Decreased snake venom metalloproteinase effects via inhibition of enzyme and modification of fibrinogen

  title={Decreased snake venom metalloproteinase effects via inhibition of enzyme and modification of fibrinogen},
  author={Vance G. Nielsen and Marco Cerruti and Olivia M. Valencia and Quinlan Amos},
Since the introduction of antivenom administration 120 years ago to treat venomous snake bit, it has been the gold standard for saving life and limb. However, this therapeutic approach is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases by modification of fibrinogen with iron and carbon monoxide and by inhibiting these Zn2+ dependent… 

Anticoagulant activity of krait, coral snake, and cobra neurotoxic venoms with diverse proteomes are inhibited by carbon monoxide.

Given that individual neurotoxin activity often depends on intact activity that includes anticoagulant action, it may be possible that carbon monoxide inhibits neurotoxicity.

Carbon monoxide inhibits hemotoxic activity of Elapidae venoms: potential role of heme

Data demonstrate indirectly that the biometal heme is likely bound to these disparate venoms as an intermediary modulatory molecule and may be a potential modulator of heme as a protective mechanism for venomous snakes against injury from their own proteolytic venoms.

Characterization of the Rabbit as an In Vitro and In Vivo Model to Assess the Effects of Fibrinogenolytic Activity of Snake Venom on Coagulation

It was determined with thrombelastography that 15 times the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site.

Role of heme modulation in inhibition of Atheris, Atractaspis, Causus, Cerastes, Echis, and Macrovipera hemotoxic venom activity

It is demonstrated in vitro and in vivo that coagulopathy-inducing venom exposed to carbon monoxide is inhibited, potentially by an attached heme, and indirectly that the heme is likely bound to these disparate venoms as an intermediary modulatory molecule.

Carbon monoxide inhibits the anticoagulant activity of phospholipase A2 purified from Crotalus adamanteus venom

  • V. Nielsen
  • Biology, Chemistry
    Journal of Thrombosis and Thrombolysis
  • 2018
Findings open the possibility that other PLA2 contained in snake venom with multiple toxicities may be heme bearing and CO-inhibitable, which have profound potential basic and clinical science implications.

Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis

There was great species-specific variation in potency and mechanism(s) responsible for the anticoagulant activity of Dendroaspis venom, with perhaps all three protein classes—3-FTx, Kunitz-type SPI and metalloproteinases—playing a role in the venoms characterized.

Crotalus atrox Venom Exposed to Carbon Monoxide Has Decreased Fibrinogenolytic Activity In Vivo in Rabbits

  • V. Nielsen
  • Biology, Medicine
    Basic & clinical pharmacology & toxicology
  • 2018
Future studies to determine whether rabbits injected with such venom subcutaneously/intramuscularly can have consequent coagulopathy abrogated by injection of carbon monoxide‐releasing molecules into the ‘bite site’ are justified are justified.

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

A novel “venom kinetomic” approach has potential to identify clinically relevant enzymatic activity and assess efficacy of antivenoms between genetically and geographically diverse species.

De Novo Assessment and Review of Pan-American Pit Viper Anticoagulant and Procoagulant Venom Activities via Kinetomic Analyses

The kinetomic profiles of venoms obtained from thirty-two Pan-American Pit Viper species are presented and it is anticipated that this approach will be utilized to identify clinically relevant hemotoxic venom enzymatic activity and assess the efficacy of locally delivered CO or systemically administered antivenoms.

Carbon monoxide releasing molecule enhances coagulation and decreases fibrinolysis in canine plasma exposed to Crotalus viridis venom in vitro and in vivo

It is shown that CORM‐2 has similar effects in vitro on plasma from naturally envenomed dogs, showing promise as an adjunct therapy for snake envenomation.



Effect of iron and carbon monoxide on fibrinogenase-like degradation of plasmatic coagulation by venoms of four Crotalus species

In vitro investigation of other fibrinogenolytic venoms is indicated to determine if iron and CO can attenuate venom compromised coagulation, as demonstrated in various Agkistrodon species and Crotalus atrox.

Effect of Iron and Carbon Monoxide on Fibrinogenase‐like Degradation of Plasmatic Coagulation by Venoms of Six Agkistrodon Species

Pre‐treatment of plasma with iron and carbon monoxide attenuated these venom‐mediated coagulation kinetic changes in a species‐specific manner, with some venom effects markedly abrogated while others were only mildly decreased.

Iron and carbon monoxide prevent degradation of plasmatic coagulation by thrombin-like activity in rattlesnake venom

  • V. Nielsen
  • Biology
    Human & experimental toxicology
  • 2016
Pretreatment of plasma with Fe and CO completely abrogated the effects of all three venoms on coagulation kinetics, and served as a rationale for future preclinical investigation of pit viper venoms that possess thrombin-like activity.

Iron and carbon monoxide attenuate degradation of plasmatic coagulation by Crotalus atrox venom

  • V. NielsenL. Boyer
  • Medicine, Biology
    Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
  • 2016
Iron and CO significantly attenuated venom-mediated degradation of plasmatic coagulation in terms of onset time, velocity of clot growth and final clot strength.

Anti-coagulant activity of a metalloprotease: further characterization from the Indian cobra (Naja naja) venom

A high molecular mass, non toxic metalloprotease the NN-PF3 with the bound Ca2+ and Zn2+ from the Naja naja venom has been studied further for its anticoagulant property. The molecular mass by

Snake venom metalloproteinases.

Iron and carbon monoxide enhance coagulation and attenuate fibrinolysis by different mechanisms

  • V. NielsenE. Pretorius
  • Biology
    Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
  • 2014
The first evidence that iron and carbon monoxide interact with key coagulation and fibrinolytic processes, resulting in thrombi that begin to form more quickly, grow faster, become stronger, and are more resistant to lysis is presented.

African Adders: Partial Characterization of Snake Venoms from Three Bitis Species of Medical Importance and Their Neutralization by Experimental Equine Antivenoms

The venoms of the three Bitis species, involved in accidents with humans in the Sub-Saharan Africa, contain a mixture of various enzymes that may act in the generation and development of some of the clinical manifestations of the envenomations.

Efficacy, safety, and use of snake antivenoms in the United States.

The efficacy of a new antivenom (CroFab; FabAV) composed of purified Fab specific to indigenous snake species has been demonstrated in prospective trials and led to advances in the understanding of antivenoms in terms of solubility and durability.

A Novel Nonhemorragic Protease from the African Puff Adder (Bitis Arietans) Venom

  • A. J. Nok
  • Biology, Chemistry
    Journal of biochemical and molecular toxicology
  • 2001
A nonhemorrhagic proteinase B‐20 from the venom of Bitis arietans has been purified to apparent electrophoretic homogeneity by chromatography on Sephadex G–100, Q‐Sepharose, and CM‐cellulose suggesting it is a metalloenzyme.