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Anesth Analg 2005;101:308-314
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000173209.76933.BE

CARDIOVASCULAR ANESTHESIA

Section Editor:
Kenneth J. Tuman

Monitoring Activated Clotting Time for Combined Heparin and Aprotinin Application: An In Vitro Evaluation of a New Aprotinin-Insensitive Test Using SONOCLOT

Michael T. Ganter, MD, DEAA*, Seraina Dalbert{dagger}, Kirk Graves, ECCP{ddagger}, Richard Klaghofer, PhD§, Andreas Zollinger, MD{dagger}, and Christoph K. Hofer, MD, DEAA{dagger}

*Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA; {dagger}Institute of Anesthesiology and Intensive Care Medicine and {ddagger}Division of Cardiac Surgery, Triemli City Hospital, Zurich, Switzerland; and §Department of Psychosocial Medicine, University Hospital Zurich, Zurich, Switzerland

Address correspondence and reprint requests to Christoph K. Hofer, MD, DEAA, Institute of Anesthesiology and Intensive Care Medicine, Triemli City Hospital Zurich, Birmensdorferstrasse 497, CH-8063 Zurich, Switzerland. Address e-mail to Christoph.hofer{at}triemli.stzh.ch.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The kaolin-based activated clotting time (ACT) is commonly used for monitoring heparin-induced anticoagulation alone and combined with aprotinin during cardiopulmonary bypass. However, aprotinin prolongs ACT measurements. Recently, a new so-called ‘aprotinin-insensitive‘ ACT test (SaiACT) has been developed for the SONOCLOT analyzer. In this study we evaluated and compared this new test for the SONOCLOT analyzer in vitro with an established kaolin-based ACT from HEMOCHRON (HkACT). Twenty-five patients undergoing elective valve surgery donated 80 mL of blood after induction of anesthesia. The blood was withdrawn in citrated tubes and processed to analyze effects of heparin (0, 1, 2, and 3 U · mL–1), aprotinin (0, 200 kIU · mL–1), and 25% hemodilution with calcium-free lactated Ringer’s solution on ACT measurements. A total of 400 blood samples were analyzed and ACT was measured in a wide, clinically relevant range in duplicate with SaiACT and HkACT. Addition of aprotinin to heparinized blood samples induced no significant changes of SaiACT measurements. By contrast, HkACT readings increased significantly: aprotinin prolonged HkACT in heparinized blood samples by 20% ± 37% (2 U · mL–1) and 24% ± 18% (3 U · mL–1), respectively, and in vitro hemodilution increased this effect.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Measurement of activated clotting time (ACT) with kaolin as the coagulation activator is a standard monitoring procedure for guiding heparin-induced anticoagulation alone and combined with aprotinin during cardiopulmonary bypass (CPB) (1–3). Aprotinin is frequently used during CPB as it reduces postoperative bleeding in patients after CPB (4). This drug is a nonspecific serine protease inhibitor and exerts antiinflammatory and antifibrinolytic properties, inhibiting the kallikrein-kinin system, plasmin activation and complement generation (5,6). Furthermore, aprotinin protects platelets by stabilizing membrane receptors and inhibits thrombin-induced platelet activation via inhibition of activation of the platelet protease-activated receptor 1 (7).

Aprotinin prolongs ACT measurements to various degrees, depending on the coagulation activator. When routine doses of heparin and aprotinin are used for CPB, kaolin-based ACT is less affected than celite-based ACT (8,9). However, kaolin-based ACT has also been shown to be prolonged significantly in the presence of aprotinin (9). The exact mechanism of aprotinin’s effect on ACT is still uncertain. The prolongation may be explained by aprotinin’s ability to inhibit contact activation in vitro (10,11).

