Caution in Using the Activated Partial Thromboplastin Time to Monitor Argatroban in COVID-19 and Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT)

Abstract

Introduction Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients’ baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. Methods Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. Results Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. Conclusions We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.

Monitoring of Argatroban in Critically Ill Patients: A Prospective Study Comparing Activated Partial Thromboplastin Time, Point-of-Care Viscoelastic Testing with Ecarin Clotting Time and Diluted Thrombin Time to Mass Spectrometry

“…Most cases of ecarin test inaccuracy were related to samples with low argatroban plasma concentrations, for which ecarin-clotting time test overestimated argatroban concentrations. In contrast to this finding, activated PTT generally failed to detect argatroban overdosing, and for activated PTT, this plateau effect has been described 12,40 and could be related to high FVIII levels, 13,43 which was not investigated in our study. In contrast, an overestimation of low argatroban plasma concentrations in the ecarin test has not been described so far.…”

“…Furthermore, Guy et al 39 reported similar results for the monitoring of argatroban in patients with vaccine-induced thrombocytopenia and thrombosis, concluding that the significant differences between activated PTT and diluted TT could have a relevant clinical impact. 12 Siegmund et al 40 compared different activated PTT assays to an ecarin-based assay with argatroban-spiked blood from different donors and reported wide differences between the different activated PTT agents, as well as the plateau effect for some activated PTT agents. They concluded that an ecarin-based assay should be preferred over activated PTT.…”

“…In this situation, activated PTT sensitivity for anticoagulatory effects is reduced, an in vitro effect that may not necessarily reflect the clinical coagulation status in these patients and that can lead to an underestimation of the anticoagulation effects of argatroban or heparin. [12][13][14] On the other hand, septic or ECMO patients frequently present with decreased FXII values, resulting in a prolonged activated PTT, which does not correlate with increased bleeding risk but may lead to an overestimation of the anticoagulation effects of argatroban or heparin. 15 As an alternative to activated PTT testing, diluted thrombin time (TT) 16 or ecarin-dependent assays 17 can be used to monitor direct thrombin inhibitors including argatroban.…”

“In Less than No Time”: Feasibility of Rotational Thromboelastometry to Detect Anticoagulant Drugs Activity and to Guide Reversal Therapy

“…aPTT is recommended for routine use, but very low doses often result in prolonged aPTT, and the correlation between aPTT values and plasma argatroban concentration is poor [ 96 , 97 , 98 , 99 , 100 ]. In the high-dose range, ecarin clotting time (ECT) has been proposed [ 101 ]; however, this test is only available in specialized hospitals.…”

Novel Monitoring and Dose Adjustment of Argatroban, a Direct Thrombin Inhibitor, to Maintain Therapeutic Anticoagulation in a Patient With Antiphospholipid Antibody Syndrome, Heparin-Induced Thrombocytopenia, and COVID-19 Pneumonia

“…When samples were further analyzed by LC MS/MS, the results were more likely to be concordant with the dTT versus aPTT results for both bivalirudin and argatroban-treated samples ( 6 ). An additional recent study, specifically in three patients with COVID-19 suggested unreliability of the aPTT in monitoring argatroban ( 8 ). In total, these studies demonstrate that dTT levels, in contrast to aPTT levels, can be a more consistent measure of anticoagulant effect in certain patients treated with DTIs.…”