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Communications to the Editor |

The Heparin Anti-Xa Therapeutic Range : Are We There Yet? FREE TO VIEW

Maureen A. Smythe, PharmD, FCCP; Joan C. Mattson, MD; John M. Koerber, BS Pharm
Author and Funding Information

Affiliations: Wayne State University Detroit, MI William Beaumont Hospital Royal Oak, MI,  University of Calgary Calgary, AB, Canada

Correspondence to: Maureen A. Smythe, PharmD, FCCP, Department of Pharmacy Services, William Beaumont Hospital, 3601 West 13 Mile Rd, Royal Oak, MI 48073; e-mail: msmythe@beaumont.edu



Chest. 2002;121(1):303-304. doi:10.1378/chest.121.1.303
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To the Editor:

The published supplement (January 2001)1by the American College of Chest Physicians’ (ACCP) Conference on Antithrombotic Therapy is a well-recognized, valuable publication that many clinicians frequently consult. The consensus guidelines provide a critical appraisal of the literature involving the therapeutic use of anticoagulants, antiplatelet agents, and thrombolytics. Therapeutic recommendations are graded by supporting levels of evidence.2 The purpose of this letter is to highlight a change in the recommendation for monitoring unfractionated heparin and to encourage further changes in future consensus recommendations.

The Fifth ACCP Consensus Conference published in 19983 provided a grade A1 recommendation regarding the monitoring of unfractionated heparin in the treatment of venous thromboembolism (A1 is the strongest recommendation). The recommendation was to adjust the dose of unfractionated heparin in order to prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to a heparin level of 0.2 to 0.4 U/mL by protamine titration or 0.3 to 0.6 or 0.7 U/mL by heparin anti-factor Xa analysis.45 This recommendation appeared again in the Sixth ACCP Consensus Conference published earlier this year,1 although the grading has been reduced to a 1C+.6The reduction in the strength of the recommendation is appropriate, as the supporting data come from extrapolation of randomized controlled trials. However, the implied uniform equivalency in heparin levels performed by protamine sulfate titration and heparin anti-factor Xa analysis is concerning. The suggestion of a standard equivalency between heparin levels by a neutralization assay and a functional assay has been questioned.7

Levine et al8in 1994 reported an equivalency between heparin levels by protamine sulfate titration and heparin anti-factor Xa analysis. Heparin levels by protamine sulfate titration of 0.2 to 0.4 U/mL were equivalent to chromogenic heparin anti-factor Xa levels of 0.35 to 0.67 U/mL using the Stachrom technique. Since then, however, a number of investigators913 have reported varying equivalency between heparin levels by protamine sulfate titration and levels by heparin anti-factor Xa analysis. Kitchen et al12 evaluated five chromogenic heparin anti-factor Xa assays in comparison with a protamine sulfate titration assay in samples from 43 patients receiving unfractionated heparin. The average chromogenic heparin anti-factor Xa levels that were equivalent to a heparin level of 0.2 U/mL and 0.4 U/mL by protamine sulfate titration were 0.27 U/mL and 0.44 U/mL. The maximum difference in the mean heparin level by chromogenic anti-factor Xa assay was 0.08 U/mL or 25%. Comparisons of mean heparin levels between chromogenic assays revealed individual differences of > 0.25 U/mL. These investigators also assessed the equivalency of the heparin anti-factor Xa levels using the Stachrom technique to protamine sulfate titration. Levels of 0.29 to 0.49 U/mL by heparin anti-factor Xa analysis were equivalent to heparin levels of 0.2 to 0.4 U/mL by protamine sulfate titration. This equivalency is significantly different than that reported earlier by Levine et al.8 Kovacs et al13 evaluated the impact of varying laboratory instruments and assay kits on heparin levels by chromogenic heparin anti-factor Xa analysis in 42 patients receiving unfractionated heparin. Significant differences in heparin anti-factor Xa levels were found when heparin levels were compared between instruments as well as between commercially available assays.13 The mean difference in heparin levels by anti-factor Xa analysis was as high as 0.16 U/mL. The authors concluded that the therapeutic range for heparin anti-factor Xa analysis may need to be specific for the instrument and method. It is clear that a single equivalency between protamine sulfate titration assays and chromogenic heparin anti-factor Xa assays does not exist. The range of heparin levels by chromogenic anti-factor Xa analysis that have been reported to be equivalent to heparin levels of 0.2 to 0.4 U/mL by protamine sulfate titration are shown in Table 1 . Clinicians should be aware that in addition to chromogenic anti-factor Xa assays, clot-based anti-factor Xa assays are also available. These different anti-factor Xa assay techniques have been shown,12 to produce different results. In summary, differences in heparin anti-factor Xa levels can be explained by variations in a number of factors, including assay technique (chromogenic or clot-based), instrumentation, type of commercially available assay, the use of exogenous anti-thrombin III, the use of a standard heparin preparation, varying approaches to data fitting, and variations in the process for establishing assay equivalency.12,14

The current ACCP recommendations for monitoring unfractionated heparin therapy accommodate for the well-known problem of significant variability in aPTT reagent sensitivity. Unfortunately, the recommendations do not account for or discuss the variability in heparin levels by heparin anti-factor Xa assay. As anti-factor Xa assays become automated and more routinely available, these differences will become increasingly important to recognize. The desired aPTT range would vary significantly if defined by a heparin anti-factor Xa therapeutic range of 0.30 to 0.67 U/mL vs 0.29 to 0.49 U/mL. Perhaps the College of American Pathologists in conjunction with the National Committee for Clinical Laboratory Standards need to develop guidelines for the performance of heparin anti-factor Xa levels and a process for establishing assay equivalence. Until then, we endorse the recommendation by Kovacs et al13 that the therapeutic range for heparin levels by heparin anti-factor Xa analysis be instrument and assay specific. We encourage the discussion of variability in heparin anti-factor Xa levels in the monitoring of unfractionated heparin therapy in the Seventh ACCP Consensus Conference.

