CJA
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ferring, M.
Right arrow Articles by Ricou, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferring, M.
Right arrow Articles by Ricou, B.
Canadian Journal of Anesthesia 48:1155-1160 (2001)
© Canadian Anesthesiologists' Society, 2001
Neuroanesthesia and Intensive Care

Point of care and central laboratory determinations of the aPTT are not interchangeable in surgical intensive care patients

[Les examens visant à déterminer le TCA, réalisés au chevet du malade ou dans un laboratoire central, ne sont pas interchangeables pour les patients des soins intensifs chirurgicaux]

Martine Ferring, MD, Guido Reber, PhD*, Philippe de Moerloose, MD*, Paolo Merlani, MD, Marc Diby, RN and Bara Ricou, MD

From the Divisions of Surgical Intensive Care, Department of Anesthesiology, Pharmacology and Surgical Intensive Care and the Hemostasis unit,
* Division of Angiology and Hemostasis, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland.

Professor Philippe de Moerloose, Hemostasis Unit, University Hospital, Geneva, 1211 Geneva 14, Switzerland. Phone: 0041-22-37 27 752; Fax: 0041-22-37 29 777; E-mail: philippe.deMoerloose{at}hcuge.ch


   Abstract
TOP
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: The objective of the study was to compare a bedside whole blood activated partial thromboplastin time (aPTT) performed by a point of care (POC) apparatus (CoaguCheck® Pro) in surgical intensive care (SIC) patients with a conventional aPTT obtained from the central laboratory.

Methods: The prospective concomitant measurements of the two aPTT were performed in 233 samples from 46 consecutive patients admitted after cardiovascular or major abdominal surgery.

Results: Inter-operator, inter-instrument and inter-cartridge variability of the new device measured in three healthy volunteers and in nine patients in stable condition (controls) was low (F test: P=0.86). The agreement by Bland and Altman between POC and central laboratory aPTT (-20.2 ± 18.8 sec) was not satisfactory. The agreement between POC and central laboratory aPTT in patients after surgery was worst (-17 ± 33.1 sec). Heparin treatment or timing of blood sampling after intensive care admission (<48 hr vs >48 hr) did not influence the agreement. The correlation between POC or central laboratory aPTT and anti-factor Xa activity was poor (r2 0.077 and 0.181 respectively). The test which correlated the best to heparin doses was anti-factor Xa activity (r2 0.714).

Conclusion: POC aPTT and central laboratory aPTT showed a poor agreement in SIC patients admitted after surgery, although in healthy volunteers or in control patients, this agreement was better. The best test to monitor heparin treatment in this setting was anti-factor Xa activity.


   Introduction
TOP
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
COAGULATION disorders are observed commonly in surgical intensive care (SIC) patients. Coagulation tests are, therefore, performed frequently, particularly the activated partial thromboplastin time (aPTT) which is used widely because it allows the detection of various coagulation abnormalities as well as the monitoring of heparin therapy.

The time from venipuncture to the availability of aPTT results from the central laboratory can be very long.1–4 Such delays hinder rapid diagnosis of coagulation disorders and adequate anticoagulation to be achieved rapidly. Rapid knowledge of aPTT results should allow the implementation of measures to decrease bleeding as well as the prevention of thrombotic complications.

A portable bedside point of care instrument (POC: CoaguCheck® Pro, Boehringer Mannheim Diagnostics, USA, Roche Diagnostics, Switzerland), which allows aPTT measurements in three minutes, has been shown to be accurate in both controls, anticoagulated and/or coronary unit patients1,2,5–7 and therefore may be of interest also in SIC patients. However, there are only few data available on the usefulness and reliability of such a device for these patients.4,8 The objective of this study was to evaluate prospectively the accuracy of POC in comparison with central laboratory aPTT after cardiovascular or abdominal surgery.


   Patients and methods
TOP
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients and data collection
Consecutive patients admitted to the SIC at Geneva University Hospital after cardiovascular or major abdominal surgery were enrolled from July 12 to August 20, 1999. Patients with known previous coagulation disorders were excluded. Patients were tested at six-hour intervals from admission until achievement of normal aPTT values given by the central laboratory. IV heparin was then started either for prophylactic or therapeutic use. The aPTT was thereafter determined routinely once daily and four hours after any change of heparin dosing.

