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Abstract

Article: Schiele F, van Ryn J, Newsome C, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121: 3554-3562.Keywords: Dabigatran, Fab antidote, Preclinical research. Background: Advances in anticoagulation for patients at risk for thromboembolic disorders have led from the use of indirect thrombin inhibitors (like warfarin) to direct inhibitors including dabigatran. Dabigatran therapy is more convenient for patients and has less reported complications than warfarin in large studies. However, when bleeding occurs during dabigatran therapy or a need for emergent surgery arises, there is no effective reversal modality and mortality in these circumstances is seemingly high.Research objective: Characterize the structure and test the ability of a novel anti-dabigatran fab to reverse anticoagulant effects x and in vivo.Methods: Antibodies were cloned after dabigatran exposure in mice, purified, and then humanized. The antidabigatran fab was then tested in vitro for the ability to reverse dabigatran anticoagulation, structurally characterized via crystallography, and examined for intrinsic coagulant effect. The derived fab was also tested in vivo in dabigatrananticoagulated rats.Results: Intact mouse antibodies, purified mouse antibodies, and humanized fab bound dabigatran as measured via ELISA. These antibodies also reversed prolonged plasma thrombin time in a dose dependent manner. Detailed crystallography revealed that the final humanized fab is composed of two variable light and heavy chain domains and two constant domains. The dabigatran binding site is a polar pocket surrounded by a hydrophobic area. Dabigatran binds at the polar pocket in a similar manner to thrombin binding. In the third phase of the study, investigators performed further assays to investigate fab binding to thrombin and other thrombin substrates. There was no observed binding nor procoagulant effects. Lastly, a single fab dose reversed prolonged thrombin time in rats despite continuous infusion of dabigatran.Conclusion: The derived anti-dabigatran fab bound with high affinity, reversed anti-coagulant effects in vitro/in vivo, and lacked intrinsic thrombin-like procoagulant effects.Critique: This is an elegant study that demonstrates the ability to produce a novel fab that specifically binds to dabigatran and reverses its anticoagulant effect without untoward procoagulant activity. All investigators are employees of the manufacturer of dabigatran.Implication for toxicologists: This report is promising in that we may have an effective and safe therapy for direct thrombin inhibitor in the reasonable future.Article: Manini AF, Stimmel B, Vlahov D. Racial susceptibility for QT prolongation in acute drug overdose. J Electrocardiol. 2014 (in press).