Further evidence of the limitations of Activated Partial Thromboplastin Time to monitor Argatroban

Abstract

Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietinreceptor agonists: a single-center, long-term follow-up. Haematologica, 99, 937-944. Khellaf, M., Viallard, J.F., Hamidou, M., Cheze, S., Roudot-Thoraval, F., Lefrere, F., Fain, O., Audia, S., Abgrall, J.F., Michot, J.M., Dauriac, C., Lefort, S., Gyan, E., Niault, M., Durand, J.M., Languille, L., Boutboul, D., Bierling, P., Michel, M. & Godeau, B. (2013) Further evidence of the limitations of Activated Partial Thromboplastin Time to monitor ArgatrobanThe British Committee for Standards in Haematology Guideline on the diagnosis and management of heparin-induced thrombocytopenia (2nd Edition) recommends that argatroban should be monitored using an activated partial thromboplastin time (APTT) ratio target of 1Á5-3Á0, but not exceeding 100 s (Watson et al, 2012). This is based on multicentre heparin-induced thrombocytopenia (HIT) studies (Lewis et al, 2001) and a trial of argatroban in healthy subjects (Swan et al, 2000). To the best of our knowledge the first reference to APTT not exceeding 100 s is in Lewis et al (2001). A subsequent retrospective analysis of the trial by Lewis et al (2001) showed that an APTT exceeding 100 s was significantly associated with major bleeding compared to a lower APTT (Hursting & Verme-Gibboney, 2008). Recruitment to this trial permitted a baseline APTT ratio of 2Á0 prior to initiation of argatroban and it is unclear how bleeding was related to baseline APTT, which could offer an alternative explanation for the increased bleeding tendency found. Swan et al ( Siegmund et al (2008) demonstrated that, to achieve a two-fold increase in APTT, significantly different argatroban concentrations were needed depending on the underlying clinical condition and on the reagent used. A two-fold increase in APTT in plasma spiked with argatroban from healthy volunteers (HV) and patients with liver disease (LD) with the four reagents required HV/LD concentrations of 0Á73/0Á46; 0Á82/0Á64; 1Á14/0Á69; 0Á86/0Á47 lg/ml. They also showed that the APTT was over 100 s in all but one LD sample; these patients would receive lower doses of argatroban than individuals without liver disease. We previously reported a significantly higher APTT ratio (2Á6) in spiked normal plasma with Actin FS when compared to Actin FSL 2Á2, SynthASil 2Á1, APTT-SP 2Á2; also reflected in patient samples (Actin FS mean APTT ratio 1Á89 versus SynthASil ratio 1Á56), mean argatroban 0Á47 lg/ml (Guy et al, 2015). We report here further concerns about the use of the APTT ratio and the recommendation that the APTT should not exceed 100 s. Residual plasma of 9 patients (57 samples) receiving argatroban were tested on a Sysmex CS5100i (Sysmex, Milton Keynes, UK) with the APTT reagents Actin FS, Actin FSL, Pathromtin SL (all Siemens, Erlangen, Germany), SynthASil, SynFAx and APTT-SP (all Werfen, Bedford, MA, USA). The argatroban concentration was determined using the Hemoclot thrombin inhibitor assay (HTI) (Hyphen Biomed, Neuville-sur-Oise, France)...

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

“…3 Limitations of the APTT for monitoring argatroban have been reported in several publications. 4,5 Despite this, both the British Committee for Standards in Haematology 6 and the American College of Chest Physicians 7 guidelines suggest users monitor the anticoagulation through the APTT ratio. Keyl et al 8 showed that in critically ill patients on argatroban there is a poor correlation between APTT values and drug concentration (r 2 = 0.28) with a flattening of the dose response with increasing argatroban concentration.…”

More on the Limitations of the Activated Partial Thromboplastin Time for Monitoring Argatroban Therapy

“…Thus, some of these results would have suggested the patient was over-anticoagulated (if the Actin FS was used for monitoring, thereby indicating the dose should be reduced), whereas no action would be taken if using SynthAsil. In our previous data, 9 we demonstrated that SynthAsil and Actin FSL had similar low aPTT ratios with patients on argatroban, whereas Actin FS gave higher aPTT ratios in patient samples. Actin FSL was used in the initial trial of healthy patients, which gave rise to the aPTT ratio range of 1.5 to 3 times baseline aPTT.…”

“…We agree that there is no agreed therapeutic range for argatroban by drug concentration, but this is not sufficient reason to rely solely on the aPTT. It is also of concern that some recommendations utilize 100 seconds as a cutoff because we have demonstrated, 9 as have others, 11 that this may sometimes lie within the therapeutic range of 1.5 to 3 by aPTT ratio. More data are needed to link argatroban concentrations to clinical outcomes during therapy for heparininduced thrombocytopenia (HIT).…”

“…In addition, we have demonstrated that there are different sensitivities to argatroban with different aPTT reagents in samples collected from patients during argatroban therapy 9 and in spiked plasma prepared by addition of drug to plasma in vitro. 10 In our study of patient samples, 9 the reagent least sensitive to argatroban (among six reagents studied) was Actin FSL (with a mean ratio of 1.6 in 57 patient samples) with the most sensitive being SynFAx (with mean aPTT ratio of 2.3).…”

Argatroban is stable in citrated whole blood for 24 hours

“…To the best of our knowledge, no data have been published for argatroban stability in whole blood. Argatroban has the recommendation for monitoring by APTT ratio; however, this has been shown to have limitations as well as loss of sensitivity at high argatroban levels, which could be suggestive of toxic levels . In addition to monitoring through APTT, it is possible to quantify the plasma argatroban concentration by various methods: Ecarin chromogenic Assay (ECA), HPLC, in‐house anti‐iia methods, dilute thrombin time methods (in‐house or HTI method), and ecarin clotting time (ECT).…”