To assess the inter-operator, inter-instrument and inter-cartridge variability of aPTT measured by POC, three healthy volunteers and nine SIC stable patients (before SIC discharge, without known bleeding disorder and without coagulation abnormalities) were tested (controls).

The study was approved by the Ethical Committee for Human Research of our institution.

POC and central laboratory aPTT and anti-factor Xa activity
The aPTT was determined both in the central laboratory (conventional method) and in the SIC (POC). Blood was drawn into a syringe by direct venipuncture whenever possible, or through an arterial catheter from which 10 mL (ten times the dead space) of blood4 were withdrawn prior to collection of the sample in order to minimize its contamination with heparin from the continuous irrigation systems attached to the invasive catheter. A drop of whole blood was deposited on the prewarmed aPTT cartridge of the POC, and the remainder dispensed into the tube for central laboratory assessment. The maximum delay between blood sampling and central laboratory measurement was 60 min.

For the aPTT determined in the central laboratory, plasma (citrated blood, 0.129 mol•L–1 sodium citrate) was obtained by centrifugation at 3500 x g for ten minutes at 15–20°C. Actin (Dade Behring) was used as the source of phospholipid and activator (ellagic acid). The tests were performed with automated coagulometers, either a Behring Coagulation System or a Behring Coagulation Timer (all from Dade Behring, Marburg, Germany). Maximal measuring time was set at 200 sec, the reference range being 25 to 31 sec.

Heparin concentrations were evaluated with an anti-factor Xa (anti-FXa) chromogenic assay (Berichrom Heparin, Dade Behring) and the Behring Coagulation System. Since bovine antithrombin is also present in the reagent, the test is independent of its actual concentration in the sample.9 The target values depends on the clinical situation (therapeutic ranges from 0.3 to 0.6 U•mL–1).

The POC provided by CoaguCheck® Pro is a battery-powered, portable laser photometer using a phospholipid (soybean phosphatide) as platelet substitute and a bovine brain sulfatide as activator of intrinsic coagulation. 45 µL samples of capillary, arterial or venous whole blood can be used. Instructions for use were explained to the nursing team during 20 min teaching sessions, three times per week, for four weeks. The monitors were checked every two days (20 measurements) with two level control cartridges. Each two weeks, a lyophilized whole blood internal quality control was conducted. Reference interval was established previously by the manufacturer (range 20.2 to 40.8 sec). Three portable devices were utilized. Inter-operator, inter-instrument and inter-cartridge variability of POC aPTT was determined by simultaneous analysis of the same blood sample drawn from 12 control patients by three different nurses.

Data were analyzed according to the administration of heparin, aprotinin, aspirin and clopidogrel before SIC admission.

Statistical analysis
Statistical analysis was performed on a Macintosh computer utilizing Statview II software (Abacus Concepts, Berkeley, California, USA). Results were analyzed either by Bland and Altman10 for comparison of similar assays and by linear regression analysis for different assays. To be interchangeable, we determined a priori an upper limit of ten seconds as an acceptable difference between the two methods, as it would not modify clinical management. Inter-operator, inter-instrument and inter-cartridge variability of POC aPTT were assesed by F test. We planned to analyze >200 samples to demonstrate in different subgroups of 25 samples a r >0.4 with P <0.05.

For calculation purposes, when a sample was not clottable, an arbitrary 200 sec clotting time was assigned (three samples with POC aPTT and two samples with central laboratory aPTT and two with both tests).


   Results
TOP
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
SIC patients
Forty-six patients were included in the study. Table IGo shows the patients' characteristics on admission. Two hundred thirty-three aPTT measurements were realized, 181 from cardiovascular and 52 from abdominal surgery patients. For each point, the difference between the clotting times obtained with the two assays was plotted as a function of their mean. Only clottable samples are represented. As shown in Figure 1Go, agreement between central laboratory aPTT and POC aPTT was poor (-17 ± 33.1 sec). There was an important dispersion of values and a trend towards longer clotting times with POC. When the patients were divided according to the type of surgery, the agreement was slightly better in abdominal (-23.3 ± 25.5 sec) than in cardiovascular surgery patients (-15.2 ± 35 sec). The mean difference between the two methods was lower in samples collected in the initial 48 hr (-11.5 ± 33 sec) as compared to samples collected after 48 hr (-27.5 ± 31 sec). Heparin did not influence the agreement (-20.8 ± 27 sec).


