The multiple faces of the partial thromboplastin time APTT

Abstract

In his review, White concluded that for 50 years, the activated partial thromboplastin time (APTT), along with Quick's prothrombin time (PT), has defined an era of coagulation [1]. For decades, these two coagulation assays have been the mainstay for adjusting doses of unfractionated heparin [2, 3] and coumarins [4], respectively. However, whereas there is good evidence that the result of the PT [expressed as an International Normalized Ratio (INR)] predicts the efficacy and safety of coumarins [5, 6], the evidence that the APTT predicts these outcomes for heparin is less secure. Indeed, based on the totality of the data, it could be argued that the APTT is only marginally relevant to the efficacy and safety of heparin treatment. In a study published in 1972, Basu and associates reported that heparin doses that prolonged an APTT to 1.5–2.5 times control were associated with a reduced risk for recurrent thromboembolism [7]. This conclusion was based on the results of a retrospective analysis of a prospective study and was never confirmed prospectively. Despite this shortcoming, a therapeutic APTT range of 1.5–2.5 times control gained widespread acceptance and became standard practice [8-10]. Subsequently, as for the PT test, it was shown that due to marked variability in the sensitivity of APTT reagents to heparin, the use of a fixed APTT ratio for all reagents is inappropriate. The magnitude of the variability in responsiveness of APTT reagents is at least as large as for the PT test. Thus, at a plasma heparin concentration of 0.3 IU mL−1 measured by factor (F)Xa inhibition, the corresponding APTT results range from 48 to 108 s, depending on the reagent used [11, 12]. Further, an anti-FXa level range of 0.3–0.7 IU mL−1, the generally accepted criterion standard for the therapeutic range for heparin, corresponds to APTT ratios of between 1.6 and 2.7 to 3.7 and 6.2 times control with different reagents [11-15]. Therefore, the use of a ‘standard’ APTT therapeutic range of 1.5–2.5 for all reagents would be expected to lead to systematic administration of subtherapeutic doses of heparin in many hospitals. The College of American Pathologists [16] and other organizations have joined the American College of Chest Physicians [17] in advising against the use of ‘standard’ or fixed APTT therapeutic ranges, such as 1.5–2.5 times control. Instead, they recommend that the therapeutic APTT range for the treatment of venous thrombosis be calibrated specifically for each reagent lot–coagulometer combination by determining the APTT values that correlate with anti-FXa levels of 0.3–0.7 IU mL−1 in plasma samples from at least 30 heparin-treated patients. If this type of calibration cannot be performed, the use of an APTT ratio of 2.0–3.5 times control with modern APTT reagents is preferable to an APTT ratio of 1.5–2.5 times control [12, 18]. Why was a heparin level range of 0.3–0.7 IU mL−1 by FXa inhibition selected as the target for the treatment of venous thromboembolism? This range was derived from a post hoc analysis of the clinical study by Basu and colleagues [7] (described above) and a subsequent animal study by the McMaster group that showed that thrombus extension was prevented by heparin given in a dose that prolonged the APTT ratio to 1.5–2.5 times control; an APTT ratio that was shown to correspond to a heparin level by protamine titration of 0.2–0.4 U mL−1[19]. Subsequently, it was shown that this heparin level was equivalent to 0.3–0.7 IU mL−1 by FXa inhibition. Rather shaky foundations upon which to build a universal therapeutic range! Despite using a standard APTT ratio (usually 1.5–2.5 times control), most contemporary clinical trials have reported that heparin is effective and relatively safe for the treatment of venous thromboembolism [18, 20, 21] and for acute coronary ischemia [22]. How can the apparent contradictions between the use of a fixed APPT ratio with the attendant variability in the achieved anticoagulant effect of heparin be reconciled with its apparent effectiveness in contemporary clinical trials in venous thromboembolism and acute coronary ischemia? A relationship has been reported between the dose of heparin administered and its efficacy [9, 23, 24] and safety [25, 26], and since a relationship exists between heparin dose and APTT, it would be expected that the anticoagulant effect of heparin, as measured by the APTT, would have some predictive effect for heparin's efficacy and safety. However, neither a meta-analysis [27] nor a subgroup analysis [28] of three randomized trials that compared unfractionated heparin with low-molecular-weight heparin demonstrated a relationship between a ‘subtherapeutic’ APTT and the risk of recurrent venous thromboembolism in patients who received adequate starting doses of heparin (see below). Thus, it is likely that the initial dose of heparin is a better determinant of efficacy than the APTT response. Further, a randomized trial comparing the safety and efficacy of heparin monitoring according to the APTT and anti-FXa levels in patients with subtherapeutic APTTs despite high doses of heparin demonstrated that dose escalation to achieve a therapeutic APTT can be avoided if the heparin level is therapeutic [29]. This suggests that in patients requiring high doses of heparin, it is more appropriate to use anti-FXa levels, rather than the APTT, to guide therapy. Heparin in starting doses of about 5000 U (or 70 U kg−1) followed by 1200–1300 U h−1 (or 18 U kg−1 h−1) is more effective than no heparin or than lower doses of heparin for the treatment of venous thrombosis [9, 23, 30]. Perhaps, after an initial adequate dose, continued high doses of heparin are not a necessary requirement for efficacy, particularly if a vitamin K antagonist is started soon after initiating treatment with heparin. Although heparin-associated bleeding is likely to be influenced by the dose administered, patient-related factors, particularly recent surgery or trauma, are probably much more predictive of bleeding than APTT results [31]. The subject of APTT monitoring to guide heparin dosage is becoming moot with the introduction of new anticoagulants that are at least as effective as heparin, despite being used in fixed or weight-adjusted doses without monitoring with coagulation assays [20-22, 32, 33]. Although these new anticoagulants exhibit less variability in their anticoagulant response to fixed dosing than heparin, their anticoagulant response is still quite variable among patients. Fortunately, they have been evaluated without coagulation monitoring, because had this been a part of the clinical development process, the convenience of fixed dosing for thrombosis treatment might have been replaced by a new wave of expensive coagulation tests to guide dosing. We are grateful to R. Raschke, J. Ginsberg and C. Kearon for their helpful comments.