Recently, a new ACT test has been developed for the SONOCLOT analyzer and is called SONOCLOT’s aprotinin-insensitive ACT, SaiACT (Sonoclot® Coagulation & Platelet Function Analyzer, Sienco Inc., Wheat Ridge, CO). This SaiACT test is designed to provide a heparin dose response substantially unaffected by aprotinin. Like other ACT machines, the SONOCLOT analyzer also incorporates a mechanical means to detect a fibrin clot. Blood is added to the SaiACT cuvette containing a blend of celite that provides contact activation and a type of clay that neutralizes aprotinin and is only a poor activator of coagulation. The two materials perform separate roles within the test: celite is formulated to provide the desired activation characteristics, and the amount of clay has been selected by the manufacturer to neutralize up to 320 kallikrein inhibiting units (kIU) of aprotinin (personal communication Sienco Inc.). After mixing the sample with these two materials, the change in impedance to movement imposed by the developing clot is measured on a small probe vibrating at an ultrasonic frequency in the coagulating blood sample. The kaolin-based ACT from HEMOCHRON (HkACT; Hemochron® 801, International Technidyne Corp., Edison, NJ) uses glass tubes containing kaolin as coagulation activator and a small cylindrical magnet which, when bound up in the developing clot, activates the detector to stop the counter of the machine.

No data have been published evaluating the new SaiACT cuvette for the SONOCLOT. The aim of the present pilot laboratory-based study was to evaluate this new SaiACT test in vitro using clinically relevant concentrations of heparin, aprotinin, and hemodilution.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With local ethics committee approval and patient written informed consent, 25 patients undergoing elective valve surgery donated 80 mL of blood immediately after induction of anesthesia and placement of an unheparinized central-venous catheter. Patients with coagulation disorders (including pharmacologically induced coagulopathies, i.e., pretreatment with any anticoagulants or antiplatelet drugs) and emergency procedures were excluded.

The blood was withdrawn in citrated tubes (sodium citrate 0.109 mol/L; Vacuette® 9NC, Greiner Bio-One, Austria) and then transferred to 16 test tubes. These tubes were divided into two groups (Fig. 1)—heparin only, to measure effects of heparin with and without hemodilution on ACT; and heparin + aprotinin, to measure the effects of heparin and aprotinin, with and without hemodilution. The test tubes were processed immediately to obtain a total of 16 different measurement conditions. First, heparinization was achieved by adding porcine heparin (Liquemin®, Roche Pharma, Switzerland) to get a final concentration of heparin in the test tubes of 0, 1, 2, and 3 U · mL–1, respectively. Then, aprotinin (Trasylol®; Bayer Pharmaceuticals Corp., Germany) was added to the heparin + aprotinin group to achieve a final concentration of aprotinin 200 kIU · mL–1 in the test tubes. The concentrations of heparin were chosen to reflect therapeutic heparinization during CPB; the level of aprotinin used is consistent with steady-state concentration during large-dose aprotinin administration for CPB. To study the influence of hemodilution, calcium-free lactated Ringer’s solution (Laboratory Dr. Bichsel AG, Switzerland) was added to half of the test tubes to produce 25% dilution (by volume, not weight).



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  		Figure 1. Study overview. Testing was performed after recalcification with SONOCLOT’s aprotinin-insensitive activated clotting time (ACT) (SaiACT) and HEMOCHRON’s kaolin-based ACT (HkACT), both in duplicate.

 

After warming the blood samples to 37°C and recalcification, ACT was measured in duplicate by two ACT analyzers according to the manufacturer’s instructions. The SONOCLOT analyzer with the new aprotinin-insensitive ACT test (SaiACT; Sonoclot® Coagulation & Platelet Function Analyzer, Sienco Inc., Wheat Ridge, CO; normal range in whole blood 62–93 s) and the HEMOCHRON analyzer with the standard kaolin-based ACT test (HkACT; Hemochron® 801, International Technidyne Corp., Edison, NJ; normal range in whole blood 91–151 s) were used. For the SaiACT, recalcification was performed by adding 15 µL of 0.25 M CaCl2 to the test cuvette. Then, 360 µL of the blood specimen was placed in this cuvette, mixed and analyzed. For HkACT, 83 µL of 0.25 M CaCl2 was added to the cuvette prior to adding 2 mL of blood. The performance of each machine was verified with recommended quality control tests according to the manufacturers. Results were recorded as mean of duplicate measurements for each of the devices. All measurements were performed by the same investigator to avoid inter-observer variability.

