|Year : 2012 | Volume
| Issue : 4 | Page : 287-290
Therapeutic decision analysis for monitoring UFH therapy using activated partial thromboplastin time compared with anti-Xa assay
Zinab Mourad1, Wafaa El-Neanaey1, Wael Shaalan2, Mohamed A. Faghry3
1 Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Vascular Surgery, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Vascular Surgery, Medical Military Academy, Alexandria, Egypt
|Date of Submission||20-Jun-2012|
|Date of Acceptance||15-Jul-2012|
|Date of Web Publication||21-Jun-2014|
Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria
Source of Support: None, Conflict of Interest: None
At present, the traditional activated partial thromboplastin time (a-PTT) of 1.5–2.5 times the control value for monitoring unfractionated heparin (UFH) therapy continues to be used in the coagulation laboratory of Alexandria Main University Hospital. This study was conducted for the following reasons: to evaluate the relationship between heparin concentration and a-PTT results using Sysmex CA-1500; to define thea-PTT therapeutic range for our system; and to assess the level of agreement between a-PTT results and those obtained using the anti-Xa assay for monitoring UFH therapy.
A significant positive correlation between a-PTT and anti-Xa assay results was noted (P=0.907, r=0.000, and P=0.098, r=0.000, for therapeutic a-PTT and therapeutic ratio, respectively). Regression analysis was carried out to determine the anti-Xa-derived therapeutic range (a-PTT results that correspond to a plasma heparin concentration of 0.3–0.7 U/ml by anti-Xa assay). The a-PTT therapeutic range was 64.4–107.93 s; the therapeutic range for the a-PTT ratio was 2.13–3.56 and that for the1.5–2.5 control method was 45.27–75.75 s. The agreement between the the a-PTT therapeutic range and the results of the anti-Xa assay was 78%, whereas the agreement between the 1.5–2.5 control method and the anti-Xa assay was 0.097%. Moreover, the potential for over therapeutic levels occurs more frequently with the 1.5–2.5 control method.
Anti-FXa-derived therapeutic range on Sysmex CA-1500 is superior to that obtained using the 1.5–2.5 control method in clinical decision making. Therapeutic ranges for various a-PTT reagent–coagulometer combinations could be provided by reagent manufacturers or central reference laboratories to the institutions that are not equipped to measure anti-Xa or to those for which the access to plasma samples from treated patients is limited.
Keywords: anti-Xa, activated partial thromboplastin time, unfractionated heparin therapy
|How to cite this article:|
Mourad Z, El-Neanaey W, Shaalan W, Faghry MA. Therapeutic decision analysis for monitoring UFH therapy using activated partial thromboplastin time compared with anti-Xa assay. Egypt J Haematol 2012;37:287-90
|How to cite this URL:|
Mourad Z, El-Neanaey W, Shaalan W, Faghry MA. Therapeutic decision analysis for monitoring UFH therapy using activated partial thromboplastin time compared with anti-Xa assay. Egypt J Haematol [serial online] 2012 [cited 2018 Mar 18];37:287-90. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/287/134979
| Introduction|| |
Although the use of low-molecular-weight heparin (LMWH) is increasing, unfractionated heparin (UFH) is still widely used to treat venous and arterial thromboembolic disorders 1.
Both UFH and LMWH achieve their anticoagulant effect by binding to antithrombin and by accelerating antithrombin-dependent inhibition of thrombin and coagulation factors IX, X, XI and XII. Compared with LMWH, UFH exhibits a more marked variability in anticoagulant response among individuals. This variability was caused, at least in part, by nonspecific binding of the negatively charged polysaccharide chains to positively charged plasma proteins and by nonspecific binding of UFH to platelets and activated endothelial cells 2,3.
Activated partial thromboplastin time (a-PTT) continues to be the principal method by which laboratories monitor intravenous UFH therapy. Because anticoagulant response to UFH varies among patients, the standard method of care is to monitor UFH and make dose adjustments on the basis of a-PTT results 1,4.
