Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia.
School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia.
Toxins (Basel). 2024 Oct 6;16(10):430. doi: 10.3390/toxins16100430.
Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans ( species) and brown snakes ( species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by / venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.
澳大利亚的眼镜蛇科蛇毒具有独特的促凝血作用，利用凝血酶 FXa（Factor Xa）作为毒素，这一特征是该进化枝的基本特征。随后，在太攀蛇（物种）和棕色蛇（物种）的最后共同祖先中，毒素因子 Va（Factor Va）被招募。凝血酶原（Factor II）的激活被认为是致死性凝血功能障碍的主要机制，但这一假设从未得到过验证。/蛇毒对因子 VII（Factor VII）的额外激活，历史上被认为是一种次要的、不重要的新颖性。本研究旨在通过测试具有促凝血作用的广泛分类学范围的澳大利亚眼镜蛇科物种，研究有毒 FVII 激活相对于凝血酶原激活的意义。评估了 FVII 或凝血酶原的激活情况，以及涉及这些过程的结构变化，包括有和没有因子 Va 作为辅助因子的情况。所有促凝血物种都可以激活 FVII，这确立了这一基本特征。相比之下，只有一些谱系能够激活凝血酶原，表明这是一个衍生特征。对于能够激活两种酶原的物种，FVII 的激活始终比凝血酶原更强。因子 Va 被揭示为 FVII 激活的必需辅助因子，这是以前未记录的机制。毒液中缺乏因子 Va 的物种利用内源性血浆因子 Va 发挥这种活性。人 FXa:FVa 复合物激活 FVII 的能力也被揭示为内源性凝血级联中的新反馈回路。毒素序列分析确定了对凝血酶原激活这一衍生特征至关重要的结构变化。本研究改变了人们对眼镜蛇科蛇毒激活凝血因子的理解方式，强调了 FVII 激活在澳大利亚眼镜蛇科蛇毒对凝血级联产生的病理生理影响中的关键作用。它还记录了因子 Va 作为 FXa 的内源性和毒液形式的 FVII 激活辅助因子的新用途。这些发现对于开发更好的抗蛇毒血清和治疗蛇咬伤患者至关重要，并且对药物设计和凝血障碍的治疗具有更广泛的意义。该研究还推进了蛇毒进化生物学的知识。
