X Marks the Clot: Evolutionary and Clinical Implications of Divergences in Procoagulant Australian Elapid Snake Venoms

Australian elapid snakes possess potent procoagulant venoms, capable of inducing severe venom-induced consumption coagulopathy (VICC) in snakebite victims through rapid activation of the coagulation cascade by converting the FVII and prothrombin zymogens into their active forms. These venoms fall into two mechanistic categories: FXa-only venoms, which hijack host factor Va, and FXa:FVa venoms, containing a complete venom-derived prothrombinase complex. While previous studies have largely focused on human plasma, the ecological and evolutionary drivers behind prey-selective venom efficacy remain understudied. Here, thromboelastography was employed to comparatively evaluate venom coagulotoxicity across prey classes (amphibian, avian, rodent) and human plasma, using a taxonomically diverse selection of Australian snakes. The amphibian-specialist species <i>Pseudechis porphyriacus</i> (Red-Bellied Black Snake) exhibited significantly slower effects on rodent plasma, suggesting evolutionary refinement towards ectothermic prey. In contrast, venoms from dietary generalists retained broad efficacy across all prey types. Intriguingly, notable divergence was observed within <i>Pseudonaja textilis</i> (Eastern Brown Snake): Queensland populations of this species, and all other <i>Pseudonaja</i> (brown snake) species, formed rapid but weak clots in prey and human plasma. However, the South Australian populations of <i>P. textilis</i> produced strong, stable clots across prey plasmas and in human plasma. This is a trait shared with <i>Oxyuranus</i> species (taipans) and therefore represents an evolutionary reversion towards the prothrombinase phenotype present in the <i>Oxyuranus</i> and <i>Pseudonaja</i> last common ancestor. Clinically, this distinction has implications for the pathophysiology of human envenomation, potentially influencing clinical progression, including variations in clinical coagulopathy tests, and antivenom effectiveness. Thus, this study provides critical insight into the ecological selection pressures shaping venom function, highlights intraspecific venom variation linked to geographic and phylogenetic divergence, and underscores the importance of prey-focused research for both evolutionary toxinology and improved clinical management of snakebite.