Context makes the clot: Evolutionary and translational mismatches in snake venom thrombin-like enzyme-induced fibrin-clot formation between human and diverse animal plasmas

Snake venoms produce dynamic effects upon the blood chemistry of both prey species and human bite victims. However, comparative testing to ascertain differential coagulotoxic effects between humans and animals, and therefore the suitability of animal models to predict human effects, are scarce. To fill this knowledge gap, this study tested how pitviper with thrombin-like venoms act across vertebrate plasmas and whether animal models predict human outcomes. We evaluated Deinagkistrodon acutus, Gloydius tsushimaensis, Ovophis okinavensis, Protobothrops mangshanensis, and Trimeresurus albolabris using thromboelastography on human, rodent, avian, and amphibian plasmas. Assays quantified initiation, kinetics, and maximal clot strength. On human plasma, all venoms were thrombin-like, acting in a pseudo-procoagulant manner to form weak, transient fibrin clots. Clinically this would result in a net anticoagulant effect through fibrinogen depletion. However, the results on animal plasmas differed markedly. At the dose tested which produced a potent response in human plasma, none of the venoms displayed the thrombin-like activity on any animal plasma. Instead, there were a myriad of other strong activities suggesting destructive cleavage of fibrinogen, inhibition of clotting enzymes, and activation of clotting factor zymogens. As such, the potent thrombin-like activity on human plasma appears to be an evolutionary bioproduct, rather than one that is selected for prey plasma. Translationally in this case, the animal models did not reliably predict the mechanistic underpinnings of human fibrinogen-depleting snakebite outcomes. This emphasises the importance of preclinical testing of venom effects to predict snakebite coagulotoxic outcomes, which should be based upon human plasma testing rather than animal models. These results underscore how snake venom research is fundamentally at the intersection between evolutionary biology and toxicology, with a single data set having implications for diverse, yet interlocking, fields of research. These outcomes suggest that, for at least thrombin-like serine proteases, animal models in general are poor predictors of potential human clinical effects, and reciprocally that effects on human material are poor predictors of potential prey pathophysiological effects exerted by these toxic enzymes. Other coagulotoxic enzymes should be examined for similar discrepancies between animal and human plasmas, and consequently the utility of animal models as predictors of human clinical effects.