A 2016 review on parenteral direct thrombin inhibitors (DTIs) notes that although activated partial thromboplastin time (aPTT) is the standard monitoring assay for argatroban and bivalirudin, its clinical utility is limited by reagent-dependent variability, nonlinear or plateauing dose–response at higher drug concentrations, and unreliable interpretation in patients with baseline aPTT prolongation. To address these limitations, the review describes drug-calibrated assays, including dilute thrombin time (dTT), which can quantify DTI exposure more reliably than screening tests. Because conventional thrombin time is excessively sensitive to DTIs, dilution of patient plasma in pooled normal plasma yields a measurable clotting time that correlates with drug concentration. Using 26 patient specimens receiving argatroban, a linear relationship between dTT and argatroban concentration was demonstrated, allowing derivation of a tentative dTT range corresponding to approximately 0.6–1.8 µg/mL, while emphasizing that therapeutic targets require local laboratory validation. The review notes that the same methodological principles apply to bivalirudin, although detailed correlation data are presented primarily for argatroban, and concludes that dTT may serve as a useful adjunctive or alternative monitoring strategy when aPTT is unreliable or unresponsive. [1]
A recent single-center retrospective analysis evaluated dTT–based monitoring of bivalirudin in pediatric patients supported by ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO). Analysis of 115 plasma samples from 11 VAD patients and 105 results from 11 ECMO patients demonstrated a strong correlation of a bivalirudin-calibrated dTT with anti–factor IIa activity (R² = 0.94) and standard dTT (R² = 0.87), whereas correlation with aPTT was poor (R² = 0.10 in VAD patients and R² = 0.004 in ECMO patients), supporting superior analytical alignment of dTT with bivalirudin exposure. Complementing these findings, a separate 2024 conference abstract examined operational and economic outcomes of dTT-based monitoring during the first five days of ECMO support and reported fewer laboratory tests in bivalirudin-treated pediatric patients compared with unfractionated heparin, including fewer complete blood counts (17.7 vs 19.6 tests, p = 0.012), fibrinogen measurements (14.8 vs 18.0, p = 0.003), unfractionated heparin levels (7.1 vs 19.0, p <0.001), and antithrombin levels (6.3 vs 15.6, p <0.001), along with lower per-test monitoring costs for dTT ($126 vs $211) and reduced average daily monitoring costs ($2164 vs $3226). Taken together, these data support both the analytical validity and practical feasibility of dTT-based bivalirudin monitoring in pediatric mechanical circulatory support, while interpretation is limited by small sample size, single-center experience, absence of defined therapeutic targets, lack of clinical outcome correlations, and reliance on abstract-level cost data. [2], [3]
Several referenced in vitro studies compared monitoring of DTI with dTT with aPTT. A 2007 study collected blood samples from 63 patients and added argatroban, bivalirudin, and lepirudin at varying concentrations. Accurate DTI concentration was not achieved with aPTT measurements in patients with lupus inhibitors, low vitamin K-dependent factors, or elevated d-dimer levels, while dTT demonstrated accurate results in nearly all samples. Furthermore, estimated drug concentration using aPTT assay was also incorrect in numerous samples with normal baseline aPTT for all three DTIs. A 2014 study investigated differences between aPTT and dTT, as well as ECA and prothrombinase-induced clotting time (PiCT) tests in 235 excess plasma samples treated with argatroban, bivalirudin, or dabigatran. aPTT was found to correlate poorly compared to other tests in both bivalirudin- and argatroban-containing samples. ECA and dTT demonstrated the more accurate correlations. Similar conclusions were drawn in a 2016 study, reiterating the poor linear correlation with aPTT, results which may also be further hindered by patient-specific factors, including deficiencies in coagulation factors, hypercoagulation states, or antiphospholipid antibody syndrome. The use of the aPTT assay in these scenarios may result in incorrect dosing and potentially detrimental effects. [4], [5], [6]