UFH is monitored by ACT, APTT, and anti-Xa. Of the three tests above, anti-Xa is considered to be more reliable than the other two,5 however, anti-Xa is not as commonly ordered or as often (many times a day) due to its high cost and complicating techniques. ACT is considered as the most common test being a fast and inexpensive method despite its limited reliability.3, 5 The value of the APTT test in monitoring UFH in ECMO has recently gained more attention. In recent studies, APTT moderately correlated with anti-Xa, UFH dose, and UFH concentration, while ACT poorly correlated with anti-Xa, UFH dosing, and UFH concentration.11, 14–17 These researches were mainly done in pediatric ECMO patients. Most of the reagents for the anti-Xa assay require a patient’s endogenous antithrombin instead of adding exogenous antithrombin because the prevalence of antithrombin deficiency in the general population is very low. However, acquired antithrombin deficiency has been associated with patients on ECMO, which results in a lower value of anti-Xa than heparin concentration. Therefore, we investigated the subgroup of patients without antithrombin deficiency, when the anti-Xa value correlates better with heparin concentration in order to reappraise the value of ACT and APTT tests.
In our study, there was a strong positive relationship between the value of APTT and the value of anti-Xa (r = 0.72, p < 0.001), especially in normal antithrombin level group (r = 0.80, p < 0.001). Meanwhile, ACT value correlated poorly with anti-Xa, even in the subgroup of patients with normal antithrombin level. Khaja et al. also found that APTT value correlated closer with anti-Xa than ACT value (r = 0.364 vs 0.125, respectively). However, this study was conducted on infants with a small sample size (21 patients) and no analysis on the role of antithrombin. In another study by Liveris et al., 17 pediatric and neonatal ECMO patients had shown similar results; the correlation of coagulation monitoring assay with UFH dose was poor with ACT assay, moderate with APTT assay, and strong with anti-Xa assay.11 There have been few studies to evaluate the correlation of ACT, APTT, anti-Xa, and heparin dose in adult ECMO patients. One research by Atallah et al. on 46 patients receiving ECMO found a Pearson correlation of APTT and heparin dose from 0.43 to 0.54; meanwhile, the Pearson correlation of ACT was only 0.11–0.14.14 However, the UFH dose cannot represent efficacy or concentration of UFH in adult patients, especially in critically ill patients and ECMO patients.
The ACT is a whole blood test, therefore it is influenced by all of the properties in the hemostasis system rather than only being effective to UFH. ACT is also prone to technical errors. Within the results of this study, we showed that when taking antithrombin level into consideration, ACT in the group without antithrombin deficiency was statistically higher. Unlike ACT, the APTT value correlated strongly with anti-Xa at the same time. Beside the fact that APTT is a more reliable tool to monitor anticoagulatory activity, APTT assay in our study was also done by both photo-optical and magnetic measurement methods. This helped to minimize the weaknesses of the test in cases of increased bilirubin or hemolysis, and increased the sensitivity of the test.
In regards to the UFH dose, it is usually only maintained within the therapeutic range so no outlier value was observed. In patients without antithrombin deficiency, APTT and anti-Xa values were strongly and positively correlated with each other and with UFH dose. Therefore, the UFH dose was lower and less fluctuating. For patients with antithrombin deficiency, ACT, APTT, and anti-Xa values were lower and did not correlate well with each other, causing a higher and unsteady UFH dose.
The results of this study have shown that APTT is more reliable than ACT in monitoring the efficacy and titrating UFH dose in adult patients on ECMO. We also found that the value of APTT in monitoring UFH was no less than anti-Xa level for the following reasons: (1) In patients without antithrombin deficiency, APTT strong correlation with anti-Xa; (2) In patients with antithrombin deficiency, both APTT and anti-Xa did not correlate well with UFH dose; (3) APTT is common and can be performed several times a day for monitoring UFH. In the future, APTT should be reaccessed in parallel with a more precise measuring method than the traditional quantitative anti-Xa method, such as measurement of anti-Xa by adding exogenous antithrombin in patients with antithrombin deficiency.
Strengths and limitations
To our knowledge, this is the first study that was conducted on adult ECMO patients to assess ACT, APTT, anti-Xa, and UFH dose in regarding to antithrombin level, through which to determine the relationship of these tests in different perspective.
Several limitations might be taken into account when considering our results. Firstly, this is a single-center study, so our results might have limitations when trying to generalize for other ICUs or other settings. Secondly, our sample was small, yet still sufficient to achieve the study goal.