Basal but divergent: Clinical implications of differential coagulotoxicity in a clade of Asian vipers

Debono, Jordan; Bos, Mettine H.A.; Coimbra, Francisco; Ge, Lilin; Frank, Nathaniel; Kwok, Hang Fai; Fry, Bryan G.

doi:10.1016/j.tiv.2019.03.038

Cited by 36 publications

(54 citation statements)

References 59 publications

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“…Ecological niche partitioning and a shift in diet would contribute to venom evolution of the species across varying localities and habitats, with consequential impacts upon relative clinical effects Fry et al, 2008). Such wide variation depicted within a single genus has also been shown within many other groups of closely related snakes, each inhabiting slightly varied ecological niches (Debono et al, 2019a;Debono et al, 2019c;Debono et al, 2017a;Dobson et al, 2018;Rogalski et al, 2017) as well as variation between localities of the same species (Sousa et al, 2018). While some ontogenetic shift has been shown within one species of Gloydius (Gao et al, 2013), due to lack of sample availability the impact upon relative coagulotoxicity was not investigated in the present study and should be the subject of future work.…”

Section: Discussionmentioning

confidence: 60%

“…To evaluate the comparative ability of D. typus and T. mossambicanus venoms to activate FX and prothrombin, assessment was carried out using a Stago STA R Max coagulation analyser robot following the previously validated colorimetric assay (Debono et al, 2019a). Zymogen testing revealed that neither species was able to activate FX (data not shown).…”

Section: Fx and Prothrombin Activationmentioning

confidence: 99%

“…To determine the relative rate of Factor X activation or prothrombin activation by venom samples, a colorimetric assay was performed previously validated by us (Debono et al, 2019a). A working stock clotting.…”

Section: Factor X Activation and Prothrombin Activationmentioning

confidence: 99%

“…Venoms were ascertained for their ability to clot or inhibit the clotting of recalcified plasma, or to form fibrin clots in fibrinogen solutions using methods previously validated by us (Debono et al, 2019a;Debono et al, 2019c;Debono et al, 2017a). Healthy human plasma (citrate 3.2%, Lot#1690252, approval #16-04QLD-10) was obtained from the Australian Red Cross ( Relative clotting was then monitored for 999 sec or until plasma clotted (whichever was sooner).…”

Section: Coagulation Analysismentioning

confidence: 99%

“…Additional procoagulation (Factor X and prothrombin activation) or anticoagulation (inhibition of FXa, prothrombinase complex formation, thrombin, or fibrinogen cleavage, Table 6.2) assays were also conducted, using methods previously validated by us (Debono et al, 2019a;Debono et al, 2019c;Youngman et al, 2018). To identify the possible target in the clotting cascade which the venom was acting upon, inhibition assays were performed in which either plasma or individual clotting factors were incubated with the sample venom, as shown in (Youngman et al, 2018).…”

Section: Coagulation Analysismentioning

confidence: 99%

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A blood bond: evolutionary, pathophysiological and biodiscovery implications of coagulotoxic snake venoms

Debono¹

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Snakebite is a massive global burden and is a neglected area of tropical diseases. Snake venom neurotoxins have been the subject of intense research efforts, albeit significantly less is known about coagulotoxins. Venoms can deleteriously affect any physiological system reachable by the bloodstream, including being able to directly interfere with the coagulation cascade. Such coagulopathic toxins may be either anticoagulant or procoagulant and snake venoms are unique in their use of procoagulant toxins for predatory purposes. Our limited knowledge into the mechanisms of action of snake venom hinders our understanding of the clinical pathologies and also restricts our use of these powerful natural products as lead compounds in drug design and development. Two snake families which exhibit coagulant properties and lead to a range of clinical pathologies are vipers, Viperidae, and non-front-fanged snakes, Colubridae. The primary focus of this thesis was to investigate and compare the coagulotoxicity effects and mechanisms of various species of known venomous snakes that effect coagulation. Species chosen for this investigation have had limited previous research conducted, thus a knowledge gap in the literature remains. These coagulant properties were investigated through a multi-disciplinary approach, highlighting key results from both families.Data chapters 2 and 3 explore venom from the boomslang (Dispholidus typus) and the twig snakes (Thelotornis species) -iconic African snakes belonging to the family Colubridae. Both species produce strikingly similar lethal procoagulant pathologies. Despite these similarities, antivenom is only produced for treating bites by D. typus, and the mechanisms of action of both venoms have been understudied. We found that T. mossambicanus produced a significantly stronger coagulation response compared to D. typus, governed by strong prothrombin activation through PIII-SVMPs.Despite similarities in symptoms and clinical manifestations, venom composition differs widely between the two species, recovered from a combined approach of venomics and transcriptomics. The neutralising capability of the available boomslang antivenom was also investigated on both species, with it being 11.3 times more effective upon D. typus venom than T. mossambicanus. Envenomation by Crotalinae such as Asian pit vipers can induce multiple clinical complications resulting from coagulopathic and neuropathic effects. Data chapters 4 -8 investigate the Asian Pit Viper clade. While intense research has been undertaken for some species, such as Calloselasma rhodostoma, functional coagulopathic effects have been neglected. As these species' venoms affect the blood coagulation cascade and are known to produce haemorrhagic shock in envenomed patients, we investigated their effects upon coagulation using venoms of 33 species from the Asian pit viper clade including Azemiops, Calloselasma, Deinagkistrodon, Gloydius, Hypnale, Protobothrops, Trimeresurus and Tropidolaemus. Fibrinogen was the main coagulation target among th...

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