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Anesth Analg 2000;90:1281-1285
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effect of Epsilon-Aminocaproic Acid on HemoSTATUS® and Kaolin-Activated Clotting Time Measurements

Rao Saleem, MD*, Matthew Bigham, MD*, Edward Spitznagel, PhD{ddagger}, and George J. Despotis, MD*,{dagger}

Departments of *Anesthesiology and {dagger}Immunology and Pathology, {ddagger}Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri

Address correspondence and reprint requests to George Despotis, MD, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
New point-of-care assays have been used to identify patients with heparin resistance (i.e. heparin dose response test; Medtronic Blood Management, Parker, CO) and who have platelet dysfunction (i.e. HemoSTATUS®; Medtronic Blood Management). We examined the effect of epsilon-aminocaproic acid on results from these two point-of-care tests in patients undergoing cardiac surgery. Twenty patients scheduled for elective cardiac surgical procedures were enrolled in this prospective study. HemoSTATUS® clot ratio (% maximal) values in Channels (Ch) 3–6 (Ch 3: 26 ± 25, Ch 4: 66 ± 23, Ch 5: 84 ± 20, Ch 6: 106 ± 18) obtained after the IV administration of epsilon-aminocaproic acid were similar to values obtained before the administration of this agent (Ch 3: 26 ± 20, Ch 4: 69 ± 23, Ch 5: 86 ± 19, Ch 6: 109 ± 14). Slope values (86 ± 23 s · U-1 · mL-1) and projected heparin concentrations (4 ± 1 U/mL) obtained before the administration of epsilon-aminocaproic acid were similar to slope values (88 ± 21 s · U-1 · mL-1) and projected heparin concentrations (4 ± 1 U/mL) values obtained after administration of this agent. Our data indicate that HemoSTATUS® clot ratio values and heparin dose response values are not significantly affected after IV dosing of epsilon-aminocaproic acid.

Implications: Values from two activated coagulation time-based test systems used to identify significant heparin resistance or platelet dysfunction after cardiopulmonary bypass were not significantly affected by epsilon-aminocaproic acid administered IV.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Cardiopulmonary bypass (CPB) results not only in multiple hemostatic abnormalities, such as decreases in clotting factors secondary to hemodilution (1), but also quantitative and qualitative disorders of platelet function (2). Contact and tissue factor-mediated activation of the hemostatic system during CPB results in excessive thrombin and fibrinolytic activity. The efficacy of prophylactic use of agents with antifibrinolytic properties has been demonstrated in several studies involving patients undergoing cardiac surgery (3–9). The two agents that can be used to specifically inhibit fibrinolysis include epsilon-aminocaproic acid (EACA) and tranexamic acid (TA). EACA and TA are synthetic antifibrinolytics that act by forming a reversible complex with plasminogen, thereby preventing its binding to fibrin (10). In addition to preservation of fibrinogen, factor V and VIII (11), antifibrinolytics may protect platelet function during CPB by inhibiting the degradation of surface glycoprotein 1b receptors by plasmin (12).

Currently, the activated coagulation time (ACT) test is the most commonly used method to monitor heparin-induced anticoagulation before and during CPB (13). The ACT reflects whole blood clotting via contact activation of the hemostatic system as induced by either kaolin or celite. Modifications of the ACT method, such as the kaolin-based heparin dose response testTM (HDR; Medtronic Blood Management, Parker, CO) and the celite-based Heparin Response TestTM (HRT; International Technidyne Inc., Edison, NJ), have been developed to estimate heparin requirements and to identify patients with heparin resistance. These automated or semiautomated tests that contain known amounts of heparin evaluate the responsiveness of ACT values to heparin and facilitate construction of heparin ACT-response curves (14–16).

Excessive bleeding with cardiac surgery appears to be largely a result of CPB-induced, transient platelet dysfunction (17–19). A new whole blood point-of-care test (HemoSTATUS®TM; Medtronic Blood Management, Parker, CO) has been developed and evaluates the acceleration of kaolin-activated ACT values by platelet activating factor (PAF).

