Elsevier

Thrombosis Research

Volume 105, Issue 5, 1 March 2002, Pages 401-405
Thrombosis Research

Brief Communication
Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia

https://doi.org/10.1016/S0049-3848(02)00049-XGet rights and content

Abstract

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of non-human origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients. It has been reported that between 44-74% of lepirudin-treated HIT patients develop drug-specific antibodies that either enhance or suppress the anticoagulant activity of lepirudin. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials, including those in HIT patients, or in postmarketing safety surveillance of over 4,800 patients treated in Japan. To confirm the lack of antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of re-exposed patients. Paired, pre-therapy and post-therapy (≥7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 μg/mL similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pre-therapy versus post-therapy plasma (P>0.6). In trials, mean argatroban doses during initial therapy versus re-exposure were not different among individuals anticoagulated for the treatment or prophylaxis of thrombosis (P=0.60) or during percutaneous coronary interventions (P=0.79), with no discernable pattern of suppression or enhancement of argatroban anticoagulation. Consistent with the lack of reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect across clinical trials and post-marketing safety surveillance, these data support the lack of anti-argatroban antibodies that affect drug activity in argatroban-treated HIT patients.

Introduction

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis [1], [2], [3], [4], [5]. A general recommendation for managing HIT is to eliminate all heparin sources and initiate alternative anticoagulation for treatment of thrombosis and, if desired, for prophylaxis of thrombosis [2], [3], [4], [5]. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of nonhuman origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients [4], [5].

Eichler et al. [6] suggest that HIT patients may have an increased risk of developing immune responses to drugs. Between 44% and 74% of lepirudin-treated HIT patients develop drug-specific antibodies [6], [7], [8] that appear typically 8–9 days after initial exposure, often persist for ≥6 months [6], and increase upon reexposure [9]. These drug-specific antibodies enhance the anticoagulant activity of lepirudin in 45% of patients and suppress its activity in 6% of patients [6]. Hence, patients require careful monitoring during lepirudin therapy to avoid bleeding complications and also for anaphylactic reaction. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials [4], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], including those in HIT patients [4], [18], [19], [20], or in the postmarketing safety surveillance of over 4800 patients treated in Japan between 1991 and 1998. In trials, HIT patients have received prolonged exposure to argatroban (up to 59 days) as well as repeated exposure, including 58 patients reexposed for the prophylaxis or treatment of thrombosis [19] and 17 patients who underwent multiple percutaneous coronary interventions (PCIs) using argatroban anticoagulation [20].

To confirm that argatroban therapy does not generate activity-altering antibodies in HIT patients, we examined plasma from argatroban-treated patients for evidence of anticoagulant-enhancing or -suppressing activity and also evaluated dosing patterns of reexposed patients.

Section snippets

Plasma for in vitro analyses

Fifteen argatroban-treated HIT patients from study ARG-911 [4] (n=11) or study ARG-310 [20] (n=4), and for whom retained (−70 °C storage), citrated plasma from baseline and posttherapy was available, were randomly selected for the evaluation of anticoagulant activity-altering antibody. Baseline plasma was collected ≤24 h prior to initiation of argatroban. Posttherapy plasma was collected after 7 days of therapy in ARG-911 (≥4 h after stopping therapy when plasma drug levels would be expected to

Dose–response, in vitro

Table 1 presents the aPTTs and antithrombin activities of plasma pools (baseline and posttherapy from argatroban-treated HIT patients) containing varying concentrations of argatroban. As shown in both assays, the baseline and posttherapy plasmas demonstrated similar dose–response profiles. The aPTTs in the baseline pool were 4–9 s greater than in the posttherapy pool; however, this is within the reproducibility of the aPTT assay. The absolute increases in the aPTT and antithrombin assay over

Discussion

This study was designed to investigate whether argatroban-treated HIT patients develop antibodies that functionally enhance or inhibit the anticoagulant effects of argatroban. There has been no suggestive evidence to date of clinically significant antibodies to argatroban in clinical studies, which is not unexpected because argatroban is a small synthetic molecule. It has been postulated, however, that HIT patients may have an increased risk of developing immune responses to drugs [6], and a

Summary

To confirm the lack of clinically significant antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of reexposed patients. Paired pretherapy and posttherapy (≥7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 μg/ml similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pretherapy versus

Acknowledgements

The authors wish to express their gratitude to Drs. Jawed Fareed and Harry L. Messmore for helpful discussions on this study, and Texas Biotechnology (Houston, TX) and GlaxoSmithKline for financial support.

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