Statistical analysis was done using StatView® for Windows, version 5.01® (SAS Institute Inc, Cary, NC) and SPSS for Windows, Release 12.0.2 (SPSS Inc, Chicago, IL). Normal distribution of the data was examined by the Kolmogorov-Smirnov test. Pearson correlation and Bland and Altman analysis were performed for comparison of SaiACT with HkACT (12). Bias was defined as the mean of difference between the two techniques (SaiACT - HkACT), and ± 2 standard deviations (SD) of the bias reflect upper and lower limits of agreement. Pearson correlations for samples without and with aprotinin were compared by Fisher’s z-transformation and Hotelling Williams test. ANOVAs with post hoc Bonferroni-Dunn correction and two-sided paired Student’s t-test were performed to test the effect of heparin, aprotinin and hemodilution on HkACT and SaiACT readings. Test variability of duplicate measurements was calculated as percentage of the mean of duplicate measurements. Unless otherwise stated, data are presented as mean ± sd. P values < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
A total of 400 blood samples from 25 patients were analyzed (aortic valve surgery n = 20, mitral valve surgery n = 5; age 66 ± 12 yr, hematocrit 41 ± 5%, INR 0.96 ± 0.08, platelet count 242 ± 72 x 109 L–1). ACT measurements were done in duplicate with SaiACT (n = 800) and HkACT (n = 800): 87% of all ACT results were <600 s. Both analyzers were user friendly and no technical or handling problems occurred with either device during the study period.

Baseline values in the heparin only group (native blood samples) tended to be lower for SaiACT than HkACT (P = 0.059, Table 1). Twent-five percent hemodilution by calcium-free lactated Ringer’s solution significantly decreased SaiACT in these blood samples but HkACT remained unchanged (SaiACT = –18 ± 40 s [P = 0.030] HkACT = 0 ± 37 s [P = 0.959]; PSaiACT vsHkACT < 0.001). As a result, a significantly larger negative mean bias was observed for hemodiluted samples at baseline (Table 2). Administration of heparin resulted in a comparable prolongation of SaiACT and HkACT values for both undiluted and diluted samples (Tables 1 and 2). Hemodilution of heparinized blood samples induced a significant but comparable prolongation of both SaiACT and HkACT measurements (SaiACT: +43 ± 94 s [P < 0.001]; HkACT: +37 ± 82 s [P = 0.004]; PSaiACT vsHkACT = 0.119). Overall mean bias between the two measurement techniques was –5 ± 27 s for undiluted samples (Fig. 2A) and –7 ± 32 s for diluted samples (Fig. 2B). Linear regression analysis revealed a comparable strong correlation between SaiACT and HkACT for both undiluted and diluted samples (r2 = 0.966 and r2 = 0.967, respectively).


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  		Table 1. Effect of Heparin and Aprotinin on Activated Clotting Times (ACT) for SONOCLOT’s Aprotinin-Insensitive ACT (SaiACT) and HEMOCHRON’s Kaolin-Based ACT (HkACT) of Undiluted Blood Samples

 

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  		Table 2. Effect of Heparin and Aprotinin on Activated Clotting Times (ACT) for SONOCLOT’s Aprotinin-Insensitive ACT (SaiACT) and HEMOCHRON’s Kaolin-Based ACT (HkACT) of Hemodiluted Blood Samples

 


View larger version (28K):
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  		Figure 2. Bland and Altman analysis for SONOCLOT’s aprotinin-insensitive activated clotting time (ACT) (SaiACT) and HEMOCHRON’s kaolin-based ACT (HkACT) in undiluted (A) and diluted (B) heparin only blood samples. Hemodilution = 25% in vitro dilution with calcium-free lactated Ringer’s solution. Heparin only = blood samples receiving a final concentration of heparin of 0, 1, 2, and 3 U · mL–1. Mean bias = mean difference between measurements (SaiACT – HkACT) ± 2 sd (upper and lower limits of agreement).

 

Compared with the heparin only group, baseline measurements in heparin + aprotinin samples showed that addition of aprotinin 200 kIU · mL–1 to undiluted samples decreased SaiACT readings significantly (Fig. 3), whereas HkACT values remained unchanged. This effect was less marked in diluted samples. Administration of aprotinin in heparinzed blood samples prolonged HkACT and SaiACT measurements to a different degree (Tables 1 and 2): HkACT was significantly prolonged by aprotinin at heparin concentrations of 2 U · mL–1 and 3 · U mL–1 whereas SaiACT was not altered significantly (Figs. 3 and 4). Use of aprotinin in hemodiluted and heparinzed blood samples further enhanced the findings seen without hemodilution. Therefore, mean bias between the two measurement techniques was significantly increased (Table 2 and Fig. 4). Correlation of SaiACT versus corresponding HkACT values for heparin + aprotinin samples resulted in a strong correlation (r2 = 0.892). However, this correlation was significantly different from the correlation of ACT measurements for heparin only samples (P = 0.049).