View this table:
[in this window]
[in a new window]
  		TABLE I Patients characteristics at SIC admission (n=46)
 


View larger version (27K):
[in this window]
[in a new window]
  		FIGURE 1 Agreement between activated partial thromboplastin time measured by CoaguCheck® Pro point of care and by central laboratory in different situations (A-F). The bias represents the systematic error between the two assays (bold line), the mean difference ± 2 standard deviations represents the limit of agreement or the 95% confidence interval (dotted line). The confidence interval of the difference between the two methods falls in all subgroups outside the a priori required upper limit of ± 10 sec (grey area) to accept the interchangeability of methods. Samples that were not clottable with one or both assays were omitted.

A: Samples drawn from all patients; B: Samples drawn from cardiovascular patients; C: Samples drawn from abdominal surgery patients; D: Samples obtained during initial 48 hr surgical intensive care unit (SICU) stay; E: Samples obtained 48 hr after SICU admission; F: Samples drawn from patients on heparin therapy.

 
POC as well as central laboratory aPTT values correlated poorly with heparin dosage (r2 0.035 and r2 0.061 respectively) and anti-FXa (r2 0.077 and 0.181 respectively). The best correlation with heparin dosage was obtained with anti-FXa activity measurements (r2 0.714; Table IIGo).


View this table:
[in this window]
[in a new window]
  		TABLE II Correlation between CoaguCheck® Pro aPTT, central laboratory aPTT, anti-FXa assay and heparin dosage
 
Aprotinin administration (n=14) during extracorporeal circulation or protamine administration (n=26) before SIC admission did not influence significantly the degree of agreement between central laboratory and POC aPTT (data not shown). Antiplatelet agent (aspirin and clopidogrel), renal insufficiency/failure, hepatic alterations, anemia, thrombocytopenia and temperature alterations before or during SIC did not alter the agreement between central laboratory and POC aPTT (data not shown).

In all the subgroups, the 95% of differences between the two methods fell outside the a priori assigned ± 10 sec difference required to accept the interchangeability of the methods.

Controls: Healthy volunteers and stable SIC patients
POC aPTT measurements performed by three nurses (three devices) on the same samples showed good correlation between each other (F test: P=0.86). In these samples, the agreement between mean POC aPTT and central laboratory aPTT values was better (-20.2 ± 18.8 sec) than in control SIC patients (Figure 2Go). The correlation between central laboratory aPTT and heparin doses or anti-FXa activity was good (r2 0.932 and r2 0.841 respectively) and the correlation between mean POC aPTT values and heparin doses or anti-FXa activity was satisfactory (r2 0.700 and r2 0.484).



View larger version (22K):
[in this window]
[in a new window]
  		FIGURE 2 Agreement between point of care and central laboratory activated partial thromboplastin time in healthy volunteers and control patients. The bias represents the systematic error between the two assays (bold line), the mean difference ± 2 standard deviations represents the limit of agreement or the 95% confidence interval (dotted line). The confidence interval of the difference between the two methods falls outside the a priori required upper limit of ± 10 sec (grey area) to accept the interchangeability of methods.

 

   Discussion
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our study in patients just admitted in SIC after surgery shows that the agreement between aPTT values obtained with POC and those from the central laboratory is poor, in contrast to the results obtained in controls. No acceptable agreement was found when considering either all patients, subgroups of patients or controls. Indeed, the data presented in Figure 1Go indicate that the two assays give discordant results. POC aPTT tend to be longer than central laboratory aPTT and this difference tends to increase with prolonged aPTT. Heparin and all other treatments tested or the time after SICU admission did not appear to be associated with the poor agreement observed. Analysis of subgroups of patients and of samples drawn in different clinical conditions, or under different therapeutic regimens, could not identify a major factor influencing the agreement or the correlation.