Two studies demonstrated that UFH therapy prolonging a-PTT to 1.5–2.5 times the control value was associated with a reduction in the risk for recurrent thrombosis.
On the basis of this evidence, use of a-PTT with a therapeutic range of 1.5–2.5 times the control value to monitor UFH became standard practice 5,6.
The use of the fixed ratio method to define the a-PTT therapeutic range was later questioned when it was noticed that various a-PTT reagent–coagulometer combinations and different lots of the same reagent sometimes differ markedly in their dose response to UFH 7,8.
Both the College of American Pathologists (CAP) and the American College of Chest Physicians (ACCP) recommended that site-specific validation of the heparin therapeutic range should be established 1,7. At present, the traditional a-PTT of 1.5–2.5 times the control value for monitoring UFH therapy continues to be used in the coagulation laboratory of Alexandria Main University Hospital. This study aimed: to evaluate the relationship between heparin concentration and a-PTT results using Sysmex CA-1500; to define an a-PTT therapeutic range for our system; and to assess the level of agreement between results of a-PTT and the anti-Xa assay for monitoring UFH therapy.
| Methods and subjects|| |
The present study included 50 adult patients undergoing UFH therapy for a variety of clinical indications. They were admitted to the Vascular Surgery Department of Alexandria Main University Hospital and Alexandria Armed Forces Hospital. All patients had a normal PT and a-PTT with a baseline international normalized ratio (INR) of less than 1.3 before initiation of UFH therapy, and no patient was on concomitant warfarin or other medications reported to affect coagulation testing. Twenty healthy controls of matched age and sex were also included in the study.
Informed consent was obtained from patients before starting the study and the study was approved by the Ethics Committee of the Faculty of Medicine, Alexandria University.
All individuals under study were subjected to the following:
- Full history taking including the demographic data of patients and the clinical indications for UFH therapy.
- Baseline sample collection for PT and a-PTT using Sysmex-CA 1500 (Siemens Health care Diagnostics Inc., USA).
- Analysis of the complete blood count (CBC) using Sysmex XT-1800 (Siemens Health care Diagnostics Inc., USA).
- Collection of a second sample, which was done only 4–6 h after intravenous infusion of the bolus dose; this sample was used for the following:
- determination of therapeutic a-PTT and CBC.
- antifactor Xa assay using Berichrom heparin on Sysmex-CA 1500 (Siemens Health Care Diagnostics Inc., USA) 9.
Blood specimens were drawn from each patient under aseptic conditions by venipuncture of the extremity opposite that into which the infusion was being administered to avoid artefacts because of possible contamination of the sample by heparin infusion. Drawing blood using an indwelling catheter was avoided because of possible contamination of the sample with heparin from the catheter. Venous blood samples were collected into siliconized vacuum tubes containing a final concentration of 3.2% trisodium citrate. All samples were centrifuged within 1 h of sample collection to avoid heparin neutralization from platelet factor 4 and processed immediately for a-PTT assay using a single lot of pathromtin-SL reagent for the entire study. The remaining plasma samples were stored in capped plastic tubes at −20°C for anti-FXa assay to be conducted within 1 month. The therapeutic a-PTT range was calculated by identifying the a-PTT values corresponding to anti-FXa levels of 0.3–0.7 IU/ml. Changes in reagent lots and/or instrumentation require revalidation of the therapeutic range. Laboratories may repeat the same validation process or analyse samples from patients receiving intravenous heparin therapy using the original a-PTT reagent lot or method and the new a-PTT lot. Thereafter, results are compared to determine a clinically equivalent response. The mean difference between results from the lot used to establish the a-PTT therapeutic range and those from a subsequent lot not exceed 7 s 10.
Data were analysed using the SPSS V (17) computer program (SPSS Inc., Chicago, Illinois, USA) 11.
