticoagulation for CPB. Additional heparin in 5,000 unit increments was administered to maintain the ACT at least 400 s. Supplemental ATIII therapy was not routinely administered to patients with ACT less than 400 s, unless there was congenital ATIII deficiency or until approximately 600 units/kg of heparin was administered. After CPB, protamine (Elkins Sinn, Inc., Cherry Hill, NJ) was given over a 20-min period, in a ratio of 1 mg/100 units of the total heparin dose.

Coagulation Testing
ACT (Hemochron, International Technidyne Corp., Edison, NJ) was measured using 2 ml of whole blood in a celite-activated tube placed into the Hemochron machine. ACT was measured at baseline (presternotomy), after heparinization, every 30 minutes during CPB, and after protamine.

HiTT was performed using a test tube containing lyophilized thrombin reagent. The tube was prewarmed in the Hemochron machine and hydrated with 0.5 mL of distilled water, after which 1.5 mL of whole blood was added. The HiTT tube was then inserted into the Hemochron well and the time to clot formation measured in the standard fashion. HiTT was measured at the following 4 time points concomitant with ACT: baseline, after heparinization, after 30 min of CPB, and after protamine.

The in vitro heparin dose response was measured at baseline using the Heparin Response Test tube. This tube contains 6 units of heparin to which 2 mL of whole blood is added. It is inserted into the Hemochron machine, and a clotting time is measured. This clotting time is the ACT to a known concentration (6 units/2 mL or 3 units/mL) of heparin and is useful for calculating heparin sensitivity.

Baseline coagulation testing in all patients included a platelet count, prothrombin time, activated partial thromboplastin time, and fibrinogen level. In a subset of patients in both Group H and the REF group, one additional citrate-containing tube was centrifuged and the platelet-poor plasma isolated and stored in aliquots at -70°C. This was for the later measurement of thrombin-ATIII (TAT) complex and fibrin monomer and was drawn at baseline, after 30 min of CPB, and after protamine administration.

Transfusion therapy after protamine administration was guided by data from laboratory-based tests. Additional protamine (50 mg) was given if ACT exceeded baseline by 15%. Platelets (6 units) were transfused for platelet count <100,000/µL, and 2 units of fresh frozen plasma was given for prothrombin time >150% of control. Cryoprecipitate (10 units) was transfused for fibrinogen level <100 mg/dL. Chest tube drainage at 24 h, autotransfusion volume, and transfusion requirements were recorded.

Statistical Analysis
Patients were divided into groups based on the presence (Group H) or absence (REF group) of preoperative heparin therapy. These groups were compared with respect to baseline coagulation variables, intraoperative ACT and HiTT responses, and postoperative markers of thrombin formation and activation. Normally distributed data were analyzed using unpaired Student’s t-test or two-way analysis of variance for repeated measures with post-hoc Tukey’s t-test. These data are reported as the mean ± standard deviation. Data not conforming to a standard Gaussian distribution were analyzed using the Kruskal-Wallis analysis of variance and are reported as median (range). Categorical variables were analyzed using 2 test; P < 0.05 was considered statistically significant.

	Results

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Sixty-five patients were enrolled and completed the protocol. Thirty-three were in Group H and 32 in the REF group. After studying the first 45 patients, the protocol was amended so that the final 20 patients had plasma markers of TAT and fibrin monomer measured. Twelve of these patients were in Group H and 8 were in the REF group. All patients underwent elective CABG with CPB. One patient in Group H had a combined CABG plus mitral valve replacement, and this was the only patient who received prophylactic antifibrinolytic therapy. This patient’s data were excluded from the analysis. No patient received post-CPB antifibrinolytic therapy nor supplemental ATIII therapy. One patient in each group had reoperative sternotomy. No patient returned to the operating room for exploration for bleeding postoperatively, and no patient died during the study period. The only preoperative difference between the groups was a lower platelet count in Group H (P = 0.05) (Table 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Activated clotting time (ACT) and high-dose thrombin time (HiTT) at four time points during the perioperative period are shown. Solid lines indicate patients not on preoperative heparin (REF group), and dashed line indicates patients who were receiving preoperative heparin infusion (Group H). ** ACT was significantly different between REF and H groups by analysis of variance (P < 0.003). Differences were significant at baseline, after heparinization, and at 30 min on cardiopulmonary bypass (CPB 30) (P < 0.01). HiTT was not different at any time point in REF and H groups. Data for one patient having a combined procedure and who received antifibrinolytic therapy are excluded from analysis.