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  		Figure 3. Influence of aprotinin on SONOCLOT’s aprotinin-insensitive activated clotting time (ACT) (SaiACT) and HEMOCHRON’s kaolin-based ACT (HkACT) on undiluted (A) and diluted samples (B). Hemodilution = 25% in vitro dilution with calcium-free lactated Ringer’s solution. Heparin only = blood samples receiving a final concentration of heparin of 0, 1, 2, and 3 U · mL–1; heparin + aprotinin = blood samples receiving aprotinin in a final concentration of 200 kIU · mL–1, additionally. *P < 0.05 heparin only compared with heparin + aprotinin, **P < 0.001 heparin only compared with heparin + aprotinin, §P < 0.05 SaiACT compared with HkACT, §§P < 0.001 SaiACT compared with HkACT.

 


View larger version (29K):
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  		Figure 4. Bland and Altman analysis for SONOCLOT’s aprotinin-insensitive activated clotting time (ACT) (SaiACT) and HEMOCHRON’s kaolin-based ACT (HkACT) in undiluted (A) and diluted (B) heparin + aprotinin blood samples. Hemodilution = 25% in vitro dilution with calcium-free lactated Ringer’s solution. Heparin + aprotinin = blood samples receiving aprotinin in a final concentration of 200 kIU · mL–1, additionally. Mean bias = mean difference between measurements (SaiACT – HkACT) ± 2 sd (upper and lower limits of agreement).

 

Overall test variability was comparable for both ACT measurement techniques in undiluted and diluted heparin only blood samples (SaiACT = 8.0 ± 6.1% and HkACT = 7.9 ± 6.0%; PSaiACT vsHkACT = 0.686). In heparin + aprotinin samples a significantly different test variability between SaiACT and HkACT was observed (SaiACT = 8.0 ± 6.9%, HkACT = 9.4 ± 8.5%; PSaiACT vsHkACT < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present in vitro study, the new SaiACT showed readings in heparinized blood samples similar to HkACT. Addition of aprotinin to heparinized blood samples induced no significant change of SaiACT measurements. By contrast, HkACT readings were significantly prolonged and in vitro hemodilution further increased this effect.

The ACT reflects the amount of time to form a clot by contact activation of the coagulation cascade. ACT measurement may be performed using different coagulation activators, each with unique characteristics. Contact activators commonly used in ACT tests include diatomaceous earth (celite), clay (kaolin), glass-beads, or a blend of these materials. Method validation for ACT tests is difficult, since there is no "gold standard" measurement. We compared the new SaiACT with HkACT, because kaolin-based ACT is a current clinical standard of care to monitor effects of heparinization alone and combined with aprotinin during CPB (1–3).

ACT monitoring of heparinization is not without limitations, and its use has been criticized because of significant variability and the absence of a correlation with plasma heparin concentrations during CPB (3). It has been suggested that many factors—patient, operator and equipment—can alter ACT. Therefore, ACT prolongation during CPB is not necessarily caused by heparin administration alone and may be associated with patient hypothermia (1), inadequacy of specimen warming (13), hemodilution (13), quantitative and qualitative platelet abnormalities (14), or aprotinin infusion (8,9).

Aprotinin inhibits contact activation, preferentially celite-mediated activation in vitro (10,11) and it even may have intrinsic anticoagulant properties (8,15). Interestingly, administration of another antifibrinolytic drug—tranexamic acid—did not appear to differentially affect celite- and kaolin-based ACT values (16). Since a potential anticoagulant effect of aprotinin is unclear, the prudent approach is to ensure that heparin anticoagulant effects seen with the ACT test used are comparable regardless of the presence or absence of aprotinin. Overestimation of anticoagulation, i.e., prolonged ACT, implies a potentially hazardous risk of subtherapeutic heparin anticoagulation and must be avoided during CPB. Koster et al. (17) showed that heparin management with kaolin-based ACT resulted in lower heparin concentrations compared with a heparin-concentration-based anticoagulation management during CPB. These smaller heparin concentrations in patients managed by kaolin-based ACTs were associated with increased hemostatic activation and inflammatory response.

