**8. Monitoring parameters for anticoagulation therapy**

Therapeutic anticoagulation is the gold standard for the management of VTE. The narrow therapeutic efficacy window creates challenges in drug selection and monitoring to deliver the appropriate dose to prevent further embolic events while not causing a life-threatening bleed. Historically, guidelines in VTE management include the option of continuous UFH; however, LMWH and direct factor Xa inhibitors have begun to displace UFH as first-line agents [1, 5, 16]. Traditionally, aPTT has served as the marker of therapeutic anticoagulation in patients with VTE due to the exclusive use of UFH [60–67]. Despite decades of experience with aPTT values, challenges in the precision monitoring of anticoagulation continue to create therapeutic dilemmas for clinicians [61, 62]. The lack of standardized methods in monitoring and individualized patient factors, including biological variables and heparin resistance, are credited as most problematic when using aPTT to measure the effect of UFH [63, 64]. While aPTT values remain the standard for measuring the effects of UFH, anti-factor Xa (anti-Xa) heparin assay (HA) is recommended as a monitoring option in place of aPTT values by the American College of Chest Physicians (ACCP) and the College of American Pathologists (CAP) [16, 46]. Anti-Xa levels demonstrate greater consistency in measuring anticoagulation, since they are based on the functional activity of all heparins [66, 67]. Comparatively, the aPTT test measures the function of the intrinsic and common pathways of the coagulation cascade, which can have significant variability among individuals [45, 62, 63].

The implementation of heparin dosing protocols has improved the uniformity of therapeutic anticoagulation with UFH. Most of these protocols are "weight-based," and changes in the units of UFH per hour are adjusted based on the aPTT values [68]. This method of dosing UFH has led to concerns regarding both "over" and "under" anticoagulation using aPTT-level directed therapy. Combining aPTT and anti-Xa levels has been proposed as a method to overcome the variable swings commonly seen in patients with multiple comorbidities, obesity, older age (>70 years), 16 drug-induced coagulopathies, pharmacokinetic changes, and preexisting genetic alterations [44, 45, 60, 62, 65–67]. Some hospital systems have transitioned from the use of aPTT to anti-Xa HA altogether and are reporting the faster attainment of therapeutic anticoagulation in addition to the elimination of multiple laboratory tests and dosage changes [66].

Based on numerous studies, anti-Xa levels have been shown to be a viable alternative to aPTT to achieve and maintain therapeutic anticoagulant levels with UFH [42, 60, 63, 68–70]. Anti-Xa levels have provided a more consistent method of monitoring a patient's response to UFH and demonstrate fewer blood samples and dosage adjustments compared to aPTT values [62, 67].

INR monitoring is recommended more frequently upon warfarin initiation (once a day) and can be extended to typically once a month once INR is stable and in a therapeutic range [26].

Routine laboratory monitoring is not indicated for DOAC, but anti-factor Xa (FXa) can be useful for excluding clinically important levels of DOAC [29]. Edoxaban may elevate the PT and aPTT, but FXa activity may be a better measure of effectiveness [46]. Fondaparinux does not require laboratory monitoring as well. Anti-factor Xa activity is probably the assay for monitoring fondaparinux but is not usually obtained in real time [32]. For the qualitative assessment of dabigatran, thrombin time (TT) and aPTT may be used, with TT being sensitive to dabigatran even at low drug concentrations [29].