Despite a consistently lower ACT during CPB, Group H and the REF group did not differ during or after CPB with respect to thrombin generation, measured by the formation of TAT (Fig. 2). The groups also did not differ in thrombin activity, as assessed by the formation of fibrin monomer (Fig. 3). The groups did not differ in chest tube drainage or in transfusion requirements.

View larger version (13K): [in this window] [in a new window]   Figure 2. Thrombin-antithrombin III (TAT) levels in patients not receiving preoperative heparin (REF group) and those receiving preoperative heparin (Group H), at three time points during the perioperative period. There were no significant differences between groups. Data for one patient having a combined procedure are excluded from analysis. CPB 30' = after 30 min of cardiopulmonary bypass.

View larger version (14K): [in this window] [in a new window]   Figure 3. Fibrin monomer levels were measured at three time intervals in the perioperative period in patients not receiving preoperative heparin (REF group) and those receiving preoperative heparin (Group H). There were no significant differences between groups. Fibrin monomer levels are displayed in nanomolar concentrations. Data for one patient having a combined procedure are excluded from analysis. CPB 30' = after 30 min of cardiopulmonary bypass.

	Discussion

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It has been demonstrated that patients receiving preoperative heparin therapy can develop an acquired heparin resistance characterized by a diminished increase in ACT after heparin given for CPB (6,8). Esposito et al. (9) compared the initial ACT response in cardiac surgery patients receiving heparin preoperatively to those patients who were not on prior heparin. Patients receiving heparin preoperatively had a significantly lower ACT after a 4 mg/kg heparin bolus. Further analysis of the two groups revealed no difference in plasma heparin level, ATIII activity, clotting factors, fibrinogen concentration, or platelet count. Therefore, heparin resistance, demonstrated by low ACT levels in the patients receiving preoperative heparin, was not attributable to different baseline levels of ATIII, or other coagulation factors. In fact, the only predictive variable for heparin resistance was a lower baseline ACT.

We prospectively compared patients receiving preoperative heparin therapy to those not receiving heparin preoperatively. We demonstrated in vitro, and in vivo, that ACT increases to a lesser degree in response to a bolus dose of heparin in Group H patients and that significantly fewer Group H patients attained the frequently applied threshold ACT of 480 s. We also found that the HiTT, measured after the bolus dose of heparin, was not different in these two groups, nor were postoperative markers of thrombin activity (TAT complexes and fibrin monomers). Thus, despite lower ACT values, and values at or below the commonly accepted threshold, thrombin activity and fibrin formation are still similarly inhibited. This raises the question of what ACT value should be considered safe in this patient population, and whether ACT is the appropriate coagulation test for patients receiving preoperative heparin infusions.

A number of scientific investigations suggest that CPB can be safely conducted using lower heparin doses and lower threshold ACT values (9,10) without pathologic consumption of coagulation factors. Still, another body of literature supports the contention that low ACT values indicate subclinical consumption of coagulation factors, and preservation of these factors can be accomplished by the maintenance of higher ACT values and a stable heparin concentration (11). However, these investigations have not specifically addressed the use or specific role of ACT monitoring in patients receiving preoperative heparin therapy.

Wang et al. (2) evaluated the in vitro and in vivo anticoagulation effects of heparin using the ACT and HiTT, although patients on prior heparin therapy were excluded from their study. HiTT correlated linearly with heparin concentration and was not affected by hemodilution or hypothermia, whereas the linear relation of ACT with heparin during CPB was lost (2). When compared with the ACT, HiTT is less influenced by the dilution of clotting factors with crystalloid priming fluid during CPB in pediatric patients during cardiac surgery (12). Furthermore, HiTT measurement is not altered by aprotinin therapy (13).

HiTT is a modification of TT that uses a larger dose of thrombin to assay heparin anticoagulant effect at the doses of heparin used for CPB. As a measure of thrombin activity, HiTT assays anticoagulant activity at the final common pathway of the coagulation cascade (fibrinogen conversion to fibrin) and thus may be less susceptible to error or artifact than the ACT, which measures anticoagulant activity both at the intrinsic pathway and the final common pathway. For this reason, HiTT may also be a more sensitive test of the anti-IIa effects of heparin than the anti-Xa effects. Also, we used bovine heparin that typically has less anti-Xa activity and may be associated with more platelet activation than porcine heparin derivatives. This may have further accentuated the different diagnostic capabilities of the HiTT versus ACT.