Table Graphic Jump Location
Table 1. Heparin Chromogenic Antifactor Xa Levels Equivalent to 0.2 to 0.4 U/mL by Protamine Titration
Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001; 119(suppl):1S–370S.
 
Guyatt, G, Schunemann, H, Cook, D, et al Grades of recommendation for antithrombotic agents.Chest2001;119(suppl),3S-7S
 
Fifth ACCP Consensus Conference on Antithrombotic Therapy. Chest 1998; 114(suppl):1S–769S.
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest1998;114(suppl),561S-578S
 
Hirsh, J, Warkentin, TE, Raschke, R, et al Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.Chest1998;114(suppl),489S-510S
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest2001;119(suppl),176S-193S
 
Smythe, MA, Koerber, JK Heparin monitoring: the confusion continues.Pharmacotherapy1999;19,1240-1242. [PubMed] [CrossRef]
 
Levine, MN, Hirsh, J, Gent, M, et al A randomized trial comparing activated partial thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.Arch Intern Med1994;154,49-56. [PubMed]
 
Kitchen, S, Preston, FE The therapeutic range of heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays.Thromb Haemost1996;75,734-739. [PubMed]
 
Taylor, CT, Petros, WP, Ortel, TL Two instruments to determine activated partial thromboplastin time: implications for heparin monitoring.Pharmacotherapy1999;19,383-387. [PubMed]
 
Baker, BA, Adelman, MS, Smith, OA, et al Inability of the activated partial thromboplastin time to predict heparin levels.Arch Intern Med1997;157,2475-2479. [PubMed]
 
Kitchen, S, Theaker, J, Preston, FE Monitoring unfractionated heparin therapy: relationship between eight anti-Xa assays and a protamine titration assay.Blood Coagul Fibrinolysis2000;11,137-144. [PubMed]
 
Kovacs, MJ, Keeney, M, Mackinnon, K, et al Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin.Clin Lab Haematol1999;21,55-60. [PubMed]
 
Olson, JD, Arkin, CF, Brandt, JT, et al College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy, laboratory monitoring of unfractionated heparin therapy.Arch Pathol Lab Med1998;122,782-798. [PubMed]
 
To the Editor:

The authors of the preceding letter identify another frailty of anticoagulant monitoring. The issue of standardization needs to be addressed. The hope for the future is replacement of therapies that require anticoagulant monitoring with those that do not; low molecular weight heparin therapy offers such an alternative in the majority of patients.


Figures

Tables

Table Graphic Jump Location
Table 1. Heparin Chromogenic Antifactor Xa Levels Equivalent to 0.2 to 0.4 U/mL by Protamine Titration

References

Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001; 119(suppl):1S–370S.
 
Guyatt, G, Schunemann, H, Cook, D, et al Grades of recommendation for antithrombotic agents.Chest2001;119(suppl),3S-7S
 
Fifth ACCP Consensus Conference on Antithrombotic Therapy. Chest 1998; 114(suppl):1S–769S.
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest1998;114(suppl),561S-578S
 
Hirsh, J, Warkentin, TE, Raschke, R, et al Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety.Chest1998;114(suppl),489S-510S
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest2001;119(suppl),176S-193S
 
Smythe, MA, Koerber, JK Heparin monitoring: the confusion continues.Pharmacotherapy1999;19,1240-1242. [PubMed] [CrossRef]
 
Levine, MN, Hirsh, J, Gent, M, et al A randomized trial comparing activated partial thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.Arch Intern Med1994;154,49-56. [PubMed]
 
Kitchen, S, Preston, FE The therapeutic range of heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays.Thromb Haemost1996;75,734-739. [PubMed]
 
Taylor, CT, Petros, WP, Ortel, TL Two instruments to determine activated partial thromboplastin time: implications for heparin monitoring.Pharmacotherapy1999;19,383-387. [PubMed]
 
Baker, BA, Adelman, MS, Smith, OA, et al Inability of the activated partial thromboplastin time to predict heparin levels.Arch Intern Med1997;157,2475-2479. [PubMed]
 
Kitchen, S, Theaker, J, Preston, FE Monitoring unfractionated heparin therapy: relationship between eight anti-Xa assays and a protamine titration assay.Blood Coagul Fibrinolysis2000;11,137-144. [PubMed]
 
Kovacs, MJ, Keeney, M, Mackinnon, K, et al Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin.Clin Lab Haematol1999;21,55-60. [PubMed]
 
Olson, JD, Arkin, CF, Brandt, JT, et al College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy, laboratory monitoring of unfractionated heparin therapy.Arch Pathol Lab Med1998;122,782-798. [PubMed]
 
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