Kaolin-based ACT is less affected by aprotinin than celite-based ACT, most likely because kaolin binds aprotinin (18) and because kaolin more potently activates coagulation than celite (10). Another newly developed ACT test, Max-ACT (Helena Laboratories, Beaumont, TX) uses a similar principle, a blend of different activators (celite, kaolin, and glass) to maximally activate the coagulation system (19). Indeed, a recent study by Jones et al. (9) showed that Max-ACT values remained almost unchanged in both unheparinized and heparinized blood samples after administration of aprotinin in vitro. By contrast, SaiACT uses celite as contact activator and a type of clay to neutralize aprotinin. As shown in the present study, the new SaiACT was not significantly affected by aprotinin compared with HkACT in vitro (Fig. 3).

Results from different ACT tests cannot be used interchangeably. Different activators have different characteristics and interactions, and even the same coagulation activator manufactured by different companies respond differently under similar conditions (9). This variability highlights the importance of establishing appropriate instrument-specific reference values for monitoring anticoagulation. Different baseline values for SaiACT must be considered when used as alternative to HkACT. In the present study, baseline SaiACT values were 4% less compared with HkACT in citrated blood samples, on average. This finding has to be considered when using SaiACT to guide anticoagulation during CPB. Surprisingly, addition of aprotinin in undiluted samples without heparin decreased SaiACT measurements significantly (Table 2). Explanations of this in vitro effect may be vague and speculative. However, it may be possible that the in vitro interaction of celite, aprotinin binding clay and aprotinin without heparin is responsible for this finding. In a study investigating the effect of aprotinin on thrombelastography (TEG®), use of different activators also resulted in different effects on TEG® tracings (20).

Hemodilution, which is frequently seen during anesthesia and surgery, may interfere with coagulation. Activation of early stages of coagulation, resulting in mild hypercoagulability in vitro, is observed with 33% hemodilution using crystalloids (21–23). In the present study, we could show this effect with SaiACT in native blood samples undergoing 25% hemodilution, but not with HkACT. It has been shown in vivo, that antithrombin declines after administration of crystalloids and that this decline is out of proportion to that expected by hemodilution alone (24).

Test variability was similarly large for both SaiACT and HkACT in the present study. According to the manufacturers of both analyzers, coefficient of variation should not exceed 5% under control conditions. Nonetheless, published data on performance of ACT devices in control plasma and whole blood differ largely. Coefficient of variation, however, was mostly less than 10% (2,25), which is similar to our findings.

Some limitations of the present study have to be considered. In vitro assays do not reflect physiological reactions to correct coagulation impairments, such as recruitment of additional resources of the coagulation system in vivo. We studied only a single dose of aprotinin (200 kIU · mL–1) and 25% hemodilution with calcium-free lactated Ringer’s solution, consistent with steady-state conditions during CPB. This may not necessarily reflect the early phase of CPB. Much larger concentrations of aprotinin may be present with a large dose aprotinin regimen (300–500 kIU · mL–1) and maximum hemodilution from initiating CPB may be more profound. Furthermore, different volumes of blood used to measure ACT with the SONOCLOT (360 µL) and the HEMOCHRON analyzer (2 mL) have to be considered. Both measurements may be affected to a varying degree by external conditions: Large volume ACT tests may be more influenced by temperature and the hypercoagulability seen in hemodiluted blood samples may depend on the sampling volume (26). Moreover, the present study was performed in citrated blood samples after recalcification. There are currently no published data on the reproducibility of recalcified blood samples for SaiACT. The only study evaluating recalcified blood samples with the SONOCLOT analyzer was done by Ekback et al. (27), who showed a 2.7 times larger variability for citrated blood samples compared with fresh blood samples (celite-based ACT).

In conclusion, the present data show that kaolin-based ACT assessed by HkACT, a clinical standard to monitor anticoagulation during CPB, is significantly prolonged after administration of aprotinin to heparinized blood samples in vitro. By contrast, the new SaiACT was stable and only minimally affected by aprotinin. However, before this new test can be widely recommended for clinical use, additional in vivo investigations will be required to determine whether this new method is clinically useful and safe for guiding heparin anticoagulation.


   Footnotes
 
This work has been presented in part at the annual meeting of the American Society of Anesthesiologists, Las Vegas, NV, October 2004.

Accepted for publication March 2, 2005.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Right arrow Blood
Right arrow Heart
Right arrow Monitoring (Non-cardiac)

Lippincott, Williams & Wilkins 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 HighWire Press