Effects of Heme Modulation on Ovophis and Trimeresurus Venom Activity in Human Plasma

Ryan W Matika,Vance G Nielsen,Nathaniel Frank

doi:10.3390/toxins10080322

Ryan W Matika, Vance G Nielsen + Show 1 more

Open Access

https://doi.org/10.3390/toxins10080322

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Journal: Toxins	Publication Date: Aug 8, 2018
Citations: 6	License type: CC BY 4.0

Affiliation: University of Arizona, Oshkosh (United States)

Abstract

Geographic isolation and other factors result in evolution-driven diversity of the enzymatic composition of venom of pit vipers in the same genus. The present investigation sought to characterize venoms obtained from such genetically diverse Ovophis and Trimeresurus pit vipers utilizing thrombelastographic coagulation kinetic analyses. The coagulation kinetics of human plasma were assessed after exposure to venom obtained from two Ovophis and three Trimeresurus species. The potency of each venom was defined (µg/mL required to equivalently change coagulation); additionally, venoms were exposed to carbon monoxide (CO) or a metheme-inducing agent to modulate any enzyme-associated heme. All venoms had fibrinogenolytic activity, with four being CO-inhibitable. While Ovophis venoms had similar potency, one demonstrated the presence of a thrombin-like activity, whereas the other demonstrated a thrombin-generating activity. There was a 10-fold difference in potency and 10-fold different vulnerability to CO inhibition between the Trimeresurus species. Metheme formation enhanced fibrinogenolytic-like activity in both Ovophis species venoms, whereas the three Trimeresurus species venoms had fibrinogenolytic-like activity enhanced, inhibited, or not changed. This novel “venom kinetomic” approach has potential to identify clinically relevant enzymatic activity and assess efficacy of antivenoms between genetically and geographically diverse species.

Highlights

Geographic isolation of venomous snakes within the same genus is associated with evolution-driven diversity of the enzymatic composition of their venom, which is affected by diet [1,2,3]
During preliminary work with increasing concentrations of venom, it appeared to be predominantly anticoagulant with decreasing maximum rate of thrombus generation (MRTG, a measure of velocity of clot growth) and total thrombus generation (TTG, a measure of thrombus strength) values; time to maximum rate of generation thrombus generation (MRTG) (TMRTG, a measure of speed of onset of coagulation) minutes) values seemed to decrease with increasing venom concentrations
carbon monoxide (CO)-inhibitable, fibrinogenolytic-like activity that was unaffected by either inactive releasing molecule (iRM) or PHA. This investigation achieved its stated goals of characterizing the potency, anticoagulant/procoagulant nature, and heme-modulated behavior of these diverse Asian pit viper venoms

Summary

Introduction

Geographic isolation of venomous snakes within the same genus is associated with evolution-driven diversity of the enzymatic composition of their venom, which is affected by diet [1,2,3]. A prime example of this sort of diversity are the numerous Ovophis and Trimeresurus species of Asian pit viper that are scattered across the Indian subcontinent, Southeast Asia, Japanese islands, and islands throughout and just beyond the South China Sea [4]. Proteomic investigation of the effects of geography-driven diversity of venom composition is important, as the toxic enzymes/compounds of any particular venom may or may not be neutralized by antivenom prepared with venom obtained from related but physically separated and genetically distinct species [1,3,4]. Given that coagulopathy following envenomation by snakes with hemotoxic agents continues to be a major cause of international morbidity and mortality [5], identification of the major effects of any specific venom on coagulation provides insight into potential therapies [6,7,8,9,10,11]

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