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

The genus <i>Bitis</i> comprises 17 snake 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 <i>Bitis (B. arietans</i> and again in the common ancestor of the clade consisting of <i>B. gabonica, B. nasicornis, B. parviocula</i> and <i>B. rhinoceros</i>) induce an array of debilitating effects including anticoagulation, hemorrhagic shock and cytotoxicity, whilst the dwarf species <i>B. atropos</i> 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 <i>B. worthingtoni,</i> suggesting anticoagulant venom is a derived trait within the <i>Bitis</i> genus and has been secondarily amplified on at least four occasions. A wide range of anticoagulant mechanisms were identified, such as coagulant and destructive activities upon fibrinogen in both giant and dwarf <i>Bitis</i> and the action of inhibiting the prothrombinase complex, which is present in a clade of dwarf <i>Bitis</i>. Antivenom studies revealed that while the procoagulant effects of <i>B. worthingtoni</i> 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 <i>Bitis</i> genus and that clinical management strategies are limited for the procoagulant effects of <i>B. worthingtoni</i>, 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.