Clinical implications of differential procoagulant toxicity of the palearctic viperid genus Macrovipera, and the relative neutralization efficacy of antivenoms and enzyme inhibitors

Chowdhury, Abhinandan; Zdenek, Christina N.; Dobson, James; Bourke, Lachlan A.; Soria, Raúl; Fry, Bryan G.

doi:10.1016/j.toxlet.2020.12.019

Cited by 19 publications

(32 citation statements)

References 81 publications

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“…Consistent with previous results demonstrating that Daboia and Macrovipera species have extremely potent procoagulant (Factor X activating) venoms ( 38 ), this study revealed that the largest Vipera species ( V. ammodytes ) was also the most potent Vipera in activating Factor X, with one population (Lake Skadar, Montenegro) even approaching that of Daboia and Montivipera speed of action. Consistent with the link between size and relative FX activation levels of the venoms, the more diminutive sister species V. transcaucasiana and all other smaller Vipera species were comparably less potent than V. ammodytes.…”

Section: Discussionsupporting

confidence: 91%

“…However, like shown previously for Daboia and Macrovipera venoms ( 38 ) none of the Vipera venoms clotted fibrinogen with the assay measurements reaching the machine maximum of 999 seconds. The clotting time for the thrombin positive control was (seconds +/- SD) 3.6 +/- 0.1 seconds.…”

Section: Resultssupporting

confidence: 85%

“…Fluoroskan Ascent™ (Thermo Scientific, Vantaa, Finland) was employed to detect Factor X and prothrombin activation based on the results of the above methods ( 38 , 39 ). Table 1 reagents were manually plated in 384-well plates (black, lot#1171125, Nunc™ Thermo Scientific, Rochester, NY, USA), followed by automated pipetting of 70 μl of buffer containing 5 mM CaCl2,150 mM NaCl, and 50 mM Tris-HCl (pH 7.3) and Fluorogenic Peptide Substrate, (ES011Boc-Val-Pro-Arg-AMC.…”

Section: Methodsmentioning

confidence: 99%

“…Determination of venom effects upon coagulation was done using the STA-R Max ® (Stago, Asnières sur Seine, France) coagulation analyser and adapted from validated coagulation assay protocols (36)(37)(38)(39). 1mg/ml venom stocks (50% glycerol/ 50% deionized water) were diluted to 100 mg/ml with OK Buffer (Stago catalogue #00360) to prepare the working stock, which was later loaded into the analyser for running 8-point concentration curves with serial dilutions of 1, 1/2, 1/5, 1/12.5, 1/ 30, 1/80, 1/160, and 1/400 (final reaction concentrations of venom).…”

Section: Effects Upon Clotting Times Of Plasma and Fibrinogen Coagulotoxicity Effects On Plasma And Fibrinogenmentioning

confidence: 99%

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Venom-Induced Blood Disturbances by Palearctic Viperid Snakes, and Their Relative Neutralization by Antivenoms and Enzyme-Inhibitors

et al. 2021

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Palearctic vipers are medically significant snakes in the genera Daboia, Macrovipera, Montivipera, and Vipera which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition is that of a small-bodied, lowland species, extensive diversification has occurred in body size, and niche specialization. Using 27 venom samples and a panel of in vitro coagulation assays, we evaluated the relative coagulotoxic potency of Palearctic viper venoms and compared their neutralization by three antivenoms (Insoserp Europe, VIPERFAV and ViperaTAb) and two metalloprotease inhibitors (prinomastat and DMPS). We show that variation in morphology parallels variation in the Factor X activating procoagulant toxicity, with the three convergent evolutions of larger body sizes (Daboia genus, Macrovipera genus, and Vipera ammodytes uniquely within the Vipera genus) were each accompanied by a significant increase in procoagulant potency. In contrast, the two convergent evolutions of high altitude specialization (the Montivipera genus and Vipera latastei uniquely within the Vipera genus) were each accompanied by a shift away from procoagulant action, with the Montivipera species being particularly potently anticoagulant. Inoserp Europe and VIPERFAV antivenoms were both effective against a broad range of Vipera species, with Inoserp able to neutralize additional species relative to VIPERFAV, reflective of its more complex antivenom immunization mixture. In contrast, ViperaTAb was extremely potent in neutralizing V. berus but, reflective of this being a monovalent antivenom, it was not effective against other Vipera species. The enzyme inhibitor prinomastat efficiently neutralized the metalloprotease-driven Factor X activation of the procoagulant venoms. In contrast, DMPS (2,3-dimercapto-1-propanesulfonic acid), which as been suggested as another potential treatment option in the absence of antivenom, DMPS failed against all venoms tested. Overall, our results highlight the evolutionary variations within Palearctic vipers and help to inform clinical management of viper envenomation.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Effects Upon Clotting Times Of Plasma and Fibrinogen Coagulotoxicity Effects On Plasma And Fibrinogenmentioning

confidence: 99%

See 2 more Smart Citations

Venom-Induced Blood Disturbances by Palearctic Viperid Snakes, and Their Relative Neutralization by Antivenoms and Enzyme-Inhibitors

et al. 2021

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“…Thus, there is a knowledge gap regarding ex vivo efficacy of varespladib at varying concentrations and the broadness of its taxonomical utility in human blood. In addition, a recent study suggested that the metalloprotease inhibitor prinomastat cross reacts with venom PLA 2 (30). That study, however, only included viperid venoms and thus the intriguing ability of prinomastat to neutralize anticoagulant activity of PLA 2 in cobra venom was unexplored.…”

Section: Introductionmentioning

confidence: 99%

The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

et al. 2021

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African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A2 (Group I PLA2) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta, N. nigricollis, and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei, N. katiensis, and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei, N. katiensis, and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA2 (Group II PLA2). In this study prinomastat inhibited the FXa-inhibiting PLA2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.

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Taxon-selective venom variation in adult and neonate Daboia russelii (Russell's Viper), and antivenom efficacy

Zdenek

Chowdhury

Haw

et al. 2022

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Clinical implications of differential procoagulant toxicity of the palearctic viperid genus Macrovipera, and the relative neutralization efficacy of antivenoms and enzyme inhibitors

Cited by 19 publications

References 81 publications

Venom-Induced Blood Disturbances by Palearctic Viperid Snakes, and Their Relative Neutralization by Antivenoms and Enzyme-Inhibitors

Venom-Induced Blood Disturbances by Palearctic Viperid Snakes, and Their Relative Neutralization by Antivenoms and Enzyme-Inhibitors

The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

Taxon-selective venom variation in adult and neonate Daboia russelii (Russell's Viper), and antivenom efficacy

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