Species within the viperid genus Macrovipera are some of the most dangerous snakes in the Eurasian region, injecting copious amounts of potent venom. Despite their medical importance, the pathophysiological actions of their venoms have been neglected. Particularly poorly known are the coagulotoxic effects and thus the underlying mechanisms of lethal coagulopathy. In order to fill this knowledge gap, we ascertained the effects of venom upon human plasma for Macrovipera lebetina cernovi, M. l. lebetina, M. l. obtusa, M. l. turanica, and M. schweizeri using diverse coagulation analysing protocols. All five were extremely potent in their ability to promote clotting but varied in their relative activation of Factor X, being equipotent in this study to the venom of the better studied, and lethal, species Daboia russelii. The Insoserp European viper antivenom was shown to be highly effective against all the Macrovipera venoms, but performed poorly against the D. russelii venom. Reciprocally, while Daboia antivenoms performed well against D. russelii venom, they failed against Macrovipera venom. Thus despite the two genera sharing a venom phenotype (Factor X activation) driven by the same toxin type (P-IIId snake venom metalloproteases), the surface biochemistries of the toxins differed significantly enough to impede antivenom cross-neutralisation. The differences in venom biochemistry were reflected in coagulation co-factor dependence. While both genera were absolutely dependent upon calcium for the activation of Factor X, dependence upon phospholipid varied. The Macrovipera venoms had low levels of dependence upon phospholipid while the Daboia venom was three times more dependent upon phospholipid for the activation of Factor X. This suggests that the sites on the molecular surface responsible for phospholipid dependence, are the same differential sites that prevent inter-genera antivenom cross-neutralisation. Due to cold-chain requirements, antivenoms may not be stocked in rural settings where the need is at the greatest. Thus we tested the efficacy of enzyme inhibitor Prinomastat as a field-deployable treatment to stabilise patients while being transported to antivenom stocks, and showed that it was extremely effective in blocking the Factor X activating pathophysiological actions. These results thus not only shed light on the coagulopathic mechanisms of Macrovipera venoms, but also provide data critical for evidence-based design of snakebite management strategies.

中文翻译：

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古北蝰蛇属Macrovipera不同促凝血毒性的临床意义，以及抗蛇毒血清和酶抑制剂的相对中和功效

蝰蛇属Macrovipera 是欧亚地区最危险的蛇类之一，会注入大量强效毒液。尽管它们具有医学重要性，但它们的毒液的病理生理作用却被忽视了。尤其鲜为人知的是凝血毒性作用以及致死性凝血病的潜在机制。为了填补这一知识空白，我们确定了毒液对 Macrovipera lebetina cernovi, M. l. 的人体血浆的影响。莱贝蒂娜, M. l. obtusa, M. l. turanica 和 M. schweizeri 使用不同的凝血分析方案。所有五个在促进凝血的能力方面都非常有效，但在因子 X 的相对激活方面有所不同，在本研究中与更好研究的致命物种 Daboia russelii 的毒液等效。Insoserp 欧洲蝰蛇抗蛇毒血清被证明对所有巨蝰蛇毒液都非常有效，但对杜氏毒蛇毒液表现不佳。反过来，虽然 Daboia 抗蛇毒血清对杜氏杜鹃毒液表现良好，但对大蝰蛇毒液却失败了。因此，尽管两个属共享由相同毒素类型（P-IIId 蛇毒金属蛋白酶）驱动的毒液表型（因子 X 激活），但毒素的表面生物化学差异显着，足以阻碍抗蛇毒血清的交叉中和。毒液生物化学的差异反映在凝血辅因子依赖性上。虽然这两个属都完全依赖钙来激活因子 X，但对磷脂的依赖各不相同。Macrovipera 毒液对磷脂的依赖程度较低，而 Daboia 毒液对磷脂的依赖程度是 X 因子的三倍。这表明分子表面上负责磷脂依赖的位点是相同的差异位点，可以防止相互之间的相互作用。 -genera 抗蛇毒血清交叉中和。由于冷链要求，在需求最大的农村地区可能不会储存抗蛇毒血清。因此，我们测试了酶抑制剂 Prinomastat 作为一种可在现场部署的治疗方法以稳定患者同时被运送到抗蛇毒血清的疗效，并表明它在阻断因子 X 激活病理生理作用方面极为有效。因此，这些结果不仅揭示了巨蝮蛇毒液的凝血机制，