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Open AccessArticle
From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms
by
Uthpala Chandrasekara
Uthpala Chandrasekara 1,
Abhinandan Chowdhury
Abhinandan Chowdhury 1,
Lorenzo Seneci
Lorenzo Seneci 1,
Christina N. Zdenek
Christina N. Zdenek 2,
Nathan Dunstan
Nathan Dunstan 3 and
Bryan G. Fry
Bryan G. Fry 1,*
1
Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia
2
School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia
3
Venom Supplies Pty Ltd., Stonewell Rd., Tanunda, SA 5352, Australia
*
Author to whom correspondence should be addressed.
Toxins 2024, 16(10), 430; https://doi.org/10.3390/toxins16100430 (registering DOI)
Submission received: 5 September 2024
/
Revised: 30 September 2024
/
Accepted: 4 October 2024
/
Published: 6 October 2024
Abstract
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 (Oxyuranus species) and brown snakes (Pseudonaja 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 Oxyuranus/Pseudonaja 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.
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MDPI and ACS Style
Chandrasekara, U.; Chowdhury, A.; Seneci, L.; Zdenek, C.N.; Dunstan, N.; Fry, B.G.
From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms. Toxins 2024, 16, 430.
https://doi.org/10.3390/toxins16100430
AMA Style
Chandrasekara U, Chowdhury A, Seneci L, Zdenek CN, Dunstan N, Fry BG.
From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms. Toxins. 2024; 16(10):430.
https://doi.org/10.3390/toxins16100430
Chicago/Turabian Style
Chandrasekara, Uthpala, Abhinandan Chowdhury, Lorenzo Seneci, Christina N. Zdenek, Nathan Dunstan, and Bryan G. Fry.
2024. "From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms" Toxins 16, no. 10: 430.
https://doi.org/10.3390/toxins16100430
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