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. 2016 Sep 30;11(9):e0163787.
doi: 10.1371/journal.pone.0163787. eCollection 2016.

The Organophosphate Paraoxon and Its Antidote Obidoxime Inhibit Thrombin Activity and Affect Coagulation In Vitro

Valery Golderman  1 , Efrat Shavit-Stein  2 , Ilia Tamarin  3 , Yossi Rosman  4   5 , Shai Shrot  4   6 , Nurit Rosenberg  3 , Nicola Maggio  2   7 , Joab Chapman  2   7   8 , Arik Eisenkraft  4   9   10
Affiliations

The Organophosphate Paraoxon and Its Antidote Obidoxime Inhibit Thrombin Activity and Affect Coagulation In Vitro

Valery Golderman et al. PLoS One. .

Abstract

Organophosphates (OPs) are potentially able to affect serine proteases by reacting with their active site. The potential effects of OPs on coagulation factors such as thrombin and on coagulation tests have been only partially characterized and potential interactions with OPs antidotes such as oximes and muscarinic blockers have not been addressed. In the current study, we investigated the in vitro interactions between coagulation, thrombin, the OP paraoxon, and its antidotes obidoxime and atropine. The effects of these substances on thrombin activity were measured in a fluorescent substrate and on coagulation by standard tests. Both paraoxon and obidoxime but not atropine significantly inhibited thrombin activity, and prolonged prothrombin time, thrombin time, and partial thromboplastin time. When paraoxon and obidoxime were combined, a significant synergistic effect was found on both thrombin activity and coagulation tests. In conclusion, paraoxon and obidoxime affect thrombin activity and consequently alter the function of the coagulation system. Similar interactions may be clinically relevant for coagulation pathways in the blood and possibly in the brain.

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Conflict of interest statement

The authors have declared that no competing interests exist. This study was financed by a scientific grant of the Israel Defense Forces. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Figures

Fig 1
Fig 1. Paraoxon and obidoxime inhibit thrombin activity in vitro.
(A) Varying concentrations of paraoxon (500 nM, 5 μM, 28 μM, 50 μM, 0.28 mM and 0.5 mM) inhibit thrombin activity. (B) Obidoxime inhibits thrombin activity at varying concentrations. In the presence of 3 nM obidoxime there is no significant change in thrombin activity. (C) Thrombin activity is significantly inhibited when obidoxime is applied together with paraoxon.
Fig 2
Fig 2. The effects of paraoxon and obidoxime on coagulation.
(A) Prothrombin time, (B) Thrombin Time (TT) and (C) activated partial thromboplastin time (APTT) are significantly prolonged by obidoxime as well as by its combination with paraoxon.
See this image and copyright information in PMC

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