Differential procoagulant effects of saw-scaled viper (Serpentes: Viperidae: Echis) snake venoms on human plasma and the narrow taxonomic ranges of antivenom efficacies

Abstract

Saw-scaled vipers (genus Echis) are one of the leading causes of snakebite morbidity and mortality in parts of Sub-Saharan Africa, the Middle East, and vast regions of Asia, constituting a public health burden exceeding that of almost any other snake genus globally. Venom-induced consumption coagulopathy, owing to the action of potent procoagulant toxins, is one of the most relevant clinical manifestations of envenomings by Echis spp. Clinical experience and prior studies examining a limited range of venoms and restricted antivenoms have demonstrated for some antivenoms an extreme lack of antivenom cross-reactivity between different species of this genus, sometimes resulting in catastrophic treatment failure. This study undertook the most comprehensive testing of Echis venom effects upon the coagulation of human plasma, and also the broadest examination of antivenom potency and cross-reactivity, to-date. 10 Echis species/populations and four antivenoms (two African, two Asian) were studied. The results indicate that the venoms are, in general, potently procoagulant but that the relative dependence on calcium or phospholipid cofactors is highly variable. Additionally, three out of the four antivenoms tested demonstrated only a very narrow taxonomic range of effectiveness in preventing coagulopathy, with only the SAIMR antivenom displaying significant levels of cross-reactivity. These results were in conflict with previous studies using prolonged preincubation of antivenom with venom to suggest effective cross-reactivity levels for the ICP Echi-Tab antivenom. These findings both inform upon potential clinical effects of envenomation in humans and highlight the extreme limitations of available treatment. It is hoped that this will spur efforts into the development of antivenoms with more comprehensive coverage for bites not only from wild snakes but also from specimens widely kept in zoological collections.

A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite

“…3). Consistent with prior studies 36,37 , all of the tested viper venoms displayed net procoagulant activity, with the exception of B. arietans, which had no effect on plasma clotting ( The results of the SVMP and coagulation assays demonstrated that the peptidomimetic inhibitors outperformed the metal chelators and, although marimastat and batimastat are similar drugs in terms of both mechanism of action and in vitro efficacy, marimastat has a number of potential clinical advantages over batimastat, including: (i) increased solubility, (ii) excellent oral bioavailability vs. parenteral administration, and (iii) generally well tolerated vs. some reports of acute bowel toxicity 38 . Therefore, we selected marimastat as our candidate SVMP-inhibitor for use in vivo venom-neutralization experiments.…”

High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

“…Despite these identifications, and prior reports of PLA 2 s generally exerting anticoagulant activities (16), neither of these E. ocellatus PLA 2 s have previously been described as anticoagulants (33, 56, 57). Despite the venom from these species being potently procoagulant (7, 58), we only identified one XIC that could be correlated to a procoagulant bioactivity peak. This protein had a m/z -value of 1445.8645 35+ and a corresponding mass of 52015.873 Da, but could not be matched to a Mascot hit.…”

The paraspecific neutralisation of snake venom induced coagulopathy by antivenoms

“…22 ). Notably, EchiTAbG also neutralised the procoagulant venom effects of seven of the remaining nine viper species, the colubrid snake D. typus and the natricine R. subminiatus , despite these latter two species having diverged from vipers over 54 million years ago 23 (Fig.…”