The effects of EACA on results from these tests (i.e., HemoSTATUS®, HDR), which rely on fibrin formation as a clot detection endpoint, have not been previously described. Therefore, this study was designed to determine if EACA affects either in vitro assessment of platelet function (i.e., HemoSTATUS® results) or ACT (i.e. HDR) measurements in a sequential series of 20 patients undergoing cardiac surgery.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Twenty patients scheduled for elective cardiac surgical procedures involving the use of CPB were enrolled in this prospective study after obtaining informed consent in this Institutional Human Studies Committee-approved study at Barnes Hospital/Washington University Medical Center, St. Louis, MO.

Patients enrolled in this study were anesthetized with an opioid-based technique supplemented with inhaled anesthetics, muscle relaxants, and benzodiazepines. All patients enrolled in this study received EACA (5 g as a loading dose, an additional 5 g in the CPB circuit, and an infusion of 1 g/h). After rewarming the patient to 37°C, extracorporeal circulation was discontinued, and heparin was neutralized with a protamine dose based on point-of-care measurements of residual whole blood heparin concentration.

The following demographic and perioperative data were collected and recorded for each patient: age, sex, height, weight, body surface area, history of previous cardiac surgical procedure, and operative procedure.

Single blood specimens obtained from either radial and/or femoral arterial catheters after removal of six dead space blood volumes were used for measurements from on-site, whole blood assays (i.e., HemoSTATUS®, HDR). Specimens were obtained before and 10 min after systemic the IV administration of a loading dose of EACA (5 g). Platelet function measurements and HDR measurements were obtained in duplicate during the following time periods: Period 1 = before the administration of EACA; Period 2 = 10 min after the administration of EACA.

The response of the kaolin-activated ACT to heparin was evaluated with the HDR test using the Hepcon®TM instrument (Medtronic Blood Management). Hepcon® instruments were also used to measure platelet function by using a six channel PAF cartridge (HemoSTATUS®) in duplicate. The HemoSTATUS® test assesses platelet function by measuring the shortening of the kaolin-activated clotting time induced by PAF (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Channels 1 and 2 were devoid of PAF (control activated clotting time), whereas Channels 3–6 contained increasing doses of PAF (1.25, 6.25, 12.5, 150 nM). PAF-inducible acceleration of clot time was expressed as a clot ratio value and was calculated with the following formula for each PAF concentration: clot ratio = 1 - (ACT/control ACT). Clot ratio values were expressed as percent of maximal (%Maximal) and were calculated by using the mean clot ratio obtained with Channel 6 (0.51) obtained from a normal reference population (22 volunteers; Medtronic Blood Management) by using the following formula: %Maximal = (Clot ratio/0.51) x 100.

ACT (at each respective in vitro heparin concentration) and HemoSTATUS® measurements obtained before the administration of EACA were compared with measurements after the IV administration of 5 g of EACA by using Student’s paired t-test, one-way analysis of variance, and/or ranked sum nonparametric analyses. Multivariate regression analysis was used to evaluate potential effects of confounding variables (e.g. aspirin) on clotting results and to assess whether variability (e.g. SD) was increased by the use of EACA. Variability was specifically examined by using the linear relationship between the calculated values for the sum and difference between standard deviation values before and after the administration of EACA. A P value of <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Twenty patients were enrolled in the study, of which 20% were women. The average age of the patients was 67 ± 9 years, and the average body surface area was 2.1 ± 0.3 m2. The majority (75%) of the patients were undergoing primary coronary artery bypass revascularization (CABG), whereas the remaining 25% had one of the following procedures: valve repair/replacement (n = 1), repeat CABG (n = 1), CABG with valve repair/replacement (n = 1), CABG with carotid endarterectomy (n = 1), or thoracic aortic aneurysm repair (n = 1). Of the 20 patients enrolled, 17 (85%) were receiving aspirin up to the day of surgery.

HemoSTATUS® platelet function results were similar before and after the administration of EACA (Table 1) in vitro. The clotting time in Channels 1–6 and clot ratio values (both absolute and %Maximal values) in Channels 4–6 were not significantly affected by the administration of EACA. Increased variability (i.e., wider standard deviations) in coagulation results were observed after EACA administration (i.e. clot times in Channels 1–4). However, standard deviations for clot ratio and %Maximal values were not affected by EACA (Table 1).


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  		Table 1. Effect of EACA on HemoSTATUS® Results
 
ACT results at each of the heparin concentrations were similar before and after the administration of EACA (Table 2). This resulted in generation of similar slope values and projected heparin concentration values via the HDR method. Increased variability (i.e., wider SD values) in coagulation results that exceeded that observed with HemoSTATUS® results (5-fold increase in SD values) were observed after EACA administration. However, increased variability in HDR slope and projected heparin concentration values was not observed (Table 2).


