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Venomous Landmines: Clinical Implications of Extreme Coagulotoxic Diversification and Differential Neutralization by Antivenom of Venoms within the Viperid Snake Genus Bitis

Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, QLD 4072, Australia 2 Snakebite Assist, Pretoria ZA-0001, South Africa 3 Universeum, Södra Vägen 50, 412 54 Gothenburg, Sweden 4 Serpentarium Calden, Birkenweg 11, 34379 Calden, Germany
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Toxins 2019, 11(7), 422; https://doi.org/10.3390/toxins11070422
Received: 24 June 2019 / Revised: 15 July 2019 / Accepted: 16 July 2019 / Published: 19 July 2019
The genus Bitis comprises 18 species that inhabit Africa and the Arabian Peninsula. They are responsible for a significant proportion of snakebites in the region. The venoms of the two independent lineages of giant Bitis (B. arietans and again in the common ancestor of the clade consisting of B. gabonica, B. nasicornis, B. parviocula and B. rhinoceros) induce an array of debilitating effects including anticoagulation, hemorrhagic shock and cytotoxicity, whilst the dwarf species B. atropos is known to have strong neurotoxic effects. However, the venom effects of the other species within the genus have not been explored in detail. A series of coagulation assays were implemented to assess the coagulotoxic venom effects of fourteen species within the genus. This study identified procoagulant venom as the ancestral condition, retained only by the basal dwarf species B. worthingtoni, suggesting anticoagulant venom is a derived trait within the Bitis genus and has been secondarily amplified on at least four occasions. A wide range of anticoagulant mechanisms were identified, such as pseudo-procoagulant and destructive activities upon fibrinogen in both giant and dwarf Bitis and the action of inhibiting the prothrombinase complex, which is present in a clade of dwarf Bitis. Antivenom studies revealed that while the procoagulant effects of B. worthingtoni were poorly neutralized, and thus a cause for concern, the differential mechanisms of anticoagulation in other species were all well neutralized. Thus, this study concludes there is a wide range of coagulotoxic mechanisms which have evolved within the Bitis genus and that clinical management strategies are limited for the procoagulant effects of B. worthingtoni, but that anticoagulant effects of other species are readily treated by the South African polyvalent antivenom. These results therefore have direct, real-work implications for the treatment of envenomed patients. View Full-Text
Keywords: Bitis; coagulotoxicity; anticoagulant; procoagulant; snakebite Bitis; coagulotoxicity; anticoagulant; procoagulant; snakebite
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Youngman, N.J.; Debono, J.; Dobson, J.S.; Zdenek, C.N.; Harris, R.J.; Brouw, B.; Coimbra, F.C.P.; Naude, A.; Coster, K.; Sundman, E.; Braun, R.; Hendrikx, I.; Fry, B.G. Venomous Landmines: Clinical Implications of Extreme Coagulotoxic Diversification and Differential Neutralization by Antivenom of Venoms within the Viperid Snake Genus Bitis. Toxins 2019, 11, 422.

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