Next Article in Journal
Transfer of Deoxynivalenol (DON) through Placenta, Colostrum and Milk from Sows to Their Offspring during Late Gestation and Lactation
Next Article in Special Issue
Global Availability of Antivenoms: The Relevance of Public Manufacturing Laboratories
Previous Article in Journal
A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability
Previous Article in Special Issue
Innovative Immunization Strategies for Antivenom Development
Open AccessEditor’s ChoiceArticle

Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib)

1
Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, QLD 4072 Australia
2
Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands
3
Snakebite Assist, Pretoria ZA-0001, South Africa
4
Naturalis Biodiversity Center, 2333 CR Leiden, The Netherlands
*
Authors to whom correspondence should be addressed.
Toxins 2018, 10(12), 516; https://doi.org/10.3390/toxins10120516
Received: 1 November 2018 / Revised: 27 November 2018 / Accepted: 1 December 2018 / Published: 4 December 2018
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
Snakebite is a global tropical disease that has long had huge implications for human health and well-being. Despite its long-standing medical importance, it has been the most neglected of tropical diseases. Reflective of this is that many aspects of the pathology have been underinvestigated. Snakebite by species in the Elapidae family is typically characterised by neurotoxic effects that result in flaccid paralysis. Thus, while clinically significant disturbances to the coagulation cascade have been reported, the bulk of the research to date has focused upon neurotoxins. In order to fill the knowledge gap regarding the coagulotoxic effects of elapid snake venoms, we screened 30 African and Asian venoms across eight genera using in vitro anticoagulant assays to determine the relative inhibition of the coagulation function of thrombin and the inhibition of the formation of the prothrombinase complex through competitive binding to a nonenzymatic site on Factor Xa (FXa), thereby preventing FXa from binding to Factor Va (FVa). It was revealed that African spitting cobras were the only species that were potent inhibitors of either clotting factor, but with Factor Xa inhibited at 12 times the levels of thrombin inhibition. This is consistent with at least one death on record due to hemorrhage following African spitting cobra envenomation. To determine the efficacy of antivenom in neutralising the anticoagulant venom effects, for the African spitting cobras we repeated the same 8-point dilution series with the addition of antivenom and observed the shift in the area under the curve, which revealed that the antivenom performed extremely poorly against the coagulotoxic venom effects of all species. However, additional tests with the phospholipase A2 inhibitor LY315920 (trade name: varespladib) demonstrated a powerful neutralisation action against the coagulotoxic actions of the African spitting cobra venoms. Our research has important implications for the clinical treatment of cobra snakebites and also sheds light on the molecular mechanisms involved in coagulotoxicity within Naja. As the most coagulotoxic species are also those that produce characteristic extreme local tissue damage, future research should investigate potential synergistic actions between anticoagulant toxins and cytotoxins. View Full-Text
Keywords: cobra; venom; antivenom; snakebite; coagulopathy; coagulotoxicity; tissue damage; varespladib; LY315920 cobra; venom; antivenom; snakebite; coagulopathy; coagulotoxicity; tissue damage; varespladib; LY315920
Show Figures

Figure 1

MDPI and ACS Style

Bittenbinder, M.A.; Zdenek, C.N.; Op den Brouw, B.; Youngman, N.J.; Dobson, J.S.; Naude, A.; Vonk, F.J.; Fry, B.G. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins 2018, 10, 516.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop