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Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation
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Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 9732

Special Issue Editor

Prof. Dr. Vance G. Nielsen

E-Mail Website
Guest Editor
Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ 85719, USA
Interests: coagulation; thrombelastography; snake venom; heme mediated regulation; heavy metals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A variety of agents, organic (e.g., venom compounds, recombinant coagulation proteins) and inorganic (e.g., heavy metals) in nature, can inflict significant systemic morbidity and mortality via toxic hypercoagulability or anticoagulation. Characterization of the effects of such agents on fibrinolysis is also of interest. This Special Issue seeks to identify such agents, determine where within plasmatic or platelet mediated hemostasis they act, and employ novel approaches (e.g., viscoelastic methodology) to achieve these two goals. Review articles are welcome. Additional investigation to assess novel methods to attenuate pathological hypercoagulable or anticoagulated states is also sought by this issue.

Prof. Dr. Vance G. Nielsen
Guest Editor

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Published Papers (4 papers)

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Research

15 pages, 1472 KiB  
Article
Modulation of Diverse Procoagulant Venom Activities by Combinations of Platinoid Compounds
by Vance G. Nielsen
Int. J. Mol. Sci. 2021, 22(9), 4612; https://doi.org/10.3390/ijms22094612 - 28 Apr 2021
Cited by 7 | Viewed by 1736
Abstract
Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, [...] Read more.
Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, decrease or not affect the procoagulant enzyme function of venom. Thus, the purpose of this investigation was to determine if formulations of platinoid compounds could inhibit venom procoagulant activity and if the formulated compounds interacted to enhance inhibition. Using a human plasma coagulation kinetic model to assess venom activity, six diverse venoms were exposed to various combinations and concentrations of CORM-2, CORM-3, RuCl3 and carboplatin (a platinum containing compound), with changes in venom activity determined with thrombelastography. The combinations of CORM-2 or CORM-3 with RuCl3 were found to enhance inhibition significantly, but not in all venoms nor to the same extent. In sharp contrast, carboplatin-antagonized CORM-2 mediated the inhibition of venom activity. These preliminary results support the concept that platinoid compounds may inhibit venom enzymatic activity at the same or different molecular sites and may antagonize inhibition at the same or different sites. Further investigation is warranted to determine if platinoid formulations may serve as potential antivenoms. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation)
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12 pages, 1188 KiB  
Article
Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms
by Vance G. Nielsen
Int. J. Mol. Sci. 2020, 21(8), 2970; https://doi.org/10.3390/ijms21082970 - 23 Apr 2020
Cited by 31 | Viewed by 2322
Abstract
The demonstration that carbon monoxide releasing molecules (CORMs) affect experimental systems by the release of carbon monoxide, and not via the interaction of the inactivated CORM, has been an accepted paradigm for decades. However, it has recently been documented that a radical intermediate [...] Read more.
The demonstration that carbon monoxide releasing molecules (CORMs) affect experimental systems by the release of carbon monoxide, and not via the interaction of the inactivated CORM, has been an accepted paradigm for decades. However, it has recently been documented that a radical intermediate formed during carbon monoxide release from ruthenium (Ru)-based CORM (CORM-2) interacts with histidine and can inactivate bee phospholipase A2 activity. Using a thrombelastographic based paradigm to assess procoagulant activity in human plasma, this study tested the hypothesis that a Ru-based radical and not carbon monoxide was responsible for CORM-2 mediated inhibition of Atheris, Echis, and Pseudonaja species snake venoms. Assessment of the inhibitory effects of ruthenium chloride (RuCl3) on snake venom activity was also determined. CORM-2 mediated inhibition of the three venoms was found to be independent of carbon monoxide release, as the presence of histidine-rich albumin abrogated CORM-2 inhibition. Exposure to RuCl3 had little effect on Atheris venom activity, but Echis and Pseudonaja venom had procoagulant activity significantly reduced. In conclusion, a Ru-based radical and ion inhibited procoagulant snake venoms, not carbon monoxide. These data continue to add to our mechanistic understanding of how Ru-based molecules can modulate hemotoxic venoms, and these results can serve as a rationale to focus on perhaps other, complementary compounds containing Ru as antivenom agents in vitro and, ultimately, in vivo. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation)