The predictability and prediction interval were calculated using the following formula:
Confidence interval was calculated using the following formula:
using the Design of Experiments (DOE++) software (Warsaw, Poland).
| Results|| |
The age of the patients under study ranged from 26 to 85 years with a mean of 50.76±15.33 years, and the age of patients in the control group ranged from 33 to 79 years with a mean of 52.9±7.1 years.
The demographic data and indications for the patients under UFH therapy are shown in [Table 1] and [Table 2].
The mean values of therapeutic a-PTT were significantly higher than basal PTT values, as shown in [Table 3].
|Table 3: The mean values of activated partial thromboplastin time and anti-Xa assay in patients under unfractionated heparin therapy|
Click here to view
A significant positive correlation between a-PTT results and the results of the anti-Xa assay was noted (P=0.907, r=0.000, and P=0.098, r=0.000, for therapeutic a-PTT and therapeutic ratio, respectively).
In accordance with CAP guidelines, regression analysis was carried out to determine the anti-FXa-derived therapeutic range (a-PTT results that correspond to plasma heparin concentrations of 0.3–0.7 U/ml by the anti-Xa assay). The results are shown in [Table 4] and [Figure 1] and [Figure 2].
|Figure 1: Regression line for therapeutic activated partial thromboplastin time (a-PTT) versus heparin concentration using the anti-Xa assay.|
Click here to view
|Figure 2: Regression line for therapeutic activated partial thromboplastin time (a-PTT) ratio versus heparin concentration using the anti-Xa assay.|
Click here to view
The decision of dose adjustment was defined as the action taken on receipt of a-PTT or heparin assay results. Decision analysis for appropriateness of the dosage adjustment decision wasbased on a-PTT test results compared with the decision using heparin concentration results by anti-Xa assay. This analysis assumes that the decision based on heparin concentration is the correct decision. The agreement between the a-PTT therapeutic range and results of the anti-Xa assay was 78%, whereas the agreement between the results of the 1.5–2.5 control method and the anti-Xa assay was 0.097%. Moreover, the potential for over therapeutic levels in comparison with the anti-FXa-derived therapeutic range occurs more frequently with the 1.5–2.5 control method [Table 5].
|Table 5: Decision analysis for the activated partial thromboplastin time therapeutic range in patients under unfractionated heparin therapy|
Click here to view
Predictability of the heparin level from the a-PTT and the prediction interval are used to estimate the range of heparin concentration for any given a-PTT value.
B-value for lower limit of a-PTT=0.00599
B-value for upper limit of a-PTT=0.01
For example, if a-PTT=120 s, predictability of heparin level=0.79 U/ml with prediction interval=0.55–1.03 U/ml
Confidence interval was determined using the Design of Experiments (DOE ++) software (for a given a-PTT you would be 95% confident that the actual heparin level would fall within this interval).
When a-PTT=120 s
Lower limit: −0.2381+0.0067×120=0.566
Upper limit: −0.0981+0.0084×120=0.91
| Discussion|| |
a-PTT is the most widely used laboratory test for monitoring heparin therapy because it is widely available, rapid, easily automated, simple to perform and relatively inexpensive. However, the a-PTT value is influenced by reagents and methods of detection. The availability of the anti-FXa assay on automated coagulation analysers presents the opportunity to reassess the use of a-PTT as a primary laboratory tool for monitoring heparin therapy 12. The optimal a-PTT instrument would be defined as that with the highest correlation with heparin concentration and the best level of agreement with heparin concentration in clinical decision making. In the present study, regression analysis has been carried out on a-PTT versus anti-Xa assay using Sysmex CA-1500. The R2 values were 0.822 and 0.824 for therapeutic a-PTT in seconds and ratio, respectively. Smythe et al. 13 reported that R2 values were 0.82 using MDA-180 and 0.58 using a bedside CoaguloChek plus system. The variability in the reported strength of the relationship between heparin concentration and a-PTT can be explained by methodological differences including type of heparin assay, a-PTT instruments, reagents, sample size and data transformation techniques 14,15.
