Methods for the Monitoring of Direct Thrombin Inhibitors

Abstract

Direct thrombin inhibitors are available for prophylactic as well as therapeutic purposes. Application of hirudin in therapeutic doses has been shown to require drug monitoring. Currently, most experience is available for recombinant hirudin, but the principle aspects of drug monitoring are the same for all direct thrombin inhibitors. Most frequently, activated partial thromboplastin time (aPTT) and modifications of the activated clotting time (ACT) have been used for the monitoring of hirudin therapy. However, these methods are insensitive at plasma levels higher than 0.6 mg/L of hirudin, so that overdoses may be missed despite monitoring. Correlations between ecarin clotting time (ECT), enzyme immunoassays, and chromogenic substrate assays on one side and global tests on the other side are poor. Fully automated chromogenic substrate-based assays, also available as point-of-care tests (POCT), are more precise and sensitive and are not disturbed by interferents such as heparin and antithrombin. Good correlations can be observed between chromogenic assays and the ECT performed in plasma or whole blood samples. ECT can also be determined with POCT systems. Test characteristics such as imprecision and measuring range are comparable to those of the chromogenic assays. In conclusion, therapy with direct thrombin inhibitors should be monitored with chromogenic assays or ECT.

Ecarin Chromogenic Assay – A New Method for Quantitative Determination of Direct Thrombin Inhibitors Like Hirudin

“…However, it has been shown by many investigators that aPTT is not suited for quantitative hirudin determination because all aPTT assays become less responsive at increasing hirudin concentrations; therefore, toxic blood levels cannot be detected or prevented by measuring aPTT. Further limitations are the dependence of aPTT on the reagent used and the high interindividual variations of the clotting time values [1,2,17,18] .…”

“…From the variety of methods tested regarding their suitability for monitoring hirudin or other direct thrombin inhibitors, ECT and chromogenic substrate-based assays turned out as tests which can represent the clinical situation more adequately than aPTT [17,18] . Especially the ECT test is considered as a fast, highly sensitive and precise method allowing hirudin determination over a wide concentration range with low interindividual variations [20] .…”

“…the ecarin clotting time (ECT), were developed for the monitoring of anticoagulant therapy [6][7][8][9][10][11][12][13][14][15][16] . The suitability of these methods for the determination of hirudin and other direct thrombin inhibitors, their advantages and drawbacks are discussed in detail by Nowak [17] and Hafner et al [18] . These authors recommend particularly the ECT and also chromogenic substrate assays as suitable for the monitoring of therapy with direct thrombin inhibitors.…”

Bleeding Risk Comparing Targeted Low-Dose Heparin With Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention

“…Unlike UFH, in which ACT levels help quantify response to UFH, standard ACT tests for bivalirudin are used more qualitatively and correlate less well with the degree of anticoagulation. [12][13][14] Because we regarded heparin as the control group for our hypothesis, we therefore chose to use the ACT level in the UFH groups to further categorize the patient subsets.…”

Hemofiltration of Recombinant Hirudin by Different Hemodialyzer Membranes

“…There is a sufficient correlation of aPTT prolongation and hirudin plasma concentration up to 300 ng/ml plasma (20). If available, chromogenic assays or ecarin clotting time also should be used to measure r-hirudin plasma concentrations accurately (21,22).…”