The discrepancy between central laboratory and POC aPTT values may be due to the variable reductions in multiple coagulation factors in patients at their arrival to SIC. It can hardly be due to mishandling of the new device since variability of measurements made by three well-trained nurses was low. The agreement between POC aPTT and central laboratory aPTT in controls were found to be better, confirming previous data.1–7,11–14

Our results are partly in line with other studies which have evaluated POC in cardiac surgery patients. Reich et al.8 studied 141 patients and considered an accuracy of ± 10% and a precision of ± 25% as clinically acceptable. The mean error for the aPTT values was plus seven seconds and the 95% confidence interval for the bias was -21 to + 35 sec, which were considered unsatisfactory for patient management. Nuttall et al.,15 using also a Ciba Corning 512 Coagulation Monitor (the previous model of CoaguCheck® Pro), enrolled 100 patients following cardiopulmonary bypass surgery and found a correlation coefficient (r) of 0.95 between the portable device and central laboratory measurements in arterial samples drawn ten minutes after heparin neutralization. This result is far better than the one found in our study for samples without heparin (r 0.354). However, in a subsequent analysis of 148 patients, the same authors16 reported a positive and negative predictive value for bleeding tendency after cardiopulmonary bypass with bedside aPTT devices of only 33% and 89% respectively. Boldt et al.4 studied 80 patients and found an agreement of -2.8 ± 16.5 sec with POC. The time of sampling and the influence of heparin were not mentioned. Careful examination of their data indicates that the scatter of values is about three fold less than ours. Nevertheless, the 95% confidence interval reported implies a total possible difference up to 32 sec for any single measurement, which seems considerable.

In the study by Despotis et al.,17 the bias analysis of the aPTT performed by the central laboratory or the bedside device revealed an agreement of +10 ± 28.8 sec. Thus, all studies have shown an agreement with a confidence interval of the difference between the two methods superior to the a priori determined acceptable upper limit of ten seconds.

It is well known that using the same plasma, various commercial aPTT reagents give different results.18 This is particularly true for aPTT testing in heparinized patients where deviations up to 200% have been reported.19 Werner et al.20 studied the effect of analytical uncertainty of conventional and bedside assays of aPTT on clinical decisions in heparin therapy. Despite an overall agreement of about 70%, the bedside coagulation instrument correctly classified only seven (39%) of 18 specimens with subtherapeutic concentrations of heparin. In summary, our results are not unexpected, particularly given the non standardized nature of the aPTT assay, the numerous variables that can influence aPTT immediately after surgery and the different responses of both methods to factor deficiencies and heparin.17

Monitoring heparin anticoagulation in patients who have undergone surgery associated with extracorporeal circulation represents a challenge since global tests are affected by heparin administration, possible excess protamine, acquired factor(s) deficiency, disseminated intravascular coagulation, isolated primary hyperfibrinolysis as well as use of volume expanders. The relationship between the degree of anticoagulation and the extent of clotting time prolongation of global tests like the aPTT is not easy to establish, because of a wide variability in confounding factors, in individual response and also in differences in aPTT reagents and devices. Chromogenic anti-factor assays for determination of heparin concentration allow to estimate the actual contribution of heparin to the degree of anticoagulation induced by both the drug and the hemostatic abnormalities. Therefore, dose adjustments of heparin anticoagulation are difficult to achieve with the aPTT only, especially in this type of patients. This may explain the better correlation observed between heparin dosage and anti-FXa activity than between heparin dosage and either POC aPTT or central laboratory aPTT, which is due probably to the impact of low AT III and coagulation factor levels not affecting anti-FXa activity.

In conclusion, the agreement between POC and central laboratory aPTT was poor in SIC patients after surgery but better in controls. These two tests give potentially different information and only a prospective trial comparing their usefulness for predicting clinical events could allow to establish their respective utility in postoperative SIC patients.


   Acknowledgments
 
The authors thank the nursing team of the Surgical Intensive Care, with special attention to Sylvain Senechal and Sandrine Bourquin for their active participation in this study. The authors are grateful to Miss F.M. Hannes from Roche Diagnostics, Switzerland, for providing graciously the CoaguCheck® Pro devices.

Revision received August 20, 2001. Accepted for publication May 29, 2001.


