• Users Online: 88
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 37  |  Issue : 4  |  Page : 287-290

Therapeutic decision analysis for monitoring UFH therapy using activated partial thromboplastin time compared with anti-Xa assay


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 Submission20-Jun-2012
Date of Acceptance15-Jul-2012
Date of Web Publication21-Jun-2014

Correspondence Address:
Wafaa El-Neanaey
Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000419288.92101.39

Rights and Permissions
  Abstract 

Aim

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.

Results

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.

Conclusion

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 2017 Jun 28];37:287-90. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/287/134979


  Introduction Top


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 Top


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:

  1. Full history taking including the demographic data of patients and the clinical indications for UFH therapy.
  2. Baseline sample collection for PT and a-PTT using Sysmex-CA 1500 (Siemens Health care Diagnostics Inc., USA).
  3. Analysis of the complete blood count (CBC) using Sysmex XT-1800 (Siemens Health care Diagnostics Inc., USA).
  4. 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:
    1. determination of therapeutic a-PTT and CBC.
    2. antifactor Xa assay using Berichrom heparin on Sysmex-CA 1500 (Siemens Health Care Diagnostics Inc., USA) 9.


Sampling

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.

Statistical analysis

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:

a+b(PTT)

using http://www.danielsoper.com/statcalc/calc26.aspx.

Confidence interval was calculated using the following formula:

a+b(PTT)

using the Design of Experiments (DOE++) software (Warsaw, Poland).


  Results Top


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].
Table 1: Demographic data

Click here to view
Table 2: Indications for unfractionated heparin therapy

Click here to view


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].
Table 4: Activated partial thromboplastin time therapeutic ranges

Click here to view
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.

Predictability=−0.168+0.008(PTT)

Prediction interval=−0.168+B(PTT)

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 Top


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 Top


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.[16]

 
  References Top

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  Back to cited text no. 1
    
2.Lindahl U, Backstorm G, Hook M. Structure of antithrombin-binding site in heparin. Proc Natl Acad Sci USA. 1979;76:3198–3202  Back to cited text no. 2
    
3.Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the a-PTT: time for fresh look. Thromb Haemost. 2006;96:547–552  Back to cited text no. 3
    
4.Francis JL, Groce JB III. Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy. 2004;24:1085–1195  Back to cited text no. 4
    
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  Back to cited text no. 5
    
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  Back to cited text no. 6
    
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  Back to cited text no. 7
    
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  Back to cited text no. 8
    
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  Back to cited text no. 9
    
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  Back to cited text no. 10
    
11.Wallach J Interpretation of diagnostic tests. 20007th ed. Philadelphia, USA Williams and Wilkins  Back to cited text no. 11
    
12.Lehman CM, Frank EL. Laboratory monitoring of heparin therapy: partial thromboplastin time or anti-Xa assay? Lab Med. 2009;40:47–51  Back to cited text no. 12
    
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  Back to cited text no. 13
    
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  Back to cited text no. 14
    
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  Back to cited text no. 15
    
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  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods and subjects
Results
Discussion
Conclusion
Introduction
Methods and subjects
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed935    
    Printed21    
    Emailed0    
    PDF Downloaded91    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]