UBC Faculty Research and Publications

Porcine blood and surrogate markers do not prove benefit of aDabi-Fab Connors, Nicholas J; Gill, Justin; Nakanishi, Allison; Hoffman, Robert S Jun 17, 2014

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LETTERPorcine blood and surrogate markers do notprove benefit of aDabi-FabNicholas J Connors1*, Justin Gill2, Allison Nakanishi2 and Robert S Hoffman1See related research by Grottke et al., http://ccforum.com/content/18/1/R27While we read with great interest the recent reportconcerning the reversal of dabigatran-induced coagu-lopathy [1], we are concerned that methodological is-sues limit the validity of the authors’ conclusions.Firstly, it is unclear why a porcine model was utilized.Although there is clinical relevance for testing reversalagents in a trauma model, all agents were administeredex vivo. Furthermore, the established correlation be-tween the activated partial thromboplastin time (aPTT)and dabigatran concentrations in humans [2] is absentin the pig model. Potentially, porcine coagulation pa-rameters respond to dabigatran and its reversal differ-ently than humans. Most importantly, only surrogatemarkers of coagulation were reported. Having created ahemorrhagic shock model, the authors should havetested either survival or blood loss following in vivo re-versal along similar lines of investigation as their priormodel [3].Since further study is needed to determine the useful-ness of aDabi-Fab, we would recommend that ex vivostudies use human blood while animal studies focus onendpoints that have clear clinical relevance.AbbreviationaPTT: activated partial thromboplastin time.Competing interestsOG has received research funding from Novo Nordisk, Biotest, CSL Behring,Nycomed. He has also received honoraria for consultancy and/or travelsupport from Bayer Healthcare, Boehringer Ingelheim and CSL Behring. RRhas received honoraria for lectures and consultancy from CSL Behring andNovo Nordisk. JvR is an employee of Boehringer Ingelheim Pharma GmbH &Co., Germany. HMHS has received research funding from BoehringerIngelheim and honoraria for consultancy from Bayer.* Correspondence: nicholasconnors@gmail.com1Division of Medical Toxicology, Department of Emergency Medicine, NewYork University School of Medicine, 450 First Avenue, Room 123, New York,NY 10016, USAFull list of author information is available at the end of the articleAuthors' responseOliver Grottke, Joanne van Ryn, Henri MH Spronk and Rolf RossaintWe thank the authors for their interest in our article [1].We chose a porcine model to facilitate investigation ofdabigatran reversal using several different agents at differ-ent concentrations, in blood samples taken both before andafter trauma. This method was chosen mainly for ethicalreasons, to provide a basis for subsequent in vivo studies.Ex vivo studies in humans were considered, but in that set-ting blood would probably be spiked with dabigatran andthe effects of coagulation status changes following trauma(for example, hypofibrinogenemia) could not be evaluated.Clinically relevant endpoints such as blood loss are clearlymore important than laboratory data and results from aporcine model may not be reflected in human patients.These limitations are acknowledged within our article.Our article [1] presents our first investigations of dabiga-tran reversal, including the preliminary dose-finding workrequired to proceed with in vivo studies. Using a similarporcine model of trauma, we now have initial in vivo results[4]. A prothrombin complex concentrate dose of 50 IU/kgwas effective in reducing total blood loss and increasingsurvival. This indicates that our ex vivo data are applicablein vivo.We disagree that correlation between aPTT and dabiga-tran concentration is absent in the porcine model. Sensitiv-ity to dabigatran may be different in porcine versus humanplasma, and our data suggest that the aPTT-dabigatranconcentration curve is less steep in pigs than in humanswhen using actin FS (Dade Behring, Germany). However,as shown by the results of our study [1], aPTT is prolongedwith increasing levels of dabigatran in pigs.© Connors et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.Connors et al. Critical Care20142014, 18:435http://ccforum.com/content/18/3/435Author details1Division of Medical Toxicology, Department of Emergency Medicine, NewYork University School of Medicine, 450 First Avenue, Room 123, New York,NY 10016, USA. 2University of British Columbia Faculty of Medicine, 317–2194Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.Published:References1. Grottke O, van Ryn J, Spronk HM, Rossaint R: Prothrombin complexconcentrates and a specific antidote to dabigatran are effective ex-vivoin reversing the effects of dabigatran in an anticoagulation/liver traumaexperimental model. Crit Care 2014, 18:R27.2. Dager WE, Gosselin RC, Kitchen S, Dwyre D: Dabigatran effects of theinternational normalized ratio, activated partial thromboplastin time,thrombin time, and fibrinogen: a multicenter, in vitro study. AnnPharmacother 2012, 46:1627–1636.3. Pragst I, Zeitler SH, Doerr B, Kaspereit FJ, Herzog E, Dickneite G, van Ryn J:Reversal of dabigatran anticoagulation by prothrombin complexconcentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012,10:1841–1848.4. Honickel M, van Ryn J, Spronk HM, Ten Cate H, Rossaint R, Grottke O:Prothrombin complex concentrate restores haemostasis in a dabigatrananticoagulated polytrauma pig model. Crit Care 2014, 18:S40.Cite this article as: Connors et al.: Porcine blood and surrogate markersdo not prove benefit of aDabi-Fab. Critical CareConnors et al. Critical Care Page 2 of 217 Jun 201410.1186/cc139272014, 18:4352014, 18:435http://ccforum.com/content/18/3/435


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