Another approach to evaluate the use of a-PTT for UFH monitoring is to compare the clinical decisions based on a-PTT with those based on heparin levels using the anti-Xa assay. In our study, the level of agreement was 78 and 0.097% for therapeutic a-PTT and the 1.5–2.5 control method, respectively, using Sysmex CA-1500. Smythe et al. 13 compared the clinical decisions based on therapeutic a-PTT with those based on the anti-Xa assay and reported that the agreement was 82% on MDA-180 and 65% on the bedside CoaguloChek plus system.
Furthermore, we observed that the a-PTT therapeutic range with the lower limit set by the 1.5–2.5 control method was consistent with the subtherapeutic heparin level (<0.3 U/ml). These data were in agreement with those from the study by Bates et al. 7, using different coagulometers and common reagents including pathromtin-SL.
Moreover, Cuker and colleagues suggested that the anti-Xa assay can be clinically superior to both the anti-Xa correlation method and the 1.5–2.5 control method in monitoring UFH. However, its high cost and familiarity of clinicians with a-PTT limit its use 16.
| Conclusion|| |
The anti-FXa-derived therapeutic range on Sysmex CA-1500 is superior to that obtained by the 1.5–2.5 control method in clinical decision making. Therapeutic ranges for various a-PTT reagent–coagulometer combinations could be provided by reagent manufacturers or central reference laboratories to the institutions that are not equipped to measure anti-Xa or to those for which the access to plasma samples from treated patients is limited.
| References|| |
|1.||Hirsh J, Raschke R. Heparin and low-molecular weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:1885–2035 |
|2.||Lindahl U, Backstorm G, Hook M. Structure of antithrombin-binding site in heparin. Proc Natl Acad Sci USA. 1979;76:3198–3202 |
|3.||Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the a-PTT: time for fresh look. Thromb Haemost. 2006;96:547–552 |
|4.||Francis JL, Groce JB III. Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy. 2004;24:1085–1195 |
|5.||Chiu MH, Hirsh J, Yung WL, Gent M. Relationship between the anticoagulant and antithrombotic effect of heparin in experimental venous thrombosis. Blood. 1977;49:171–184 |
|6.||Basu D, Gallus A, Hish J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972;287:324–327 |
|7.||Bates MS, Weitz JI, Johnston M, Hirsh J. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med. 2001;161:385–391 |
|8.||Kitchen S, Jennigs I, Woods AT, Preston FE. Wide variability in the sensitivity of A-PTT reagents for monitoring of heparin dosage. J Clin Pathol. 1996;49:297–306 |
|9.||Lyons KS, Nesbitt V, Menown IB. Dose capping of enoxaparin results in sub-therapeutic anti-Xa level. Br J Cardiol. 2011;18:82–83 |
|10.||Olson JD, Arkin CF, Brandt JT. College of American pathologists conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122:782–798 |
|11.||Wallach J Interpretation of diagnostic tests. 20007th ed. Philadelphia, USA Williams and Wilkins |
|12.||Lehman CM, Frank EL. Laboratory monitoring of heparin therapy: partial thromboplastin time or anti-Xa assay? Lab Med. 2009;40:47–51 |
|13.||Smythe MA, Koerber JM, Westley SJ, Nwak SN. Use of the activated partial thromboplastin time for heparin monitoring. Am J Clin Pathol. 2001;115:148–155 |
|14.||Opartkiattikul N, Tientadakul P, Wongtiraporn W. Evaluation of the activated partial thromboplastin time sensitivity to unfractionated heparin using three commercial reagents: implication for therapeutic range. Siriaj Med J. 2005;57:537–540 |
|15.||Favaloro EJ, Bonar R, Sioufi J, Wheeler M, Low J. An international survey of current practice in the laboratory assessment of anticoagulant therapy with heparin. Pathology. 2005;37:234–238 |
|16.||Cuker A, Paashkin B, Konkle BA, Pipe SW, Whinna HC. Interlaboratory agreement in the monitoring of unfractionated heparin using the anti-factor Xa-correlated activated partial thromboplastin time. J T Haemost. 2008;7:80–86 |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]