ACT has been used as the "gold standard" for confirmation of adequate anticoagulation for CPB, but results are highly variable (14). Celite-activated ACT is prolonged in the presence of aprotinin (15–17). Hemodilution and hypothermia significantly increase the ACT of a heparinized blood sample, but similar increases do not occur in the absence of added heparin (3,18). ACT decreases with surgical incision (19) and increases if the tubes are not prewarmed (20). We suggest that ACT alone may not be the appropriate measure of anticoagulation for patients with acquired "heparin resistance" due to prior heparin exposure. Our results and those of Esposito et al. (9) demonstrate that, after complete heparinization, patients receiving preoperative heparin therapy have a smaller increase in ACT than those patients not receiving heparin immediately prior to operation. We further showed that markers of thrombin and fibrin formation were not increased and that HiTT was not influenced by prior heparin therapy. Thus, the diagnosis of "heparin resistance" was confined to the ACT. We are unable to answer mechanistic questions relating to this heparin-resistant patient population, since we did not measure preoperative ATIII levels, and we did not measure anti-Xa levels as a gold standard for assessment of heparin anticoagulant effect. However, we did document a lower platelet count in the patients on prior heparin therapy, indicating that some heparin-induced platelet activation may have occurred preoperatively.

A limitation of HiTT is that it cannot be used to measure baseline values in a nonanticoagulated sample. The test tube contains a large dose of thrombin reagent required to neutralize the large doses of heparin used for CPB. This rapid activation of the coagulation system causes the clotting time of a nonanticoagulated sample to be so short that it is unmeasurable. This limitation could be overcome by measuring a standard TT. Additionally, HiTT tubes require prehydration and warming. The cost of measuring HiTT includes primarily the cost of the tubes ($4.50 USD/test) if a Hemochron machine is already available.

In summary, anticoagulation for CPB in patients with acquired heparin resistance due to previous heparin therapy is difficult due to failure to raise ACT to a desired threshold value. HiTT, which is also a functional test of anticoagulation, predicts that clot formation is inhibited, and it is frequently therapeutic, even when ACT values are less than desired. The use of HiTT in this patient population suggests that additional doses of heparin may not be necessary, and that CPB can proceed without adverse sequelae using amounts of heparin similar to patients not receiving preoperative heparin infusions.

	Footnotes

 
¹ High dose thrombin time: International Technidyne, Inc., Edison, NJ, 1994.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Despotis GJ, Summerfield AL, Joist JH, et al. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076–82.[Abstract/Free Full Text]
2. Wang JS, Lin C, Karp RB. Comparison of high-dose thrombin time with activated clotting time for monitoring of anticoagulant effects of heparin in cardiac surgical patients. Anesth Analg 1994;79:9–13.[Abstract/Free Full Text]
3. Culliford AT, Gitel SN, Starr N, et al. Lack of correlation between activated clotting time and plasma heparin during cardiopulmonary bypass. Ann Surg 1981;193:105–11.[Web of Science][Medline]
4. Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 1990;49:440–4.[Abstract]
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6. Despotis GJ, Levine V, Joist JH, et al. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg 1997;85:498–506.[Abstract]
7. Moorehead MT, Westengard JC, Bull BS. Platelet involvement in the activated coagulation time of heparinized blood. Anesth Analg 1984;63:394–8.[Abstract/Free Full Text]
8. Dietrich W, Spannagl M, Schramm W, et al. The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;102:505–14.[Abstract]
9. Esposito RA, Culliford AT, Colvin SB, et al. Heparin resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;85:346–53.[Web of Science][Medline]
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11. Despotis GJ, Joist JH, Hogue CW, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996;76:902–8.[Web of Science][Medline]
12. Hyuzen RJ, van Oeveren W, Wei F, et al. In vitro effect of hemodilution on activated clotting time and high dose thrombin time during cardiopulmonary bypass. Ann Thorac Surg 1996;Aug 62:533–7.
13. Hyuzen RJ, Harder MP, Huet RC, et al. Alternative perioperative anticoagulation monitoring during cardiopulmonary bypass in aprotinin-treated patients. J Cardiothorac Vasc Anesth 1994;Apr 8:153–6.
14. Gravlee GP, Case LD, Angert KC, et al. Variability of the activated coagulation time. Anesth Analg 1988;67:469–72.[Free Full Text]
15. Wang JS, Lin CY, Hung WT, et al. In vitro effects of aprotinin on activated clotting time measures with different activators. J Thorac Cardiovasc Surg 1992;104:1135–40.[Abstract]
16. Wang JS, Lin CY, Hung WT, Karp RB. Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin. Anesthesiology 1992;77:1080–4.[Web of Science][Medline]
17. Despotis GJ, Filos KS, Levine V, et al. Aprotinin prolongs activated and nonactivated whole blood clotting time and potentiates the effect of heparin in vitro. Anesth Analg 1996;82:1126–31.[Abstract]
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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