   References
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Becker RC, Cyr J, Corrao JM, Ball SP. Bedside coagulation monitoring in heparin-treated patients with active thromboembolic disease: a coronary unit experience. Am Heart J 1994; 128: 719–23.[Medline]

2 Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994; 107: 271–9.[Abstract/Free Full Text]

3 Granger CB, Hirsh J, Califf RM, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction. Results from the GUSTO-I trial. Circulation 1996; 93: 870–8.[Abstract/Free Full Text]

4 Boldt J, Walz G, Triem J, Suttner S, Kumle B. Point-of-care (POC) measurement of coagulation after cardiac surgery. Intensive Care Med 1998; 24: 1187–93.[Medline]

5 Reiner JS, Coyne KS, Lundergan CF, Ross AM. Bedside monitoring of heparin therapy: comparison of activated clotting time to activated partial thromboplastin time. Cathet Cardiovasc Diagn 1994; 32: 49–52.[Medline]

6 Ruzicka K, Kapiotis S, Quehenberger P, et al. Evaluation of bedside prothrombin time and activated partial thromboplastin time measurement by coagulation analyzer CoaguCheck Plus® in various clinical settings. Thromb Res 1997; 87: 431–40.[Medline]

7 Solomon HM, Mullins RE, Lyden P, Thompson P, Hudoff S. The diagnostic accuracy of bedside and laboratory coagulation. Procedures used to monitor the anticoagulation status of patients treated with heparin. Am J Clin Pathol 1998; 109: 371–8.[Medline]

8 Reich DL, Yanakakis MJ, Vela-Cantos FP, DePerio M, Jacobs E. Comparison of bedside coagulation monitoring tests with standard laboratory tests in patients after cardiac surgery. Anesth Analg 1993; 77: 673–9.[Abstract/Free Full Text]

9 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 10: 399–410.[Medline]

10 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; I: 307–10.

11 Ansell J, Tiarks C, Hirsh J, McGehee W, Adler D, Weibert R. Measurement of the activated partial thromboplastin time from a capillary (fingerstick) sample of whole blood. A new method for monitoring heparin therapy. Am J Clin Pathol 1991; 95: 222–7.[Medline]

12 Zabel KM, Granger CB, Becker RC, et al. Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: results of GUSTO-I. Am Heart J 1998; 136: 868–76.[Medline]

13 Becker RC, Ball SP, Eisenberg P, et al. A randomized, multicenter trial of weight-adjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Am Heart J 1999; 137: 59–71.[Medline]

14 Eiswirth G, Walch S, Bommer J. New bedside test for monitoring anticoagulation during hemodialysis. Artif Organs 1998; 22: 346–8.[Medline]

15 Nuttall GA, Oliver WC, Beynen FM, Dull JJ, Murray MJ, Nichols WL. Intraoperative measurement of activated partial thromboplastin time and prothrombin time by a portable laser photometer in patients following cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1993; 7: 402–9.[Medline]

16 Nuttall GA, Oliver WC, Beynen FM, Santrach PJ, Strickland RA, Murray MJ. Determination of normal versus abnormal activated partial thromboplastin time and prothrombin time after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1995; 9: 355–61.[Medline]

17 Despotis GJ, Santoro SA, Spitznagel E, et al. On-site prothrombin time, activated partial thromboplastin time, and platelet count. A comparison between whole blood and laboratory assays with coagulation factor analysis in patients presenting for cardiac surgery. Anesthesiology 1994; 80: 338–51.[Medline]

18 Pedersen JT, Pincus MR, Rapiejko JA. Comparison of activated partial thromboplastin time reagents. Lab Med 1988; 19: 421–4.

19 Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer. Am J Clin Pathol 1988; 89: 19–23.[Medline]

20 Werner M, Gallagher JV, Ballo MS, Karcher DS. Effect of analytic uncertainty of conventional and point-of-care assays of activated partial thromboplastin time on clinical decisions in heparin therapy. Am J Clin Pathol 1994; 102: 237–41.[Medline]




This article has been cited by other articles:


Home page
 The Annals of PharmacotherapyHome page
S. A Spinler, A. K Wittkowsky, E. A Nutescu, and M. A Smythe
Anticoagulation Monitoring Part 2: Unfractionated Heparin and Low-Molecular-Weight Heparin
Ann. Pharmacother., July 1, 2005; 39(7): 1275 - 1285.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ferring, M.
Right arrow Articles by Ricou, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferring, M.
Right arrow Articles by Ricou, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS