Abstract
Snake envenoming causes several potentially lethal pathologies. The specific pathology is dictated by the toxin composition of venom, which varies by species, geography and ontogeny. This variation severely restricts the paraspecific efficacy of antivenoms used to treat snakebite victims. With a view to devising pathology-specific snakebite treatments, we assessed the procoagulant activity of 57 snake venoms and investigated the efficacy of various antivenoms. We find that procoagulant venoms act differentially on key steps of the coagulation cascade, and that certain monospecific antivenoms work in a previously unrecognised paraspecific manner to neutralise this activity, despite conventional assumptions of congener-restricted efficacy. Moreover, we demonstrate that the metal chelator EDTA is also capable of neutralising venom-induced lethality in vivo. This study illustrates the exciting potential of developing new, broad-spectrum, toxin-targeting antivenoms capable of treating key snakebite pathologies, and advocates a thorough re-examination of enzyme inhibiting compounds as alternative therapies for treating snakebite victims.
Highlights
Snake envenoming causes several potentially lethal pathologies
Snake venoms consist of variable mixtures of bioactive proteins with distinct antigenic signatures, which undermine the generation of a single “universal” therapy to treat all snakebite victims
While certain pathologies, such as coagulopathy, can be underpinned by few toxins targeting specific physiological targets (e.g. R. subminiatus venom potently activating prothrombin), other snake venoms are more complex and their protein constituents act in a synergistic manner to perturb various host systems[45], as evidenced by many of the procoagulant venoms in this study acting on multiple clotting factors (Fig. 2)
Summary
The specific pathology is dictated by the toxin composition of venom, which varies by species, geography and ontogeny This variation severely restricts the paraspecific efficacy of antivenoms used to treat snakebite victims. Venom-induced consumption coagulopathy, caused by procoagulant snake venoms, is said to be one of the most common medically important snakebite pathologies[14] This haemostatic alteration is characterised clinically by the depletion of fibrinogen, and caused by venom toxins continually activating and consuming various clotting factors in the coagulation cascade[14,15]. To improve our understanding of the spectrum of snakes causing venom-induced consumption coagulopathy, their mechanisms of action and to expand therapeutic options, here we characterise the procoagulant activity of venom sourced from a wide range of diverse snake species and investigate the extent to which antivenom and the metal chelator EDTA (ethylenediaminetetraacetic acid) are capable of neutralising these effects across species (paraspecificity). Our results provide support for the development of new “pathology-specific” snakebite treatments capable of neutralising key venom toxicities irrespective of the snake species responsible for envenoming
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