Drug monitoring

Monitoring of heparin or direct or acting anticoagulant (DOAC) therapy is important to ensure appropriate dosing. Direct oral acting anticoagulants are newer drugs that target activated factor X (FXa) and can be given orally unlike heparin-based anticoagulants, which are injectable (subcutaneously or intravenously) The DOACs include rivoraxaban and apixaban, which have been evaluated in dogs, cats and horses (Myers et al 2015Dixon-Jimenez et al 2016, Morassi et al 2016Conversy et al 2017, Rodriguez-Pozo et al 2017Serpa et al 2019). Guidelines for target heparin doses are extrapolated from the human literature and may not be applicable to animals. There are currently no guidelines for DOAC monitoring, however it is likely these will be extrapolated from the human literature. Most studies on therapeutic heparin monitoring have been done in dogs (Brooks, 2004). We can assess for the presence of heparin in the sample by its ability to bind to antithrombin, which then inhibits thrombin and activated factor Xa (usually) or thrombin. So in essence, we are not measuring heparin directly but indirectly through AT activity. The activity of heparin can be measured through prolongation of the activated partial thromboplastin time (APTT) and inhibition of factor Xa by AT, which is also called anti-Xa activity. The latter is performed in preference to the APTT because it is more accurate, but anti-Xa testing is only offered by some laboratories. Anti-Xa activity can be used to monitor treatment with fractionated (low molecular weight) or unfractionated heparin, but the APTT can only be used to monitor unfractionated heparin (which inhibits thrombin more than FXa). In 2019, a review of the literature by the American College of Veterinary Emergency and Critical care resulted in the consensus recommendation that therapy with unfractionated heparin in dogs should be monitored with anti-Xa activity (Sharp et al 2019). Guidelines for discontinuation of anticoagulant therapy are also provided (Brainard et al 2019).

Method of measurement

  • APTT-based testing: This can only be done for unfractionated heparin and relies on the routine APTT.
  • Anti-Xa activity: This is done for unfractionated and fractionated or low molecular weight heparin and DOACs. A standard amount of bovine factor Xa is added to the patient plasma, along with a chromogenic substrate that will be cleaved by factor Xa. If factor Xa is inhibited by heparin (through antithrombin), the substrate will not be cleaved. Thus the anti-FXa activity is inversely proportional to cleavage of the substrate. Results are expressed as Xa inhibitory units (in U/ml), using a drug specific calibrator as a standard.

Test interpretation

  • APTT-based testing: For unfractionated heparin, the target therapeutic range is an APTT that is prolonged 1.5-2.5x normal.
  • Anti-Xa activity: Target values are 0.35-0.7 U/ml for unfractionated heparin and 0.5-1.0 U/ml 2-4 hours after  low molecular weight heparin in dogs (Brooks, 1994, Sharp et al 2019).

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