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  		Table 2. Effect of Epsilon-aminocaproic acid on HDR test results
 
Coagulation results (clotting times in Channels 1–6) from the HemoSTATUS® test were not different in patients who received aspirin when compared with those who did not receive aspirin. However, clot ratio and %Maximal values in all channels (Table 3) were greater in patients who were not receiving aspirin. There were no apparent differences in clot times (0 heparin, P = 0.71; 1.5 U/mL heparin, P = 0.71; 2.5 U/mL heparin, P = 0.65) or calculated values (slope, P = 0.12; projected heparin concentration, P = 1.0) from the HDR test between patients receiving or not receiving aspirin preoperatively.


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  		Table 3. Effect of aspirin on HemoSTATUS® results
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Attention has been focused on methods to conserve blood with cardiac surgery to minimize transfusion-related sequelae, such as transmission of infectious pathogens. Intraoperative antifibrinolytic therapy has been reported as an effective means of reducing postoperative bleeding after the use of extracorporeal circulation in several studies (3–9). The efficacy of agents with antifibrinolytic properties is most likely secondary to their ability to attenuate fibrinolysis and platelet dysfunction during CPB (20). Although some authors recommend the use of EACA routinely in patients undergoing cardiac surgery (7–9), others recommend the selective use of antifibrinolytics only in high-risk patients, in part because of the potential for these agents to precipitate thrombotic complications (10), and because only certain patients display excessive fibrinolysis (21).

The ACT is used routinely to monitor anticoagulation, and derivations of this test have been developed to predict heparin dose (HDR, HRT) and to identify patients with platelet dysfunction (hemoSTATUS). We examined the effect of EACA on HemoSTATUS® and HDR test results in patients undergoing CPB because of the relative importance of these ACT-based tests on clinical management. For example, the HemoSTATUS® test correlates with platelet function and bleeding (22,23) and identifies patients who benefit from desmopressin (24). Our data reveal that the administration of EACA has no effect on platelet function measurements from the HemoSTATUS® test. Although more variability in coagulation results was observed after EACA administration, this was not accompanied by more variable clot ratio values. Consistent with previous findings (23), patients who were receiving aspirin preoperatively had lower clot ratio results (23).

The ACT method is routinely used to monitor anticoagulation during CPB, and values between 400 and 480 seconds are often maintained (13). Heparin resistance may be caused by preoperative heparin therapy, preoperative nitroglycerin infusion, perioperative acquired ATIII deficiency, or a combination of these factors (25,26). Accordingly, the HDR and HRT tests have been developed to estimate heparin requirements and identify patients with heparin resistance. Although both tests have been used in heparin management schemes (14,15), only the accuracy of the HDR test to predict the accurate initial heparin dose has been evaluated in 41 patients (16). Our data reveal that EACA does not interfere with ACT measurements or HDR-based projections of heparin requirements in our patient population. Although there was more variability in test results after EACA administration, no increased variability was observed in calculated (heparin-ACT slope, projected heparin concentration) values.

Our study was limited by the small number of patients enrolled. Accordingly, more extensive evaluations may be indicated to determine the significance of the wider variability (greater standard deviation in clotting time results) in results that were observed after EACA administration. Although we administered an isolated loading dose (5 g) of EACA, it is unknown whether a larger loading dose (e.g. 10 g), as one of several alternative dosing schemes described in the literature (27), may affect results from these tests. Butterworth et al. (27) recently demonstrated that a 100-mg/kg loading dose results in levels of 500–1000 µg/mL for at least 10–15 minutes. However, this level greatly exceeds the steady-state levels that are thought to be effective for inhibition of fibrinolysis (130 µg/mL), which in part led Butterworth et al. (27) to recommend a smaller loading dose (50 mg/kg).

Our data indicate that these ACT-based tests are not affected by EACA; however, the variability in measurement results we observed warrants more extensive investigation. Further studies are also needed to test the effect of EACA postoperatively on the HemoSTATUS® test system in patients undergoing CPB and perioperatively on other commonly used test systems (e.g. thromboelastography).


   Acknowledgments
 
Supported in part by a grant for material support from Medtronic Blood Management Inc.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 3, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press