Clinical implications of ontogenetic differences in the coagulotoxic activity of Bothrops jararacussu venoms

• Published in: Toxicology letters 2021-09, Vol.348, p.59-72
• Main Authors: Rodrigues, Caroline Fabri Bittencourt, Zdenek, Christina N., Bourke, Lachlan A., Seneci, Lorenzo, Chowdhury, Abhinandan, Freitas-de-Sousa, Luciana Aparecida, de Alcantara Menezes, Frederico, Moura-da-Silva, Ana Maria, Tanaka-Azevedo, Anita Mitico, Fry, Bryan G.
• Format: Article
• Language: English
• Subjects: Antivenom neutralisation; B. jararacussu; Coagulotoxicity; Ontogeny
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2021.05.005

•Procoagulant toxicity in Bothrops jararacussu is a function of size.•Smaller snakes have more potent venom.•Antivenom is effective against all size groups. Is snake venom activity influenced by size? This is a long-standing question that can have important consequences for the treatment of snake envenomation. Ontogenetic shifts in venom composition are a well-documented characteristic of numerous snake species. Although snake venoms can cause a range of pathophysiological disturbances, establishing the coagulotoxic profiles related to such shifts is a justified approach because coagulotoxicity can be deadly, and its neutralisation is a challenge for current antivenom therapy. Thus, we aimed to assess the coagulotoxicity patterns on plasma and fibrinogen produced by B othrops jararacussu venoms from individuals of different sizes and sex, and the neutralisation potential of SAB (anti bothropic serum produced by Butantan Institute). The use of a metalloproteinase inhibitor (Prinomastat) and a serine proteinase inhibitor (AEBSF) enabled us to determine the toxin class responsible for the observed coagulopathy: activity on plasma was found to be metalloprotease driven, while the activity on fibrinogen is serine protease driven. To further explore differences in venom activity, the activation of Factor X and prothrombin as a function of snake size was also evaluated. All the venoms exhibited a potent procoagulant effect upon plasma and were less potent in their pseudo-procoagulant clotting effect upon fibrinogen. On human plasma, the venoms from smaller snakes produced more rapid clotting than the larger ones. In contrast, the venom activity on fibrinogen had no relation with size or sex. The difference in procoagulant potency was correlated with the bigger snakes being proportionally better neutralized by antivenom due to the lower levels of procoagulant toxins, than the smaller. Thus, while the antivenom ultimately neutralized the venoms, proportionally more would be needed for an equal mass of venom from a small snake than a large one. Similarly, the neutralisation by SAB of the pseudo-procoagulant clotting effects was also correlated with relative potency, with the smaller and bigger snakes being neutralized proportional to potency, but with no correlation to size. Thromboelastography (TEG) tests on human and toad plasma revealed that small snakes’ venoms acted quicker than large snakes’ venom on both plasmas, with the action upon amphibian plasma consiste