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Variation in reagent sensitivities confounds use of the aPTT with UFH, DTI, and the combination

William E. Dager, Pharm.D., FCSHP
January, 2007

Reference: Gosselin RC, King JH, Janatpour KA, Dager WE, Larkin EC, Owings JT. Comparing direct thrombin inhibitors using aPTT, ecarin clotting time and thrombin inhibitor management testing. The Annals of Pharmacotherapy 2004; 38:1383-8.

The aPTT is a test that has several uses, and attempts to date to standardize it have not achieved desired goals. The target range for heparin is typically derived in the clinical lab based on a value that corresponds with an anti-Xa of 0.3-0.7 (functional assay) for "Treatment" related intensity of anticoagulation. This, in part, is based on extrapolations from observations in 1972 suggesting that achieving an aPTT ratio of 1.5-2.5 times control was associated with a reduction in recurrent VTE. Current reported aPTT ranges would vary considerably between reagents based on each reagent's sensitivity to heparin and how the clinical laboratory processes the sample. If the reagent used is very sensitive to heparin, a higher aPTT target range (i.e. 80-100) may occur. If a clinical trial used a reagent with a lower sensitivity to heparin, the target aPTT would be lower (i.e. 60-80). If a given site where a more sensitive reagent is used adopted the same aPTT range used in the clinical trial, the heparin doses would be lowe and the patients would be under anticoagulated. The aPTT may also be used for other purposes such as detection of lupus anticoagulant or intensity of direct thrombin inhibitor effect, where a different pattern of sensitivity may exist. Ideally, the DTI target range should be calibrated with the specific agent's concentration, but is not a current part of assay range validation steps.

The target range for a DTI was established based on the design of the clinical trials for a ratio. Typically, this is 1.5-2.5 times control (patients baseline value off heparin) when Lepirudin or Bivalirudin are used and 1.5-3.0 for Argatroban. These ranges may not correlate with the same target for heparin for a given aPTT assay. If the target for a very heparin sensitive assay is used, the potential for over anticoagulation should be considered. Of additional note is that the pharmacologic mechanisms between a DTI and unfractionated heparin are notably different and should be considered when comparing "target ranges."

Recently we evaluated several clot-based assays "in vitro" for Bivaluridin, Argatroban and Lepiridin and noted that the aPTT value reported may vary with the sensitivity of the assay. As such, the potential exists where an assay of lower sensitivity may suggest a need to increase the rate, while a very sensitive assay may suggest reducing the rate despite the presence of the same DTI serum concentration. Also, it has been noted that a flattening of the concentration to aPTT rise curve will occur (Minimal change in the aPTT as the DTI compared to the rise in the DTI concentration).

Putting this together, there is no evidence that the aPTT target for heparin is the same for a DTI. Current target aPTT ranges for heparin, and separately for each DTI should be determined independently of each other.

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Sunday, May 26, 2024