Heparin Monitoring: The Confusion Continues

Abstract

Earlier this year in Pharmacotherapy, Dr. Henry Bussey reviewed the numerous considerations and limitations of using the activated partial thromboplastin time (aPTT) for heparin monitoring. 1 The recommendations of two recent consensus papers on heparin monitoring from the American College of Chest Physicians and the College of American Pathologists were presented in his article.2, 3 Both organizations suggested that individual laboratories define their own aPTT therapeutic range. Samples from patients receiving heparin should be analyzed to determine the aPTT range that corresponds to a "therapeutic" heparin level of either 0.2-0.4 U/ml by protamine titration or 0.3-0.7 U/ml by antifactor Xa analysis.Since Dr. Bussey' s review, clinical investigations of unfractionated heparin have cited significantly different end points for heparin levels using antifactor Xa analysis. [4][5][6] The varying end points highlight another area of controversy surrounding heparin monitoring-the use of heparin levels. What is a therapeutic heparin level, and is 0.2-0.4 U/ml by protamine titration equivalent to 0.3-0.7 U/ml by antifactor Xa analysis?To attempt to answer the above questions, one must have a minimal understanding of the different heparin assays. The two most common are neutralization and functional assays. Neutralization assays estimate heparin activity by identifying the lowest amount of a substance (protamine sulfate or polybrene) that blocks prolongation of a coagulation test (i.e., thrombin) by heparin. The amount of protamine needed in the test plasma then is compared with the protamine required in a standard sample with a known heparin concentration.Functional assays measure the activity of heparin by inhibiting specific coagulation factors such as Xa or thrombin. This type of assay is based on the binding of heparin, antithrombin, and the activated coagulation factor. Residual activated coagulation factor is measured using enzyme-specific chromogenic or fluorogenic substrates.3, 7 Functional assays using antifactor Xa typically report a higher therapeutic range compared with thrombin-based protamine titration assays. This is due to the differential clearance of high-and low-molecular-weight heparin molecules. Low-molecular-weight molecules that inhibit factor Xa are cleared more slowly and thus accumulate.3 In general, antifactor Xa assays are more automated and are therefore less labor intensive to perform.The majority of data supporting a heparin concentration of 0.2 U/ml as the lower limit of the therapeutic range by protamine titration is limited to animal studies and subanalysis of clinical trials. One study reported inhibition of thrombus progression in a rabbit model with heparin concentrations of approximately 0.2 U/ml by protamine titration.8 A clinical trial comparing continuous intravenous heparin infusion with intermittent subcutaneous heparin in 115 patients found that 13 of 14 episodes of recurrent venous thromboembolism occurred during the first 24 hours in patients with a heparin concentration < ...

Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study

“…Initially, the goal therapeutic range was set at 1·5–2·5 times the control aPTT, but later it was recommended that the goal therapeutic range be based on a corresponding heparin concentration of 0·2–0·4 units/mL by protamine titration or 0·3–0·7 unit/mL by antifactor Xa assay . Unfortunately, the test suffers from variation among the different reagents and from several biological factors that do not reflect heparin activity . The main drawbacks of using aPTT for monitoring UFH infusion are constant fluctuating results, delay in reaching therapeutic range and the need for multiple dose adjustments and blood samples…”

“…4,5 Unfortunately, the test suffers from variation among the different reagents and from several biological factors that do not reflect heparin activity. 2,[6][7][8] The main drawbacks of using aPTT for monitoring UFH infusion are constant fluctuating results, delay in reaching therapeutic range and the need for multiple dose adjustments and blood samples. 2 The anti-Xa heparin assay is an attractive alternative for UFH infusion monitoring due to its lack of susceptibility to interference from elevated concentrations of factor VIII or fibrinogen that result from acute-phase reactions.…”

Antifactor Xa Levels versus Activated Partial Thromboplastin Time for Monitoring Unfractionated Heparin

“…Both the ACCP and CAP state that the therapeutic range for heparin is either 0.2-0.4 unit/ ml by protamine titration or 0.3-0.7 unit/ml with use of the antifactor Xa assay, but the implied equivalency of these values has been questioned. 4,6,36,52 Five publications using nine different assays have explored the relationship between levels obtained from different types of antifactor Xa assays versus a standard heparin level of 0.2-0.4 unit/ml by protamine titration (Table 3). 20,21,44,53,54 When all the results were examined, the range for the lower end was 0.24-0.35 unit/ml, with five of the nine values clustered at 0.28-0.30 unit/ml.…”

Weight-based heparin protocol using antifactor Xa monitoring

“…These include poor correlation with blood heparin concentration, varying response to aPTT reagents, and the responsiveness of aPTT to acute-phase reactants and other biological factors independent of heparin activity. [8][9][10][11] This has led to a search for alternative monitoring strategies. The functional heparin assay, also known as the antifactor Xa test, is the reference standard for testing the in vivo activity of heparin and has been promoted as a more favorable marker for monitoring a patient's response to heparin.…”