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12 pages, 1677 KiB  
Article
Mechanisms Responsible for the Anticoagulant Properties of Neurotoxic Dendroaspis Venoms: A Viscoelastic Analysis
by Vance G. Nielsen, Michael T. Wagner and Nathaniel Frank
Int. J. Mol. Sci. 2020, 21(6), 2082; https://doi.org/10.3390/ijms21062082 - 18 Mar 2020
Cited by 13 | Viewed by 2481
Abstract
Using thrombelastography to gain mechanistic insights, recent investigations have identified enzymes and compounds in Naja and Crotalus species’ neurotoxic venoms that are anticoagulant in nature. The neurotoxic venoms of the four extant species of Dendroaspis (the Black and green mambas) were noted to [...] Read more.
Using thrombelastography to gain mechanistic insights, recent investigations have identified enzymes and compounds in Naja and Crotalus species’ neurotoxic venoms that are anticoagulant in nature. The neurotoxic venoms of the four extant species of Dendroaspis (the Black and green mambas) were noted to be anticoagulant in nature in human blood, but the mechanisms underlying these observations have never been explored. The venom proteomes of these venoms are unique, primarily composed of three finger toxins (3-FTx), Kunitz-type serine protease inhibitors (Kunitz-type SPI) and <7% metalloproteinases. The anticoagulant potency of the four mamba venoms available were determined in human plasma via thrombelastography; vulnerability to inhibition of anticoagulant activity to ethylenediaminetetraacetic acid (EDTA) was assessed, and inhibition of anticoagulant activity after exposure to a ruthenium (Ru)-based carbon monoxide releasing molecule (CORM-2) was quantified. Black mamba venom was the least potent by more than two orders of magnitude compared to the green mamba venoms tested; further, Black Mamba venom anticoagulant activity was not inhibited by either EDTA or CORM-2. In contrast, the anticoagulant activities of the green mamba venoms were all inhibited by EDTA to a greater or lesser extent, and all had anticoagulation inhibited with CORM-2. Critically, CORM-2-mediated inhibition was independent of carbon monoxide release, but was dependent on a putative Ru-based species formed from CORM-2. In conclusion, 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. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation)
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11 pages, 964 KiB  
Article
Characterization of L-amino Acid Oxidase Derived from Crotalus adamanteus Venom: Procoagulant and Anticoagulant Activities
by Vance G. Nielsen
Int. J. Mol. Sci. 2019, 20(19), 4853; https://doi.org/10.3390/ijms20194853 - 30 Sep 2019
Cited by 3 | Viewed by 2644
Abstract
Snake venom enzymes of the L-amino acid oxidase (LAAO) class are responsible for tissue hemorrhage, edema, and derangement of platelet function. However, what role, if any, these flavoenzymes play in altering plasmatic coagulation have not been well defined. Using coagulation kinetomic analyses (thrombelastograph-based), [...] Read more.
Snake venom enzymes of the L-amino acid oxidase (LAAO) class are responsible for tissue hemorrhage, edema, and derangement of platelet function. However, what role, if any, these flavoenzymes play in altering plasmatic coagulation have not been well defined. Using coagulation kinetomic analyses (thrombelastograph-based), it was determined that the LAAO derived from Crotalus adamanteus venom displayed a procoagulant activity associated with weak clot strength (no factor XIII activation) similar to thrombin-like enzymes. The procoagulant activity was not modified in the presence of reduced glutathione, demonstrating that the procoagulant activity was likely due to deamination, and not hydrogen peroxide generation by the LAAO. Further, unlike the raw venom of the same species, the purified LAAO was not inhibited by carbon monoxide releasing molecule-2 (CORM-2). Lastly, exposure of the enzyme to phenylmethylsulfonyl fluoride (PMSF) resulted in the LAAO expressing anticoagulant activity, preventing contact activation generated thrombin from forming a clot. In sum, this investigation for the first time characterized the LAAO of a snake venom as both a fibrinogen polymerizing and an anticoagulant enzyme acting via oxidative deamination and not proteolysis as is the case with thrombin-like enzymes (e.g., serine proteases). Using this thrombelastographic approach, future investigation of purified enzymes can define their biochemical nature. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Toxic Hypercoagulation and Anticoagulation)
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