Varespladib (LY315920) neutralises phospholipase A2 mediated prothrombinase-inhibition induced by Bitis snake venoms

Abstract

Anticoagulant toxicity is a common function of venoms produced by species within the Bitis genus. Potent inhibition of the prothrombinase complex is an identified mechanism of action for the dwarf species B. cornuta and B. xeropaga, along with some localities of B. atropos and B. caudalis. Snake venom phospholipase A2 toxins that inhibit the prothrombinase complex have been identified in snake venom, including an isolated phospholipase A2 toxin from B. caudalis. Current research is investigating the ability of the drug varespladib to inhibit snake venom phospholipase A2 toxins and reduce their toxicity. In particular, varespladib is being investigated as a treatment that could be administered prior to hospital referral which is a major necessity for species such as those from the genus Bitis, due to envenomations often occurring in remote regions of Africa where antivenom is unavailable. Using previously validated coagulation assays, this study aimed to determine if the toxins responsible for inhibition of the prothrombinase complex in the venom of four Bitis species are phospholipase A2 toxins, and if varespladib is able to neutralise this anticoagulant activity. Our results demonstrate that varespladib strongly neutralises the prothrombinase-inhibiting effects of all venoms tested in this study, and that this prothrombinase-inhibiting mechanism of anticoagulant activity is driven by phospholipase A2 class toxins in these four species. This study extends previous reports demonstrating varespladib has broad efficacy for treatment of phospholipase A2 rich snake venoms, indicating it also inhibits their anticoagulant effects mediated by prothrombinase-inhibition.